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brand bevespi aerosphere inhaler

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Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Bronchospasm

Formoterol fumarate is used only 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). Long-acting β2-adrenergic agonists, such as formoterol, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.(See Asthma-related Death under Warnings/Precautions: Warnings, in Cautions.)Because of these risks, the use of formoterol for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated.(See Cautions: Contraindications.) Formoterol is used only as additional therapy in patients with asthma who are currently receiving long-term asthma controller therapy, such as inhaled corticosteroids, but whose disease is inadequately controlled with such therapy. The fixed combination of formoterol and budesonide (Symbicort) is 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 clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist. 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.Formoterol is not a substitute for corticosteroids; corticosteroid therapy should not be stopped or reduced in dosage when formoterol is initiated.(See Concomitant Anti-inflammatory Therapy under Warnings/Precautions: Warnings, in Cautions.) Formoterol or formoterol in fixed combination with budesonide should not be used in patients whose asthma is adequately controlled on low or medium dosage of inhaled corticosteroids.

In pediatric and adolescent patients with asthma who require the addition of a long-acting β2-adrenergic agonist to an inhaled corticosteroid, 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. In cases where separate administration of long-term asthma controller therapy (e.g., inhaled corticosteroids) and a long-acting β2-adrenergic agonist is clinically indicated, appropriate steps must be taken to ensure compliance with both treatment components. If compliance cannot be ensured, a fixed-combination preparation containing both an inhaled corticosteroid and a long-acting β2-adrenergic agonist is recommended.

Formoterol also is used for the prevention of exercise-induced bronchospasm when administered on an occasional, as-needed basis. The use of formoterol as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. In patients with persistent asthma, use of formoterol for the prevention of exercise-induced bronchospasm may be clinically indicated; however, the treatment of asthma should include long-term asthma controller therapy, such as inhaled corticosteroids.

Formoterol also is used as a bronchodilator alone or in fixed combination with budesonide for the long-term symptomatic treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Formoterol should not be initiated in patients with substantially worsening or acutely deteriorating asthma, which may be a life-threatening condition, and should not be used to treat acute symptoms of asthma. Formoterol in fixed combination with budesonide 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. Use of long-acting β2-adrenergic agonists with or without inhaled corticosteroids for acute exacerbations of COPD has not been evaluated. A short-acting inhaled β2-adrenergic agonist should be used intermittently (as needed) for acute symptoms of asthma or COPD.(See Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease under Warnings/Precautions: Warnings, in Cautions.)

Asthma

Considerations in Initiating Antiasthma Therapy

In the current 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) and also by response to treatment (i.e., asthma control). 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. Current 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. 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). These 2 components of asthma control (i.e., current impairment and future risk) may respond differently to treatment.

The National Asthma Education and Prevention Program (NAEPP) classifies the levels of asthma control as well controlled, not well controlled, or very poorly controlled. 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. Stepwise therapy is meant to assist, not replace, the clinical decision-making process in selecting therapy for individual patients. Once initiated, treatment is adjusted continuously according to changes in asthma control. Patients should be monitored every 2-6 weeks following initiation of therapy to ensure that asthma control is achieved. If asthma symptoms are not controlled with the current treatment regimen, treatment is stepped up until control is achieved. 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. 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. 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.

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). 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). 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. 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. Oral β2-adrenergic agonist therapy is suggested for use principally in patients unable to use inhaled bronchodilators (e.g., young children). Other experts do not recommend oral β2-agonists for relief of acute asthma symptoms. 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.

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), current 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. 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 effective and generally not preferred as initial therapy. 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. Low-dose inhaled corticosteroids also are recommended as the preferred initial therapy in such children. 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. 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.

Moderate Persistent Asthma

According to current 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. 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. (See Uses: Bronchospasm and also .) Current 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 corticosteroid 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). 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).

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. According to current asthma management guidelines, a long-acting inhaled β2-agonist (i.e., 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. 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. 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 current 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). 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).

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 current 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). Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in adolescents and adults. 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. 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. 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 current asthma management guidelines. Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in older children.

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, a short course (3-10 days) of an oral corticosteroid may be added to gain prompt control of asthma. 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.

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. 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. However, other experts do not consider regular use of oral corticosteroid therapy to be appropriate therapy in children with severely uncontrolled asthma.

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. For additional details on the stepped-care approach to drug therapy in asthma, see and also see .

