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Uses

Bronchospasm

Salmeterol xinafoate is used only with concomitant long-term asthma controller therapy, such as inhaled corticosteroids, as a long-acting bronchodilator for the treatment of asthma and prevention of bronchospasm in patients with reversible obstructive airway disease, including symptoms of nocturnal asthma. Long-acting β2-adrenergic agonists, such as salmeterol, 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 and Life-threatening Events under Cautions: Respiratory Effects.)Because of these risks, the use of salmeterol for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated.(See Cautions: Precautions and Contraindications.) Salmeterol 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 salmeterol and fluticasone propionate 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 salmeterol or salmeterol in fixed combination with fluticasone propionate), if possible without loss of asthma control, and the patient should be maintained on long-term asthma controller therapy, such as inhaled corticosteroids.Salmeterol is not a substitute for corticosteroids; corticosteroid therapy should not be stopped or reduced in dosage when salmeterol is initiated.(See Cautions: Precautions and Contraindications.) Salmeterol or salmeterol in fixed combination with fluticasone propionate 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.

Salmeterol also is used for the prevention of exercise-induced bronchospasm. The use of salmeterol 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 salmeterol 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.

Salmeterol also is used as a bronchodilator for the long-term symptomatic management of reversible bronchospasm associated with moderate to severe (forced expiratory volume in 1 second [FEV1] less than 80% predicted) chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Salmeterol in fixed combination with fluticasone propionate as the inhalation powder (Advair Diskus) is used for the maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Salmeterol in fixed combination with fluticasone propionate as the inhalation powder (Advair Diskus) also is used to reduce exacerbations of COPD in patients with a history of such exacerbations.

Salmeterol alone or in fixed combination with fluticasone propionate is not indicated for the relief of acute bronchospasm. A short-acting inhaled β2-adrenergic agonist should be used intermittently (as needed) for acute symptoms of asthma or COPD.

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 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 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 salmeterol or formoterol 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 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 Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects and also see Uses: Bronchospasm.) 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., salmeterol, formoterol), 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 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 adolescents and adults 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 (at least 2 exacerbations per year requiring oral corticosteroids) with low to high maintenance dosages of the inhaled corticosteroid and a long-acting inhaled β2-agonist 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 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, and .

Clinical Experience with Salmeterol

The initial studies supporting the indication of salmeterol for the treatment of asthma did not require the regular use of inhaled corticosteroids. However, for the treatment of asthma, salmeterol currently is indicated only as concomitant therapy with long-term asthma controller therapy, such as inhaled corticosteroids.(See Uses: Bronchospasm and also see Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects.)

Results of a limited number of comparative studies suggest that salmeterol oral inhalation powder is more effective than orally inhaled albuterol or placebo in producing bronchodilation (e.g., as determined by mean peak expiratory flow rate) and reducing nighttime awakenings, and more effective than placebo in reducing the need for rescue medication (e.g., intermittent use of a short-acting, β2-agonist bronchodilator to control asthma exacerbations). While published studies have reported a salmeterol dose of 25 mcg per inhalation of salmeterol aerosol alone (e.g., 50 mcg per 2 metered sprays) or in fixed combination with fluticasone propionate, this is the amount released during actuation from the valve stem; the dose delivered to the patient through the mouthpiece (actuator) is approximately 21 mcg per inhalation (e.g., 42 mcg per 2 metered sprays). In the Uses section, unless otherwise stated, the dose of salmeterol (as salmeterol xinafoate) administered as the aerosol is expressed in terms of the dose delivered from the mouthpiece.

In a clinical study in patients with mild to moderate asthma, some of whom were receiving concomitant therapy with orally inhaled corticosteroids, inhaled salmeterol powder 50 mcg twice daily was more effective than inhaled albuterol 180 mcg 4 times daily in improving pulmonary function (as measured by forced expiratory volume in 1 second [FEV1] and PEFR), alleviating respiratory symptoms, and reducing the need for supplemental albuterol oral inhalations. In a 12-week comparative study in patients with mild to moderate persistent asthma who were symptomatic despite receiving low to intermediate dosages of inhaled corticosteroids, salmeterol inhalation powder (50 mcg twice daily) was more effective than montelukast (10 mg daily) in improving lung function (morning PEFR) and asthma symptoms. Data from comparative studies in patients receiving salmeterol inhalation aerosol (no longer commercially available in the US) versus orally inhaled terbutaline, cromolyn sodium, or nedocromil sodium (preparations for oral inhalation no longer commercially available in the US) or individualized oral extended-release theophylline therapy also suggest greater efficacy of salmeterol therapy.

Evidence from a limited number of comparative studies in patients with mild to moderate asthma, including those who did or did not receive concurrent inhaled corticosteroid therapy, suggests similar efficacy and safety of salmeterol oral inhalation powder administered via the Serevent Diskus device and orally inhaled salmeterol aerosol (no longer commercially available in the US). However, the manufacturer states that clinical equivalence of salmeterol oral inhalation powder and oral inhalation aerosol should not be assumed in all patient populations. In a short-term (12-week), randomized clinical trial in children 4-11 years of age with mild to moderate asthma who did or did not receive concurrent inhaled corticosteroid therapy, therapy with salmeterol oral inhalation powder (50 mcg twice daily) administered via the Serevent Diskus device (with or without concurrent inhaled corticosteroids) produced improvements in peak expiratory flow rate (36-39% postdose increase compared with baseline) and FEV1 (32-33% postdose increase from baseline).

Prolonged use of some sympathomimetic amines (e.g., albuterol, isoproterenol, terbutaline) in the treatment of chronic asthma or COPD may lead to tolerance to the bronchodilating effects of these drugs, and it has been suggested that prolonged stimulation of β2-adrenergic receptors by salmeterol may have a greater potential to induce tolerance to bronchodilation than short-acting β2-agonists. However, in several studies of 1-12 months' duration in patients with mild to moderately severe asthma, salmeterol inhalation aerosol (no longer commercially available) remained effective over the study period as indicated by increases in FEV1 and PEFR and decreases in diurnal variation in PEFR, asthma symptoms, frequency of asthma exacerbations, and the need for additional relief medication.

Because of its long duration of action, salmeterol may be particularly useful for the management of asthma in patients who have nocturnal symptoms despite maintenance therapy with inhaled or oral corticosteroids, extended-release theophylline, and/or other drug therapy. Comparative studies in patients with moderate asthma and nocturnal symptoms suggest that nocturnal symptoms or the need for nocturnal relief medications was decreased with orally inhaled salmeterol as compared with patients receiving placebo, orally inhaled albuterol, oral montelukast, oral extended-release theophylline, orally inhaled nedocromil sodium (preparations for oral inhalation no longer commercially available in the US), or orally inhaled cromolyn sodium. Combined data from 2 multicenter studies in patients with asthma indicate that the mean percentage of nights with no awakenings increased from 63 to 85% following 12 weeks of therapy with salmeterol oral inhalation powder and from 68 to 71% following 12 weeks of albuterol oral inhalation therapy.

In patients with moderate to severe asthma, combined therapy with inhaled salmeterol and inhaled corticosteroids has been instituted to promote greater control of asthma symptoms. In one clinical study in patients with mild to moderate asthma, the addition of salmeterol inhalation aerosol (no longer commercially available in the US) to therapy with an orally inhaled corticosteroid and an intermittent, short-acting β2-agonist allowed a reduction in inhaled corticosteroid use while maintaining adequate asthma control.

In other clinical studies in patients with persistent asthma whose symptoms were not controlled by 336-1000 mcg/day of beclomethasone dipropionate, combined therapy with inhaled beclomethasone dipropionate (336-1000 mcg/day) and orally inhaled salmeterol aerosol with chlorofluorocarbon (CFC) propellant (42-84 mcg/day; CFC preparation no longer commercially available in the US) was more effective in improving lung function and in reducing the need for supplemental albuterol than therapy with higher dosages of beclomethasone dipropionate alone (672-2000 mcg/day).

Results from comparative clinical trials in patients with asthma not adequately controlled by 176 mcg/day of fluticasone propionate indicate that combined therapy with inhaled fluticasone propionate (176 mcg/day) and orally inhaled salmeterol aerosol with CFC propellant (84 mcg/day; CFC preparation no longer commercially available in the US) given separately was more effective in improving lung function and asthma symptoms and in reducing the need for supplemental albuterol than therapy with a higher dosage of fluticasone propionate (440 mcg/day). In addition, fewer patients receiving combined therapy experienced asthma exacerbations in these trials.

In several randomized, double-blind, placebo-controlled clinical trials in patients with mild to severe asthma, fluticasone propionate (100, 250, or 500 mcg) in fixed combination with salmeterol xinafoate (42 mcg as salmeterol) as the inhalation powder produced greater improvement in most indices of pulmonary function (e.g., mean percent change from baseline in FEV1, morning FEV1 or PEFR) than either drug alone and similar efficacy as concurrent therapy with both agents given separately. In several randomized, double-blind, comparative trials in patients with mild to moderate persistent asthma who were not optimally controlled on their current antiasthma therapy, the fixed combination of salmeterol (42 mcg twice daily) and fluticasone propionate (90, 230, or 460 mcg twice daily) with hydrofluoroalkane (HFA) propellant for oral inhalation via a metered-dose inhaler (Advair HFA) produced greater improvement in indices of pulmonary function (e.g., mean percent change from baseline in FEV1 or morning and evening PEFR) than either drug alone. In a comparative clinical trial in patients with asthma who were not controlled on high dosages of inhaled corticosteroids, salmeterol/fluticasone inhalation aerosol (salmeterol 42 mcg/fluticasone propionate 460 mcg twice daily) produced greater or similar improvement in morning PEFR than fluticasone inhalation aerosol (440 mcg twice daily) with CFC propellants (no longer commercially available in the US) or salmeterol/fluticasone inhalation powder (50 mcg of salmeterol and 500 mcg of fluticasone propionate twice daily), respectively.

Supplemental Therapy in Acute Asthma

Salmeterol has a delayed onset of action, and the drug (alone or in fixed combination with fluticasone propionate) should not be used for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm). In addition, salmeterol, alone or in fixed combination with fluticasone propionate, should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma since serious acute respiratory events, including fatalities, have been reported in such situations.(See Cautions: Precautions and Contraindications.)

All patients receiving salmeterol alone or in fixed combination with fluticasone propionate should be provided with and instructed in the use of a short-acting, inhaled β2-adrenergic agonist (e.g., albuterol) as supplemental therapy for acute symptoms. The manufacturer states that when initiating salmeterol alone or in fixed combination with fluticasone propionate in patients who have been taking short-acting, oral or inhaled β2-agonists on a regular basis (e.g., 4 times daily), these patients should be instructed to discontinue the regular use of the short-acting agent and to use short-acting, inhaled β2-agonists, not salmeterol (alone or in fixed combination with fluticasone propionate), for relief of acute symptoms, such as shortness of breath.Regular (e.g., daily) use of short-acting 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 guidelines. If such symptoms are not controlled with salmeterol plus supplemental bronchodilator therapy (i.e., if there is a need to increase the dose or frequency of administration of the short-acting sympathomimetic agent), immediate reevaluation with reassessment of the treatment regimen is required, giving special consideration to the possible need for adding additional inhaled corticosteroids or initiating systemic corticosteroids; however, the dosage of salmeterol should not be increased in such situations. If asthma deteriorates in patients receiving salmeterol in fixed combination with fluticasone propionate, immediate reevaluation with reassessment of the treatment regimen is required, with special consideration given to the possible need for increasing the strength of the fixed combination (higher strengths contain higher dosages of fluticasone propionate only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids. Patients should not increase the frequency of administration of the fixed combination. Patients receiving salmeterol alone or in fixed combination with fluticasone propionate should not use additional salmeterol or other long-acting inhaled β2-agonists (e.g., arformoterol, formoterol) for any indication.(See Cautions: Precautions and Contraindications.)

Concerns about the safety of regular use of short-acting inhaled β2-agonist bronchodilators for maintenance therapy of asthma have been raised by evidence from some studies suggesting increased morbidity and mortality in patients receiving long-term therapy with short-acting inhaled β-agonists, particularly fenoterol (currently not commercially available in the US). In a placebo-controlled, crossover study in which intermittent use of inhaled fenoterol was compared with regularly scheduled use of the drug, regular use over a 24-week period was associated with deterioration in asthma control as determined by peak expiratory flow rate (PEFR), symptoms, and use of additional inhaled bronchodilator. However, the design and interpretation of these study findings suggesting increased morbidity and mortality have been criticized, and reanalysis of these data demonstrated that the differences between treatment periods were small and unlikely to be clinically important. Data from case-control studies have been conflicting and have not demonstrated a causal relationship between inhaled β2-agonist therapy and asthma mortality. An alternative hypothesis to explain the apparent association between inhaled β-agonist use and asthma mortality is that increased use of β-agonist therapy is a marker of severe asthma. While some studies in patients with mild or moderate asthma suggest that regularly scheduled use of short-acting, inhaled β2-agonists may not cause harm, such use does not appear to have demonstrable advantages compared with intermittent use and does not adequately control asthmatic symptoms. Regular, daily use of a short-acting, inhaled β2-agonist generally is not recommended, and increased chronic use of such β2-agonists more than twice weekly (excluding use for exercise-induced bronchospasm) or acute use (e.g., repeated use over more than 1-2 days) for asthma deterioration may indicate the need to initiate or increase long-term control therapy for asthma.

Long-acting β2-adrenergic agonists, such as salmeterol, increase the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from a large study evaluating the safety of salmeterol in patients with asthma showed an increase in asthma-related deaths in patients receiving salmeterol, particularly in African-American patients. (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects and see Uses: Bronchospasm.)

Exercise-Induced Bronchospasm

Salmeterol is used for the prevention of exercise-induced bronchospasm. However, most experts consider short-acting inhaled β2-adrenergic agonists to be drugs of choice for prevention of exercise-induced bronchospasm. The manufacturer states that the use of salmeterol 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 salmeterol 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. 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.

Protection against exercise-induced bronchospasm has been noted in children (4-11 years of age) in controlled trials with salmeterol inhalation powder (50 mcg 0.5 hour prior to exercise); in 2 single-dose trials, protection against exercise-induced bronchoconstriction (as measured by a decrease in FEV1 with exercise) lasted up to 11.5 hours following the dose. In 2 single-dose, comparative clinical trials in adults and adolescents, salmeterol inhalation aerosol with CFC propellant (42 mcg; CFC preparation no longer commercially available in the US) and inhalation powder (50 mcg) demonstrated similar efficacy and safety for the prevention of exercise-induced bronchospasm. However, continued dosing with salmeterol oral inhalation aerosol (42 mcg once or twice daily for 4 weeks) has been associated with loss or waning of protection against exercise-induced bronchospasm in some patients or a decreased duration of such protection.