Clinical Experience with Formoterol

While formoterol has a more rapid onset of action than salmeterol, the clinical importance of this difference in the treatment of asthma has not been established, and neither formoterol nor salmeterol should be used to relieve symptoms of acute asthma.(See Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease under Warnings/Precautions: Warnings, in Cautions and also see

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]). Formoterol fumarate dosages of 12 or 24 mcg twice daily were associated with similar post-dose bronchodilation but serious asthma exacerbations occurred more frequently with the higher dosage. 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. A formoterol fumarate dosage of 24 mcg twice daily did not result in additional improvement in FEV1 AUC compared with the 12 mcg twice-daily dosage. Anti-inflammatory agents were continued throughout the study. While regular use of bronchodilators was not permitted during the study, orally inhaled albuterol was used as supplemental therapy for acute symptoms of asthma. 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 formoterol fumarate 12 mcg or salmeterol 50 mcg twice daily.

In 2 randomized, double-blind, placebo-controlled clinical studies in patients with mild to severe asthma, orally inhaled formoterol fumarate (9 mcg twice daily) in fixed combination with budesonide (160 or 320 mcg 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 agents given separately.

Exercise-Induced Bronchospasm

Formoterol is used for the prevention of exercise-induced bronchospasm when administered on an occasional, as-needed basis. The manufacturer states that use of formoterol as a single agent for the prevention of exercise-induced bronchospasm may be clinically indicated in patients who do not have persistent asthma. The manufacturer also states that in patients with persistent asthma, the use of formoterol for the prevention of exercise-induced bronchospasm may be clinically indicated; however, the treatment of asthma should include long-term asthma controller therapy, such as inhaled corticosteroids. The manufacturer states that the efficacy of regular, twice-daily therapy with orally inhaled formoterol for the prevention of exercise-induced bronchospasm has not been established. Experts from the NAEPP state that frequent or chronic use of a long-acting inhaled β2-agonist for exercise-induced bronchospasm should be discouraged. Such use may disguise poorly controlled persistent asthma, which should be managed with daily anti-inflammatory therapy.

In single-dose, placebo-controlled, comparative studies in a limited number of adolescents and adults (13-41 years of age) who received orally inhaled formoterol fumarate (12 mcg) or albuterol (180 mcg by metered-dose inhaler) 15 minutes prior to exercise, prevention of exercise-induced bronchoconstriction (as measured by reduction in FEV1) was greater with either treatment than with placebo. The efficacy of either drug for prevention of exercise-induced bronchospasm was similar at 15 minutes after administration, but protection against bronchospasm lasted for up to 12 hours with formoterol versus 0.25 hours with albuterol.

Chronic Obstructive Pulmonary Disease

Orally inhaled formoterol is used alone or in fixed combination with budesonide as a bronchodilator for the long-term symptomatic treatment of reversible bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

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. 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. 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.

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. Current 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-agonist (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; the highest dosage of ipratropium included in some guidelines for COPD exceeds the manufacturer's maximum recommended daily dosage (12 inhalations). 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.

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. A short-acting bronchodilator may be used as needed for relief of acute symptoms that occur despite regular use of long-acting bronchodilators. 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. 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. For additional information on the stepped-care approach to drug therapy in COPD, see

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. 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. 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. 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. 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. 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.

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

Dosage and Administration

Administration

Formoterol fumarate is administered by oral inhalation using a special oral inhaler (Aerolizer) that delivers powdered drug from capsules; other inhalers or spacer devices should not be used to administer the drug. Formoterol fumarate capsules should not be taken orally because the intended pulmonary effects will not be obtained.(See Accidental Oral Ingestion under Warnings/Precautions: General Precautions, in Cautions.)

If patients taking formoterol do not experience an improvement in control of COPD, a clinician should make sure that the patient is inhaling the drug using the oral inhaler rather than swallowing the dry-powder capsules.(See Accidental Oral Ingestion under Warnings/Precautions: General Precautions, in Cautions.)

Formoterol fumarate in fixed combination with budesonide (Symbicort) is administered by oral inhalation using an oral aerosol inhaler with hydrofluoroalkane (HFA) propellant. Formoterol fumarate/budesonide inhalation aerosol should only be used with the actuator supplied with the product. Before each inhalation, the inhaler must be shaken well for 5 seconds. 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. 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. Rinsing the mouth after inhalation of formoterol fumarate/budesonide inhalation aerosol and spitting out the water are advised. The mouthpiece of the inhaler should be wiped clean with a dry cloth every 7 days. The inhaler should be discarded when the labeled number of inhalations has been used or within 3 months after removal from the foil pouch. The canister should never be immersed in water to determine the amount of drug remaining in the canister (''float test'').

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Although each dry-powder capsule contains 12 mcg of formoterol fumarate, the precise amount of drug delivered to the lungs with each activation of the Aerolizer inhaler depends on factors such as the patient's inspiratory flow and inspiratory rate. Using standardized in vitro testing at a flow rate of 60 L per minute for 2 seconds, the Aerolizer inhaler delivered 10 mcg of formoterol fumarate per activation from the mouthpiece.