Chronic Obstructive Pulmonary Disease

Salmeterol is used as a bronchodilator for the long-term symptomatic treatment of reversible bronchospasm associated with COPD, including chronic bronchitis and emphysema. Salmeterol in fixed combination with fluticasone propionate as the inhalation powder (Advair Diskus) is used for the maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Salmeterol in fixed combination with fluticasone propionate as the inhalation powder (Advair Diskus) also is used to reduce exacerbations of COPD in patients with a history of such exacerbations. Because of its slow onset of action, orally inhaled salmeterol is not indicated as monotherapy for the initial treatment of acute episodes of bronchospasm or acute exacerbations of COPD; a drug with a shorter onset of action (e.g., a short-acting β2-adrenergic agonist) may be preferred in such cases.

In the stepped-care approach to COPD drug therapy, mild, intermittent symptoms and minimal lung impairment (e.g., 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 persistent symptoms not relieved by as-needed therapy with ipratropium or a short-acting, selective inhaled β2-agonist in patients with moderate to severe COPD (e.g., FEV1 30 to less than 80% of predicted value), a long-acting bronchodilator (e.g., orally inhaled salmeterol, formoterol, 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 high dosage of ipratropium included in some guidelines for COPD exceeds the manufacturer's maximum recommended 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 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 value, 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 details on the stepped-care approach for drug therapy in COPD, .

Orally inhaled salmeterol therapy in patients with COPD generally has produced increases in peak FEV1 averaging 7-20%. In a subset of patients from a short-term (i.e., 24-week) placebo-controlled study in patients with COPD, orally inhaled salmeterol inhalation powder produced improvement in FEV1 that was apparent on the first day of treatment, sustained over the 12-hour dosing interval, and showed no loss of effectiveness over the study period.

In two 6-month comparative trials in patients with COPD, orally inhaled tiotropium (18 mcg once daily) was more effective in improving FEV1 than salmeterol (42 mcg twice daily) inhalation aerosol (no longer commercially available in the US) after day 1 of therapy. In addition, while tiotropium or salmeterol each reduced dyspnea and improved FEV1 compared with placebo, tiotropium also was more effective than placebo in reducing COPD exacerbations and all-cause hospital admissions and improving quality-of-life scores in these trials. In another 6-month, placebo-controlled study in patients with COPD, treatment with tiotropium (18 mcg once daily) was associated with greater improvement in bronchodilation (e.g., FEV1, evening PEFR), dyspnea, and quality-of-life scores than salmeterol (42 mcg twice daily) oral inhalation aerosol.

In several randomized, double-blind, placebo-controlled studies of 6 or 12 months' duration in patients with COPD, orally inhaled salmeterol (50 mcg twice daily) in fixed combination with fluticasone propionate (250 or 500 mcg twice daily) as the inhalation powder (Advair Diskus) produced greater improvement in lung function (defined as predose or postdose FEV1) than either drug alone or placebo. The improvement in lung function with salmeterol 50 mcg and fluticasone propionate 500 mcg in fixed combination was similar to that observed with salmeterol 50 mcg and fluticasone propionate 250 mcg in fixed combination. In two randomized, double-blind, placebo-controlled studies of 12 months' duration in patients with COPD, orally inhaled salmeterol (50 mcg twice daily) in fixed combination with fluticasone propionate (250 mcg twice daily) as the inhalation powder produced a greater reduction in the annual incidence of moderate/severe COPD exacerbations and exacerbations requiring treatment with oral corticosteroids compared with salmeterol alone. No studies have been conducted to directly compare the efficacy of salmeterol 50 mcg and fluticasone propionate 250 mcg in fixed combination with salmeterol 50 mcg and fluticasone propionate 500 mcg in fixed combination on exacerbations; however, in clinical studies, the reduction in exacerbations observed with salmeterol 50 mcg and fluticasone propionate 500 mcg in fixed combination was not greater than the reduction in exacerbations observed with salmeterol 50 mcg and fluticasone propionate 250 mcg in fixed combination. In a double-blind, placebo-controlled study of 3 years' duration in patients with COPD, orally inhaled salmeterol (50 mcg) in fixed combination with fluticasone propionate (500 mcg) as the inhalation powder did not improve all-cause mortality compared with either drug alone or placebo. Salmeterol 50 mcg and fluticasone propionate 250 mcg in fixed combination twice daily is the only recommended dosage for the treatment of COPD; an efficacy advantage of the higher dosage of the fixed combination containing 50 mcg of salmeterol and 500 mcg of fluticasone propionate over the lower dosage (50 mcg of salmeterol/250 mcg fluticasone propionate) has not been established.

Dosage and Administration

Administration

Salmeterol xinafoate is administered by oral inhalation using a special preloaded oral inhaler (Serevent or Advair Diskus) that delivers powdered drug alone or in fixed combination with fluticasone propionate from foil-wrapped blisters. The manufacturer states that spacer devices should not be used with Serevent or Advair Diskus.

Salmeterol/fluticasone propionate inhalation aerosol (Advair HFA) 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 4 times 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 4 weeks 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.

The cap covering the mouthpiece should be slipped off the mouthpiece; the strap on the cap will stay attached to the mouthpiece. The patient should look for foreign objects inside the inhaler prior to use, and should check to see that the canister is fully seated within the actuator. After exhaling as completely as possible, the patient should place the mouthpiece of the inhaler well into the mouth and close the lips firmly around it. Then the patient should inhale deeply through the mouth while actuating the inhaler. The patient should remove the mouthpiece from the mouth and hold the breath for as long as possible, up to 10 seconds, and exhale slowly. It is recommended that 30 seconds elapse between inhalations. Rinsing the mouth after inhalation of salmeterol/fluticasone propionate inhalation aerosol and spitting out the water are advised. The opening for the spray of the metal canister and the mouthpiece should be wiped with a dry cotton swab and dampened tissue, respectively, at least once a week after the evening dose. The actuator should be allowed to air-dry overnight. When the dose counter on the inhaler reads ''020,'' the patient should contact the pharmacy for a refill or consult their clinician to determine whether a refill is needed. The inhaler should be discarded when the dose counter reads ''000.'' The counter should never be altered or removed from the canister.

For administration of salmeterol xinafoate alone (Serevent) or in combination with fluticasone propionate (Advair) inhalation powder via the Diskus device, the patient should hold the device in one hand, put the thumb of the other hand on the thumbgrip, and push the thumbgrip until the mouthpiece appears and snaps into position. The lever on the Diskus should then be depressed in a direction away from the patient while the inhaler is held in a level, horizontal position; the lever pierces the foil blister and releases the powdered drug into an exit port. To avoid releasing and wasting additional doses of the drug, the patient should not tilt or close the Diskus device, play with the lever, or advance the lever more than once at this point. A dose counter will advance each time the lever is depressed. Before inhaling the dose, the patient should exhale as completely as possible; the patient should not exhale into the Diskus device because pressure from the exhalation will interfere with proper inhaler operation. The patient should then place the mouthpiece of the inhaler between the lips and inhale deeply and quickly through the inhaler with a steady, even breath; pressure from the inhalation will disperse drug from the exit port into the air stream created by the patient's inhalation. The patient should remove the inhaler from the mouth, hold his or her breath for 10 seconds (or as long as comfortable), and then exhale slowly. While most patients can taste or feel a dose of drug delivered from the Diskus device, they should be instructed not to use another dose even if they do not perceive that the dose has been delivered. Rinsing the mouth after inhalation of salmeterol in fixed combination with fluticasone propionate is advised. The Diskus device may be closed and reset for the next dose by sliding the thumbgrip towards the patient as far as it will go. The inhaler should not be washed but should be stored in a dry place away from direct heat or sunlight. The inhaler should be discarded when every blister has been used, or 4 or 6 weeks after removal of the Advair Diskus or Serevent Diskus, respectively, from its foil overwrap pouch. The inhaler should not be taken apart.