Each actuation of the oral aerosol inhaler containing the fixed combination of formoterol fumarate and budesonide delivers 5.1 mcg of formoterol fumarate and 91 or 181 mcg of budesonide from the valve. Dosages of formoterol fumarate and budesonide in the fixed-combination inhalation aerosol are expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 4.5 mcg of formoterol fumarate and 80 or 160 mcg of budesonide from the actuator per metered spray. The 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. The commercially available inhalation aerosol of formoterol fumarate in fixed combination with budesonide delivers 60 metered sprays per 6- or 6.9-g canister and 120 metered sprays per 10.2-g canister.

Asthma

Formoterol Fumarate

For the prevention of bronchospasm (including nocturnal symptoms) in patients with reversible obstructive airway disease (e.g., asthma), the usual dosage of orally inhaled formoterol fumarate administered via the Aerolizer inhaler in adults and children 5 years of age or older is 12 mcg (contents of one capsule) twice daily, given approximately every 12 hours (morning and evening). The manufacturer states that administration of formoterol fumarate more frequently than twice daily or in total daily dosages exceeding 24 mcg is not recommended. In clinical trials, dosages in excess of those recommended have been associated with an increased risk of serious asthma exacerbations. Patients receiving formoterol should not use additional therapy with other long-acting β2-agonists. When a patient misses a dose of formoterol fumarate, the next regularly scheduled dose should be taken at the appropriate time; the dose of formoterol fumarate should not be doubled to replace the missed dose. If acute asthmatic symptoms arise despite therapy with formoterol, a short-acting β2-adrenergic agonist should be taken for immediate relief. Failure to respond to a previously effective dosage of formoterol fumarate may indicate seriously worsening asthma that requires prompt reevaluation.(See Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease under Warnings/Precautions: Warnings, in Cautions.)

Formoterol Fumarate/Budesonide Fixed-combination Therapy

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

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

Exercise-Induced Bronchospasm

Formoterol Fumarate

For the prevention of exercise-induced bronchospasm, the usual dosage of orally inhaled formoterol fumarate administered via the Aerolizer inhaler for adults and children 5 years of age or older is 12 mcg (contents of one capsule) administered at least 15 minutes before exercise; some clinicians suggest that advance administration of the drug may be unnecessary given formoterol's rapid onset of action. When used as needed for prevention of exercise-induced bronchospasm, protection may last for up to 12 hours. Additional doses of formoterol fumarate inhalation powder should not be used for 12 hours after administration of the drug. The manufacturer states that patients who are receiving formoterol fumarate oral inhalation powder twice daily for treatment of asthma should not take additional doses of the drug for prevention of exercise-induced bronchospasm. If twice-daily dosing of formoterol fumarate for treatment of asthma is not effective for the prevention of exercise-induced bronchospasm, add-on intermittent therapy with a short-acting bronchodilator should be used.

Chronic Obstructive Pulmonary Disease

Formoterol Fumarate

For maintenance therapy of bronchospasm in patients with chronic obstructive pulmonary disease (COPD), the usual dosage of orally inhaled formoterol fumarate administered via the Aerolizer inhaler in adults is 12 mcg (contents of one capsule) twice daily, given approximately every 12 hours. A higher dosage of formoterol fumarate (i.e., 24 mcg twice daily) has been used in patients with COPD in clinical studies; however, this dosage was not consistently more effective than a dosage of 12 mcg twice daily. A total daily dosage exceeding 24 mcg is not recommended. Failure to respond to a previously effective dosage of formoterol fumarate may indicate destabilization of COPD that requires prompt reevaluation.

Formoterol Fumarate/Budesonide Fixed-combination Therapy

For maintenance therapy of airflow obstruction in patients with COPD, the recommended dosage of the oral inhalation aerosol containing formoterol fumarate in fixed combination with budesonide in adults is 9 mcg of formoterol fumarate and 320 mcg of budesonide (2 inhalations) twice daily (morning and evening). In clinical studies, formoterol fumarate 9 mcg in fixed combination with budesonide 160 mcg (2 inhalations) twice daily did not produce greater improvements from baseline in predose FEV1 than formoterol alone or placebo; therefore, the fixed combination containing formoterol fumarate 9 mcg in fixed combination with budesonide 320 mcg (2 inhalations) twice daily is the only recommended dosage for the treatment of airflow obstruction in COPD. If shortness of breath occurs despite therapy with formoterol in fixed combination with budesonide, a short-acting inhaled β2-adrenergic agonist should be taken for immediate relief. Patients should be advised not to discontinue formoterol fumarate in fixed combination with budesonide without medical supervision, as symptoms may recur after treatment discontinuance. The manufacturer states that administration of formoterol fumarate in fixed combination with budesonide inhalation aerosol more frequently than twice daily or in excess of 2 inhalations twice daily is not recommended. Patients receiving the fixed combination of formoterol fumarate and budesonide should not use additional long-acting β2-agonists for any reason.