To obtain optimal benefit, the patient should be given a copy of the patient instructions and medication guide provided by the manufacturer with Serevent or Advair Diskus or Advair HFA.(See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects.)

Dosage

Dosage of salmeterol xinafoate is expressed in terms of salmeterol. Although each blister of the double-foil blister strip in the Serevent Diskus device contains 50 mcg of salmeterol as salmeterol xinafoate inhalation powder, the precise amount of drug delivered to the lungs with each activation of the Diskus device depends on factors such as the patient's inspiratory flow.(See Chemistry and Stability: Chemistry.)

Each blister of the double-foil blister strip in the Advair Diskus device contains 50 mcg of salmeterol as salmeterol xinafoate and 100, 250, or 500 mcg of fluticasone propionate; however, the precise amount of each drug delivered to the lungs with each activation of the Diskus device depends on factors such as the patient's inspiratory flow.(See Chemistry and Stability: Chemistry.)

Each actuation of the oral aerosol inhaler of the fixed combination of salmeterol and fluticasone propionate delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol from the valve. Dosages of salmeterol and fluticasone propionate in the fixed-combination inhalation aerosol are expressed in terms of drug delivered from the mouthpiece; each actuation of the inhaler delivers 45, 115, or 230 mcg of fluticasone propionate and 21 mcg of salmeterol from the mouthpiece. The commercially available inhalation aerosol of salmeterol in fixed combination with fluticasone propionate delivers 60 or 120 metered sprays per 8- or 12-g canister, respectively.

The manufacturer states that adjustment of salmeterol dosage alone or in fixed combination with fluticasone propionate is not necessary in geriatric patients.

Asthma

Salmeterol

When salmeterol inhalation powder is administered via the Serevent Diskus device, the usual dosage in adults and children 4 years of age or older is 50 mcg (one inhalation) twice daily, given approximately 12 hours apart (morning and evening). If a dose of salmeterol is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled. Higher dosages (e.g., 84 mcg of salmeterol twice daily as the inhalation aerosol; no longer commercially available in the US) have been used in some studies in patients with severe asthma, usually in conjunction with corticosteroids, cromolyn sodium, nedocromil sodium (preparations for oral inhalation no longer commercially available in the US), and/or theophylline; however, such dosages are more likely to be associated with adverse effects, and the manufacturer states that patients should not use more than 50 mcg (1 inhalation) twice daily (morning and evening) of salmeterol. Patients receiving salmeterol should not use additional long-acting β2-adrenergic agonists for any reason.

Patients should contact a clinician if asthma symptoms do not improve after 1 week of therapy. Failure to respond to a previously effective dosage of salmeterol may indicate destabilization of asthma that requires immediate medical attention and reevaluation of the therapeutic regimen. If symptoms arise in the period between doses, a short-acting, inhaled β2-agonist should be used for immediate relief. However, increasing use of short-acting, inhaled β2-agonists is a marker of deteriorating asthma; patients in this situation require immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional inhaled corticosteroids or initiating systemic corticosteroids. Extra/increased doses of salmeterol should not be used in such situations. Patients should be advised to contact a clinician immediately if they experience decreasing effectiveness of short-acting, inhaled β2-agonists, a need for more inhalations than usual of short-acting, inhaled β2-agonists, or a substantial decrease in lung function as outlined by the clinician. Patients should adhere to dosing schedules, including not altering the dose or frequency of use of salmeterol unless otherwise instructed by a clinician.(See Cautions: Precautions and Contraindications.)

Salmeterol is not a substitute for inhaled or oral corticosteroids, and patients receiving corticosteroid therapy should be advised not to discontinue or alter the dosage of corticosteroids without consulting a clinician, even if the patient has subjective improvement after initiating therapy with salmeterol. When initiating therapy and throughout treatment with salmeterol in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they have subjective improvement as a result of initiation of salmeterol; any change in corticosteroid dosage should be made only after clinical evaluation. In addition, all patients with asthma should be advised that they must continue regular maintenance treatment with an inhaled corticosteroid if they are receiving salmeterol. Patients also should be advised not to discontinue salmeterol without medical supervision because symptoms may recur after treatment discontinuance.(See Cautions: Precautions and Contraindications.)

Salmeterol/Fluticasone Propionate Fixed-combination Therapy

In asthmatic patients 4-11 years of age who are inadequately controlled on an inhaled corticosteroid, the recommended dosage of the commercially available inhalation powder preparation containing salmeterol in fixed combination with fluticasone propionate (Advair Diskus) is 50 mcg of salmeterol and 100 mcg of fluticasone propionate (1 inhalation) twice daily, given approximately 12 hours apart (morning and evening).

In asthmatic patients 12 years of age or older, the recommended initial dosage of the commercially available inhalation powder preparation containing salmeterol in fixed combination with fluticasone propionate (Advair Diskus) is based on the patient's asthma severity. The dosage of the inhalation powder fixed-combination preparation is 50 mcg of salmeterol and 100, 250, or 500 mcg of fluticasone propionate (1 inhalation) twice daily, given approximately 12 hours apart (morning and evening). The maximum recommended dosage of salmeterol in fixed combination is 50 mcg of salmeterol with 500 mcg of fluticasone propionate twice daily. The manufacturer states that administration of the inhalation powder of salmeterol in fixed combination with fluticasone more frequently than twice daily or exceeding 1 inhalation twice daily is not recommended.

In asthmatic patients 12 years of age or older, the recommended initial dosage of the inhalation aerosol containing salmeterol in fixed combination with fluticasone propionate (Advair HFA) is based on the patient's current asthma therapy. The dosage of the inhalation aerosol fixed-combination preparation (Advair HFA) is 42 mcg of salmeterol and 90, 230, or 460 mcg of fluticasone propionate (2 inhalations) twice daily, given approximately 12 hours apart (morning and evening). The maximum recommended dosage of salmeterol is 42 mcg in fixed combination with 460 mcg of fluticasone propionate (2 inhalations) twice daily. The manufacturer states that administration of salmeterol in fixed combination with fluticasone inhalation aerosol more frequently than twice daily or in excess of 2 inhalations twice daily is not recommended.

If control of asthma is inadequate after 2 weeks of therapy at the initial dosage, replacing the current strength of the fixed combination with a higher strength (higher strengths contain higher dosages of fluticasone propionate only) may provide additional asthma control. Patients receiving the fixed combination of salmeterol and fluticasone propionate twice daily should not use additional salmeterol or other long-acting β2-adrenergic agonists (e.g., formoterol) for any reason, including the treatment of asthma or prevention of exercise-induced bronchospasm. If a dose of salmeterol in fixed combination with fluticasone is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled. Patients also should be advised not to discontinue salmeterol in fixed combination with fluticasone propionate without medical supervision because symptoms may recur after treatment discontinuance. If a previously effective dosage of salmeterol in fixed combination with fluticasone fails to provide adequate improvement in 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 fluticasone only], adding additional inhaled corticosteroids, initiating systemic corticosteroids).(See Cautions: Precautions and Contraindications.)

Exercise-Induced Bronchospasm

For the prevention of exercise-induced bronchospasm, the usual dosage of salmeterol oral inhalation powder in adults and children 4 years of age or older is 50 mcg administered through the Serevent Diskus device at least 30 minutes before exercise.Additional doses of salmeterol should not be used for 12 hours. In addition, the manufacturer states that patients who are receiving salmeterol oral inhalation powder twice daily should not use additional salmeterol for the prevention of exercise-induced bronchospasm. Patients receiving salmeterol alone or in fixed combination with fluticasone propionate should not use additional salmeterol or other long-acting β2-adrenergic agonists (e.g., formoterol) for any reason, including prevention of exercise-induced bronchospasm.

Chronic Obstructive Pulmonary Disease

Salmeterol

For maintenance therapy of bronchospasm in patients with COPD (including chronic bronchitis and emphysema), the dosage of orally inhaled salmeterol given as the inhalation powder (Serevent Diskus) in adults is 50 mcg (1 inhalation) twice daily, given approximately every 12 hours (morning and evening). Higher dosages of salmeterol are more likely to be associated with adverse effects, and more frequent administration or administration of higher dosages (i.e., more than 1 inhalation twice daily) of the drug is not recommended by the manufacturer. Patients should not discontinue salmeterol without medical supervision because symptoms may recur after treatment discontinuance.

Salmeterol/Fluticasone Propionate Fixed-combination Therapy

For maintenance therapy of COPD, the recommended dosage of salmeterol in fixed combination with fluticasone propionate (Advair Diskus) in adults is 50 mcg of salmeterol and 250 mcg of fluticasone propionate (1 inhalation) twice daily, given approximately every 12 hours (morning and evening). If shortness of breath occurs between doses, an inhaled, short-acting β2-adrenergic agonist may be administered for immediate relief. Higher dosages of salmeterol in fixed combination with fluticasone propionate (e.g., 50 mcg of salmeterol and 500 mcg of fluticasone propionate) do not result in additional benefit and are not recommended. Patients receiving salmeterol in fixed combination with fluticasone propionate should not use additional salmeterol or other long-acting β2-adrenergic agonists (e.g., arformoterol, formoterol) for any reason, including the treatment of COPD. Patients should not discontinue salmeterol in fixed combination with fluticasone propionate without medical supervision because symptoms may recur.

Dosage in Renal and/or Hepatic Impairment

The pharmacokinetics of salmeterol have not been studied in patients with hepatic impairment. Since salmeterol is cleared predominantly by hepatic metabolism, impaired liver function theoretically may lead to accumulation of the drug in plasma. Therefore, the manufacturer recommends that patients with hepatic disease be monitored closely while receiving salmeterol therapy.

Cautions

Salmeterol xinafoate oral inhalation appears to be well tolerated when administered in recommended doses. However, long-acting β2-adrenergic agonists, such as salmeterol, 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 and Life-threatening Events under Cautions: Respiratory Effects.) In general, adverse effects reported with salmeterol in controlled studies were similar in type and frequency to those reported with other selective β2-adrenergic agonists (e.g., albuterol) or placebo. The most common adverse effects of salmeterol oral inhalation powder reported in controlled studies in patients with asthma include headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis, and tracheitis/bronchitis. The most common adverse effects of salmeterol oral inhalation powder reported in controlled studies in patients with chronic obstructive pulmonary disease (COPD) include cough, headache, musculoskeletal pain, throat irritation, and viral respiratory infection. In children 4-11 years of age with mild to moderate asthma, currently available data on adverse effects of salmeterol inhalation powder are derived principally from 2 comparative, 12-week clinical trials with salmeterol (50 mcg twice daily) and albuterol inhalation powder (200 mcg 4 times daily). In adolescents and adults with mild to moderate asthma, currently available data on adverse effects of salmeterol inhalation powder are derived principally from 2 large, 12-week comparative trials with salmeterol (50 mcg twice daily) inhalation powder and albuterol (180 mcg 4 times daily) inhalation aerosol. For adverse effects reported with salmeterol therapy in the Cautions section, a causal relationship to the drug has not always been established.

Cardiovascular Effects

Usual doses of salmeterol oral inhalation generally produce no apparent cardiovascular effects. However, salmeterol may produce a clinically important cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or cardiovascular symptoms. Although such effects are uncommon after administration of salmeterol at recommended dosages, if they occur, discontinuance of the drug may be needed. In addition, β2-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression; the clinical importance of these effects is unknown. Hypertension was reported in 4% of patients with COPD receiving salmeterol inhalation powder during clinical trials and also has been reported during postmarketing surveillance. Supraventricular tachycardia or atrial fibrillation has been reported with salmeterol inhalation powder during postmarketing surveillance. Pallor has been reported in 9% of adults and adolescents with asthma receiving salmeterol inhalation powder in clinical trials.

Nonsustained ventricular tachycardia among patients with COPD receiving salmeterol inhalation powder was reported in an incidence similar to that with placebo and fluticasone propionate. The incidence of clinically important ECG abnormalities indicating myocardial ischemia, ventricular hypertrophy, conduction abnormalities, or arrhythmias was lower in patients with COPD receiving salmeterol inhalation powder alone or in fixed combination with fluticasone propionate than in patients receiving placebo. ECG changes, including extrasystoles (supraventricular and ventricular premature complexes), also have been noted with salmeterol inhalation powder. Clinically important prolongation of the QTc interval, which potentially can cause ventricular arrhythmias, has been associated with administration of large oral or inhaled doses (about 12-20 times the recommended dose) of salmeterol or other β2-agonists. Fatalities also have been reported in association with excessive use of inhaled sympathomimetic drugs.(See Cautions: Precautions and Contraindications.) Cardiorespiratory arrest has been reported in a patient with COPD and preexisting alcoholic cardiomyopathy who had received usual dosages of orally inhaled salmeterol in conjunction with orally inhaled ipratropium and albuterol. Salmeterol is a highly selective β2-agonist, and certain cardiovascular effects (e.g., ventricular or nodal arrhythmias, severe tachycardia, anginal-type pain, myocardial ischemia) reported with less receptor-selective β2-adrenergic agonists such as isoproterenol theoretically may occur less frequently, or not at all, with salmeterol.

Nervous System Effects

In clinical trials with salmeterol inhalation powder, headache was reported in 14% of patients with COPD, 13% of adults and adolescents with asthma, and 17% of children with asthma. Migraine has been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD. In clinical studies in adults and adolescents 12 years of age or older with asthma, sleep disturbances and paresthesia occurred more frequently in patients receiving salmeterol inhalation powder than those receiving placebo. Dizziness has been reported in 4% of patients receiving salmeterol inhalation powder for the treatment of COPD. Unrest, depression, anxiety, and vertigo also have been reported rarely with salmeterol oral inhalation therapy. Anxiety has been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.