Special Populations

The manufacturer of formoterol fumarate makes no specific dosage recommendations for geriatric patients or patients with hepatic or renal impairment at this time.

When formoterol fumarate is used in fixed combination with budesonide, dosage requirements for budesonide should be considered.

The manufacturer of formoterol fumarate in fixed combination with budesonide states that dosage adjustment is not required in geriatric patients. The manufacturer of formoterol fumarate in fixed combination with budesonide makes no specific dosage recommendations for patients with hepatic or renal impairment at this time. However, since formoterol fumarate and budesonide are cleared predominantly by the liver, impaired liver function theoretically may lead to accumulation of the drugs in plasma. Therefore, the manufacturer of formoterol fumarate in fixed combination with budesonide states that patients with hepatic disease should be closely monitored.

Cautions

Contraindications

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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. (See Asthma-related Death under Warnings/Precautions: Warnings, in Cautions and also see Uses: Bronchospasm.)

Known hypersensitivity to formoterol fumarate or any other ingredient in the commercially available formulations.

Formoterol fumarate in fixed combination with budesonide (Symbicort) is contraindicated as primary treatment of status asthmaticus or other acute episodes of asthma or chronic obstructive pulmonary disease (COPD) when intensive measures are required.

When formoterol fumarate is used in fixed combination with budesonide, contraindications associated with budesonide should be considered.

Warnings/Precautions

Warnings

Use of Fixed Combinations

When formoterol fumarate is used in fixed combination with budesonide, the usual cautions, precautions, contraindications, and interactions associated with budesonide must be considered. 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.

Asthma-related Death

Long-acting β2-adrenergic agonists, such as formoterol, increase the risk of asthma-related death. In addition, available data from controlled clinical trials suggest that long-acting β2-adrenergic agonists increase the risk of asthma-related hospitalization in pediatric and adolescent patients.Because of these risks, the use of long-acting β2-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.(See Cautions: Contraindications.) However, currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma controller therapy mitigates the increased risk of asthma-related death from long-acting β2-adrenergic agonists. The US Food and Drug Administration (FDA) is requiring manufacturers of long-acting β2-adrenergic agonists to conduct additional clinical trials to further evaluate the safety of long-acting β2-adrenergic agonists when used concomitantly with inhaled corticosteroids.

Long-acting β2-adrenergic agonists, including formoterol, should only be used as additional therapy in patients with asthma who are currently receiving long-term asthma controller therapy, such as inhaled corticosteroids, but whose disease is inadequately controlled with such therapy. The fixed combination of formoterol fumarate and budesonide 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 clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist. 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. Long-acting β2-adrenergic agonists, including formoterol fumarate alone or in fixed combination with budesonide, should not be used in patients whose asthma is adequately controlled on low or medium dosage of inhaled corticosteroids. 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.(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. The increased risk of asthma-related death with salmeterol is considered a class effect of the long-acting β2-adrenergic agonists, including formoterol. However, no adequate studies have been conducted to determine whether the rate of asthma-related death is increased with formoterol. Clinical studies with formoterol 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. In addition, 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.

Acute Exacerbations of Asthma or Chronic Obstructive Pulmonary Disease

Substantially worsening or acutely deteriorating asthma may be a life-threatening condition. Formoterol oral inhalation therapy should not be initiated in patients with substantially worsening or acutely deteriorating asthma. Formoterol in fixed combination with budesonide should not be initiated in patients with rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Failure to respond to a previously effective dosage of formoterol may indicate substantially worsening asthma or destabilization of COPD that requires prompt reevaluation. 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 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. If asthma deteriorates in patients receiving formoterol in fixed combination with budesonide, 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 only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids; patients should not increase the frequency of administration of formoterol in fixed combination with budesonide.

Concomitant Anti-Inflammatory Therapy

Formoterol oral inhalation powder is not a substitute for inhaled or oral corticosteroids, and patients receiving corticosteroid therapy should be advised not to discontinue or reduce corticosteroid dosage when formoterol is initiated, since worsening of asthma may occur. 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. Patients who already require oral or inhaled corticosteroids for treatment of asthma should continue to receive such treatment even if they feel better as a result of initiation of formoterol oral inhalation therapy; any changes in corticosteroid dosage should be made only after appropriate clinical evaluation of the patient. 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.