Respiratory Effects

Asthma-related Death and Life-threatening Events

Long-acting β2-adrenergic agonists, such as salmeterol, 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 salmeterol, alone for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated.(See Cautions: Precautions and 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 salmeterol, 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 salmeterol and fluticasone propionate 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 salmeterol alone or in fixed combination with fluticasone propionate, 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 (approximately 26,000 patients) placebo-controlled study in patients receiving salmeterol xinafoate as part of an asthma treatment regimen showed an increase in asthma-related deaths in patients receiving salmeterol. In the Salmeterol Multi-center Asthma Research Trial (SMART), a 28-week safety study, patients received salmeterol 42 mcg or placebo via metered-dose aerosol with a chlorofluorocarbon (CFC) propellant (CFC preparation no longer commercially available in the US) twice daily in addition to their usual asthma therapy. The primary end point of the SMART study was the combined number of respiratory-related deaths and respiratory-related life-threatening experiences (intubation and mechanical ventilation). Secondary end points included asthma-related deaths and combined asthma-related deaths or life-threatening experiences. The risk of respiratory-related death or life-threatening experience (primary end point) was higher in patients receiving salmeterol versus placebo (relative risk: 1.4) in the SMART trial, although this difference was not statistically significant. However, analysis of secondary end points revealed a statistically significant greater risk for asthma-related death (relative risk: 4.37) or combined asthma-related death or life-threatening experience (relative risk: 1.71) with salmeterol therapy in the overall patient population compared with placebo. Results of a post hoc analysis also revealed a statistically significant greater risk for asthma-related death (relative risk: 7.26) with salmeterol therapy in African-American patients (18% of study patients) and in patients not receiving concomitant inhaled corticosteroid therapy (53% of study patients) compared with placebo. A greater risk for asthma-related death (relative risk: 5.82) was observed in white patients (71% of the study population) receiving salmeterol therapy compared with placebo; no asthma-related deaths occurred in Hispanic or Asian subpopulations. Factors possibly contributing to the increased numbers of adverse events in African-American patients include the findings that these patients had more severe asthma at baseline than white patients and that fewer African-American than white patients were receiving concomitant inhaled corticosteroid therapy (38 versus 50%, respectively). Results of post hoc analyses in pediatric patients 12-18 years of age (12% of study patients) revealed that the rate of respiratory-related deaths and life-threatening experiences was similar in both the salmeterol and placebo groups (relative risk: 1); however, the rate of all-cause hospitalizations was higher in the salmeterol group compared with the placebo group (relative risk: 2.1). Data from the SMART study are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma controller therapy mitigates the risk of asthma-related death. Because of the similar mechanism of action of long-acting β2-adrenergic agonists, the findings of the SMART study are considered a class effect of these drugs. The SMART study has been discontinued because, according to the manufacturer, the study was not designed to provide reliable findings based on analyses of patient subgroups and therefore would not answer questions raised by the interim analysis if it were continued.

A prior 16-week comparative study performed in the United Kingdom (Salmeterol Nationwide Surveillance [SNS] study) also reported a numerically, but not statistically significantly, higher incidence of asthma-related deaths in patients treated with salmeterol (42 mcg twice daily) compared with those receiving albuterol (180 mcg 4 times daily).

The SMART and SNS studies enrolled patients with asthma; no studies have been conducted that were adequate to determine whether the rate of death is increased in patients with COPD receiving long-acting β2-adrenergic agonists.

Other Respiratory Effects

Cough was reported in 5% of patients receiving salmeterol inhalation powder for the treatment of COPD. In clinical studies in adults and adolescents 12 years of age or older with asthma, sinus headache was reported more frequently in patients receiving salmeterol inhalation powder than those receiving placebo. Exacerbations of asthma have been reported in 4% of children and 3% of adults and adolescents receiving salmeterol inhalation powder for the treatment of asthma. Tracheitis/bronchitis or influenza occurred in 7 or 5%, respectively, of adults and adolescents receiving salmeterol inhalation powder. Nasal/sinus congestion or rhinitis occurred in 9 or 5%, respectively, of adults and adolescents with asthma receiving salmeterol inhalation powder. Nasal congestion or blockage, rhinitis, or sinusitis occurred in 4% of patients with COPD receiving salmeterol inhalation powder in clinical trials. Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred in at least 3% of adults and adolescents receiving salmeterol inhalation powder for the treatment of asthma in clinical trials but occurred less frequently than with placebo. However, throat irritation has been reported in 7% of patients with COPD receiving salmeterol inhalation powder in controlled clinical trials. Pharyngitis was reported in 6% of children with asthma receiving salmeterol inhalation powder in clinical trials. Lower respiratory tract signs and symptoms occurred in greater than 1% of children with asthma receiving salmeterol inhalation powder. Lower respiratory viral infection or lower respiratory tract signs and symptoms occurred in 5% or at least 1% of patients, respectively, receiving salmeterol inhalation powder for the treatment of COPD.

Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor or choking, and oropharyngeal irritation, have been reported during postmarketing experience with salmeterol oral inhalation therapy. As with other inhaled drugs, paradoxical bronchospasm, a potentially life-threatening event, also has occurred with salmeterol therapy.(See Cautions: Dermatologic and Sensitivity Reactions.)

Increased airway reactivity and variability or decreases in pulmonary function (e.g., as measured by PEFR or FEV1), in some cases progressing to respiratory arrest or death, have been reported with regular use (e.g., 2 inhalations 4 times daily) of short-acting, inhaled β-agonists and also in some patients (generally with severe and/or deteriorating asthma) receiving salmeterol oral inhalation powder. Such detrimental effects may be related to down-regulation of β-adrenergic receptors (tolerance), increased responsiveness of airways to allergens and exercise, genetic changes in β2-agonist receptor gene, or increased airway accessibility to inhaled allergens, which may lead to increased airway inflammation and reactivity and worsening of asthma symptoms. However, increased airway accessibility to inhaled allergens theoretically also would occur with long-acting bronchodilators such as extended-release theophylline.

GI Effects

Hyposalivation, dyspepsia, oral (mouth/throat) candidiasis, or GI infections were reported in at least 1% of patients with COPD receiving salmeterol inhalation powder in clinical trials. In clinical studies in adults and adolescents 12 years of age or older with asthma, nausea has been reported more frequently in patients receiving salmeterol inhalation powder than those receiving placebo. Nausea and vomiting have been reported in 3% of patients receiving salmeterol inhalation powder for the treatment of COPD. In clinical studies in patients with asthma, GI signs and symptoms occurred in greater than 1% of children receiving salmeterol inhalation powder, while oral mucosal abnormality was reported more frequently in adults and adolescents 12 years of age or older receiving salmeterol inhalation powder than those receiving placebo.

Metabolic and Electrolyte Effects

The manufacturer states that large IV doses of the β2-adrenergic agonist albuterol (IV preparation not currently commercially available in the US) have aggravated preexisting diabetes mellitus and ketoacidosis.

The manufacturer states that clinically important and dose-related changes in blood glucose and/or serum potassium concentrations have been observed infrequently during clinical studies with salmeterol oral inhalation powder at recommended dosages. No clinically important changes in glucose or potassium concentrations were reported in clinical studies in patients with asthma receiving salmeterol oral inhalation powder. In addition, no clinically important changes in serum potassium concentrations were reported in clinical studies in patients with COPD receiving salmeterol oral inhalation powder at recommended dosages. Patients should inform their clinician of the presence of diabetes mellitus prior to initiation of therapy. Salmeterol and other β2-adrenergic agonists may decrease serum potassium concentrations through increased intracellular uptake of potassium resulting from β2-receptor mediated Na- K-ATPase activation in liver and skeletal muscle. Although such reductions potentially may cause adverse cardiovascular effects, the decreases usually are transient and supplemental potassium therapy generally is not required. Hyperglycemia occurred in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD. The potential for hyperglycemia or hypokalemia with salmeterol therapy appears to be dose related. Tolerance to the hypokalemic effects of albuterol has been demonstrated but has not been reported to date with salmeterol therapy.

Musculoskeletal Effects

Musculoskeletal pain occurred in 12% of patients receiving salmeterol inhalation powder for the treatment of COPD, and muscle cramps and spasms were reported in 3% of such patients with COPD. In clinical studies in patients with asthma, joint pain was reported more frequently in adults and adolescents 12 years of age or older receiving salmeterol inhalation powder than those receiving placebo, and arthralgia or arthritis occurred in greater than 1% of children receiving the inhaled powder in such trials. Arthralgia or arthritis; muscle, bone, or skeletal pain; musculoskeletal inflammation; or muscle stiffness, tightness, or rigidity has occurred in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD in clinical trials.

Dermatologic and Sensitivity Reactions

Immediate hypersensitivity reactions, including urticaria, angioedema, rash, and bronchospasm may occur following administration of salmeterol. Anaphylactic reactions have been reported very rarely in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not receive salmeterol.(See Cautions: Precautions and Contraindications.) Anaphylaxis also has been reported during postmarketing surveillance studies with the drug.

In clinical studies in adults and adolescents 12 years of age or older with asthma, contact dermatitis and eczema were reported more frequently in patients receiving salmeterol inhalation powder than those receiving placebo. Rash, photodermatitis, or urticaria was reported in 4, greater than 1, or 3%, respectively, of children receiving salmeterol inhalation powder in clinical trials. Rash was reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.

Although the mechanism(s) has not been fully elucidated, paradoxical bronchospasm (defined as a decrease of 20% or greater in PEFR) has occurred occasionally with repeated or excessive use of orally inhaled sympathomimetic amines (especially isoproterenol). Preliminary results of a controlled study in almost 12,000 patients demonstrated that paradoxical bronchospasm occurred less frequently with salmeterol oral inhalation than with placebo (either lecithin or oleic acid) given via metered-dose inhaler (no longer commercially available), suggesting that orally inhaled ingredients other than the active drug may be more likely to produce paradoxical bronchospasm.

Other Adverse Effects

Dental discomfort and pain have been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD. In clinical studies in patients with asthma, ear symptoms have been reported in 4% of children, and localized aches and pains and fever of unknown origin have been reported more frequently in adults and adolescents 12 years of age or older receiving salmeterol inhalation powder than those receiving placebo. Otic manifestations have been reported in 3% of patients with COPD receiving salmeterol inhalation powder in clinical trials. Edema and swelling have been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD. Keratitis and conjunctivitis occurred in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD. Pain also has been reported in at least 1% of such patients. Herniated disk has been reported in at least one patient receiving inhaled salmeterol, but a causal relationship to the drug has not been established. A reduction in platelet count has been reported during long-term (1 year) therapy with salmeterol oral inhalation, but platelet count remained within the normal range and the reduction was not associated with sequelae. Elevation of hepatic enzymes was reported in at least 1% of patients with asthma receiving salmeterol oral inhalation powder in clinical studies. However, these elevations were transient and did not lead to discontinuance from the studies.

Precautions and Contraindications

When salmeterol is used in fixed combination with fluticasone propionate, the usual cautions, precautions, and contraindications associated with fluticasone propionate must be considered in addition to those associated with salmeterol.

Patients should be advised to read the Serevent or Advair Diskus or Advair HFA medication guide prior to initiating therapy with the drug and each time the prescription is refilled.

Patients should be informed that long-acting β2-adrenergic agonists, such as salmeterol, 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 and Life-threatening Events under Cautions: Respiratory Effects.) Patients also should be informed that salmeterol should not be the only therapy used for the treatment of asthma and must only be used as additional therapy when long-term asthma controller therapy (e.g., inhaled corticosteroids) does not adequately control asthma symptoms. Patients should be advised that when salmeterol is added to their treatment regimen they must continue to use their long-term asthma controller drugs.(See Uses: Bronchospasm.) Patients also should be informed that 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.

Salmeterol, alone or in fixed combination with fluticasone propionate, should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Salmeterol has not been studied in patients with acutely deteriorating asthma or COPD. Initiation of salmeterol in this setting is not appropriate. Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with substantially worsening or acutely deteriorating asthma. In most cases, these adverse events have occurred in patients with severe asthma (e.g., those with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with substantially increasing symptoms, increasing need for inhaled short-acting β2-agonists, decreasing response to usual medications, increasing need for systemic corticosteroids, recent emergency room visits, deteriorating lung function). However, such events also have occurred in patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of short-acting, inhaled β2-agonists is a marker of deteriorating asthma and failure to respond to a previously effective dosage regimen of salmeterol alone or in fixed combination with fluticasone propionate often is a sign of destabilization of asthma. In this situation in patients receiving salmeterol, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need to add additional inhaled corticosteroids or initiating systemic corticosteroids. If asthma deteriorates in patients receiving salmeterol in fixed combination with fluticasone, immediate reevaluation with reassessment of the treatment regimen is required, with special consideration given to the possible need for increasing the strength of the fixed combination (higher strengths contain higher dosages of fluticasone only), adding additional inhaled corticosteroids, or initiating systemic corticosteroids. However, extra/increased doses of salmeterol alone or in fixed combination with fluticasone propionate should not be used in such situations. Patients should be advised to contact a clinician immediately if they experience decreasing effectiveness of short-acting, inhaled β2-agonists, a need for more inhalations than usual of short-acting, inhaled β2-agonists, or a substantial decrease in lung function as outlined by the clinician. Patients should be advised not to discontinue therapy with salmeterol alone or in fixed combination with fluticasone without medical supervision since symptoms may recur following discontinuance.

Salmeterol has a delayed onset of action, and the drug alone or in fixed combination with fluticasone propionate should not be used for the relief of acute symptoms (i.e., as rescue therapy for the treatment of acute episodes of bronchospasm). A short-acting, inhaled β2-agonist, not salmeterol (alone or in fixed combination with fluticasone propionate), should be used to relieve acute symptoms such as shortness of breath. All patients receiving salmeterol alone or in fixed combination with fluticasone propionate should be provided with and instructed in the use of a short-acting, inhaled β2-agonist (e.g,. albuterol) for treatment of acute symptoms. When initiating salmeterol alone or in fixed combination with fluticasone in patients who have been taking short-acting, oral or inhaled β2-agonists on a regular basis (e.g., 4 times daily), these patients should be instructed to discontinue the regular use of the short-acting agent.