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 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.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.

Cardiovascular Effects

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

Excessive Doses

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma.

Patients receiving formoterol alone or in fixed combination with budesonide should not use additional formoterol or other long-acting β2-agonists for any reason.

Sensitivity Reactions

Immediate Hypersensitivity Reactions

Anaphylactic reactions, urticaria, angioedema, rash, and bronchospasm have been reported rarely with formoterol oral inhalation therapy.

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. If paradoxical bronchospasm occurs, formoterol should be discontinued immediately and alternative therapy instituted.

General Precautions

Acute or Worsening Asthma

Formoterol, alone or in fixed combination with budesonide, or other long-acting β2-adrenergic agonists (e.g., salmeterol) should not be used to relieve symptoms of acute asthma. Formoterol has not been studied in patients with acute asthma symptoms and additional doses of the drug should not be used in such situations. Serious exacerbations of asthma, including fatalities, have been reported when formoterol oral inhalation therapy has been used in patients with severe or acutely deteriorating asthma. In most cases, these adverse events have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating. However, such events also have occurred in a few patients with less severe asthma; the contribution of formoterol therapy in these cases has not been determined.

Failure to respond to a previously effective dosage of formoterol may indicate substantially worsening asthma or destabilization of COPD that requires prompt reevaluation. 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. If asthma deteriorates in patients receiving formoterol in fixed combination with budesonide, 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 only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids; patients should not increase the frequency of administration of formoterol in fixed combination with budesonide.

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 QTc interval, ST-segment depression) have been associated with formoterol oral inhalation therapy and may necessitate discontinuance of the drug. Cardiovascular effects generally have resolved within a few hours. 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.

Metabolic and Electrolyte Effects

Clinically important changes in blood glucose and serum potassium have been reported infrequently during long-term therapy with formoterol inhalation powder at recommended dosage.

Accidental Oral Ingestion

Few patients have reported adverse effects following inadvertent oral ingestion of formoterol dry-powder capsules for oral inhalation.(See Dosage and Administration: Administration.)

Specific Populations

Pregnancy

Category C. May interfere with uterine contractility; carefully weigh benefit versus risk in labor.

Lactation

Formoterol is distributed into milk in rats; it is not known whether formoterol is distributed into human milk. Caution is advised if formoterol is administered in nursing women. The manufacturer of formoterol in fixed combination with budesonide states that since no data from controlled trials are available on the use of this preparation in nursing women, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pediatric Use

Safety and efficacy of formoterol fumarate in children younger than 5 years of age with asthma or exercise-induced bronchospasm have not been established. 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; however, the manufacturer states that safety and efficacy of the fixed-combination preparation in children 6 to younger than 12 years of age with asthma have not been established.

Available data from controlled clinical trials suggest that long-acting β2-adrenergic agonists increase the risk of asthma-related hospitalization in pediatric and adolescent patients.(See Asthma-related Death under Warnings/Precautions: Warnings, in Cautions.) In pediatric and adolescent patients with asthma who require the addition of a long-acting β2-adrenergic agonist to an inhaled corticosteroid, 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.(See Uses: Bronchospasm.)

Geriatric Use

No substantial differences in safety and efficacy of formoterol alone or in fixed combination with budesonide relative to that in younger adults.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 1% or more of patients 5 years of age or older in clinical trials of formoterol for the treatment of asthma include viral infection, bronchitis, chest infection, dyspnea, chest pain, tremor (dose-related), dizziness (dose-related), insomnia, tonsillitis, rash, and dysphonia (dose-related). Adverse effects occurring in 1% or more of adults in clinical trials of formoterol for the treatment of COPD include upper respiratory tract infection, bronchitis, back pain, pharyngitis (dose-related), chest pain, sinusitis, fever (dose-related), leg cramps, muscle cramps (dose-related), anxiety, pruritus, increased sputum (dose-related), dry mouth, and trauma.

Drug Interactions

The following information addresses potential interactions with formoterol. When formoterol is used in fixed combination with budesonide, interactions associated with budesonide should be considered. No formal drug interaction studies have been performed to date with the fixed-combination preparation containing formoterol fumarate and budesonide.

Drugs that Prolong QT Interval

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

Sympathomimetic Agents

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

Xanthine Derivatives/Corticosteroids

Potential pharmacologic interaction (increased risk of hypokalemia).

Non-potassium-sparing Diuretics

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

Monoamine Oxidase Inhibitors/Tricyclic Antidepressants

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

β-Adrenergic Blocking Agents

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

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