Salmeterol is not a substitute for inhaled or oral corticosteroids, and patients receiving corticosteroid therapy should be advised not to discontinue or alter the dosage of corticosteroids without consulting a clinician, even if the patient has subjective improvement after initiating therapy with salmeterol, since worsening of asthma may occur. In addition, all patients with asthma should be advised that they must continue regular maintenance treatment with an inhaled corticosteroid if they are receiving salmeterol. The manufacturer states that there are no data demonstrating that salmeterol has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout therapy with salmeterol in patients receiving oral or inhaled corticosteroids for treatment of asthma, patients must continue taking a suitable dosage of corticosteroids to maintain clinical stability even if they have subjective improvement as a result of initiation of salmeterol; any change in corticosteroid dosage should be made only after clinical evaluation. Salmeterol in fixed combination with fluticasone as the inhalation aerosol (Advair HFA) should not be used to transfer patients from systemic corticosteroid therapy. Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids since death resulting from adrenal insufficiency has occurred in patients with asthma during and after such transfer.

As with other inhaled β2-adrenergic drugs, salmeterol, alone or in fixed combination with fluticasone propionate, should not be used more often or at higher than recommended dosages, or in conjunction with other preparations containing long-acting β2-adrenergic agonists, since an overdose may result. Clinically important cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients receiving salmeterol alone or in fixed combination with fluticasone propionate should not use additional salmeterol or other long-acting β2-adrenergic agonists (e.g., arformoterol, formoterol) for any reason, including prevention of exercise-induced bronchospasm or treatment of asthma or COPD.

Rarely, a patient may develop acute bronchospasm immediately upon inhalation of a sympathomimetic drug preparation. Acute bronchospasm probably represents a hypersensitivity reaction to the active drug or an ingredient in the formulation. Although it may not be possible to distinguish paradoxical bronchoconstriction or that associated with hypersensitivity to the drug or an ingredient in the formulation from worsening of the asthma, salmeterol alone or in fixed combination with fluticasone propionate should be discontinued immediately if paradoxical bronchospasm occurs. Paradoxical bronchospasm should immediately be treated with a short-acting inhaled bronchodilator, and alternative therapy should be instituted. Patients should inform their clinicians of allergic reactions to salmeterol-containing preparations, other agents, or foods (including milk proteins).

Salmeterol and other β2-adrenergic agonists may produce substantial hypokalemia in some patients, which has the potential to produce adverse cardiovascular effects (e.g., arrhythmias); however, decreases in serum potassium usually are transient and generally do not require supplementation.(See Cautions: Metabolic and Electrolyte Effects.)

Excessive β2-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/minute, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia (see Acute Toxicity: Manifestations). Therefore, salmeterol, like all preparations containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with seizure disorders or thyrotoxicosis; and in those who are unusually responsive to sympathomimetic amines. Patients should be informed of adverse effects associated with β2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Patients should inform their clinician of heart problems, hypertension, seizures, thyroid disorders, or diabetes mellitus prior to initiation of salmeterol-containing therapy. Patients receiving salmeterol oral inhalation should use other inhaled medications only as directed by their clinician.

The pharmacokinetics of salmeterol have not been studied in patients with hepatic impairment. Because salmeterol is metabolized predominantly in the liver and potentially may accumulate in the plasma of patients with hepatic impairment, such patients should be monitored closely while receiving salmeterol therapy. Patients should inform their clinician of liver dysfunction prior to initiation of therapy.

Clinicians should remain vigilant for the possible development of pneumonia in patients with COPD who are receiving the inhalation powder preparation containing salmeterol in fixed combination with fluticasone propionate (Advair Diskus), since the clinical features of pneumonia and COPD exacerbations frequently overlap. Lower respiratory tract infections, including pneumonia, have been reported in patients with COPD following the administration of inhaled corticosteroids, including fluticasone propionate and the inhalation powder preparation containing salmeterol in fixed combination with fluticasone propionate.

Because of the risk of asthma-related death and hospitalization, use of salmeterol for the treatment of asthma without concomitant use of long-term asthma controller therapy, such as inhaled corticosteroids, is contraindicated. (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects and also see Uses: Bronchospasm.) Salmeterol alone or in fixed combination with fluticasone propionate as the inhalation powder (Advair Diskus) is contraindicated in patients with severe hypersensitivity to milk proteins. Salmeterol in fixed combination with fluticasone propionate as the inhalation aerosol (Advair HFA) is contraindicated in patients with known hypersensitivity to the drugs or any ingredient in the formulation. Patients should inform their clinician of allergies to drugs or food prior to initiation of therapy. Salmeterol alone or in fixed combination with fluticasone propionate is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required.

Pediatric Precautions

Safety and efficacy of salmeterol oral inhalation powder in adolescents 12 years of age or older have been established based on adequate and well-controlled trials conducted in adults and adolescents. However, long-acting β2-adrenergic agonists, such as salmeterol, 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.(See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects.) 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.)

Safety and efficacy of salmeterol oral inhalation powder in children 4-11 years of age with asthma have been evaluated for periods not exceeding 1 year, and current data suggest that such children may receive the same dosage as adults for the treatment of asthma or exercise-induced bronchospasm. Pediatric patients should receive salmeterol therapy under adult supervision. Use of salmeterol in fixed combination with fluticasone propionate inhalation powder (Advair Diskus) in children 4-11 years of age with asthma is supported by data from one clinical trial and from extrapolation of efficacy data from older patients. Data from a 12-week study in children (4-11 years of age) with persistent asthma who were symptomatic with low dosages of inhaled corticosteroids indicate that the safety profile of salmeterol inhalation powder (50 mcg) in fixed combination with fluticasone propionate (100 mcg) inhalation powder is similar to that of fluticasone propionate monotherapy.

Safety and efficacy of salmeterol in fixed combination with fluticasone propionate inhalation powder (Advair Diskus) in children younger than 4 years of age with asthma have not been established. Safety and efficacy of salmeterol in fixed combination with fluticasone propionate inhalation aerosol (Advair HFA) in children younger than 12 years of age have not been established. Data from a limited number of adolescents 12-17 years of age receiving salmeterol and fluticasone propionate inhalation aerosol in fixed combination suggest that safety and efficacy of the fixed combination are similar to those in adults.

Geriatric Precautions

Data from trials in patients with COPD receiving salmeterol inhalation powder suggested a greater effect on FEV1 in younger adults compared with geriatric patients. No apparent differences in the type or frequency of adverse effects were noted in geriatric patients with asthma receiving salmeterol alone or in fixed combination with fluticasone inhalation aerosol (Advair HFA) or in those with COPD receiving salmeterol compared with those in the total population of patients in these studies. Clinical studies of salmeterol in fixed combination with fluticasone inhalation powder for asthma did not include sufficient numbers of patients 65 years of age or older to determine whether geriatric patients respond differently than younger patients. In clinical studies of salmeterol in fixed combination with fluticasone inhalation powder for COPD, patients 65 years of age or older experienced a higher incidence of serious adverse effects compared with those younger than 65 years of age, although the distribution of adverse effects was similar in the two groups. The possibility of greater sensitivity of some older patients cannot be ruled out. As with other β2-agonists, special caution should be observed when using salmeterol alone or in fixed combination with fluticasone in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by this class of drugs.(See Cautions: Precautions and Contraindications.) The manufacturer states that adjustment of salmeterol dosage alone or in combination with fluticasone propionate in geriatric patients solely on the basis of age is not necessary.

Mutagenicity and Carcinogenicity

No evidence of mutagenicity was observed when salmeterol was tested in several in vitro systems, including microbial and mammalian gene mutation tests and in a cytogenic assay of human lymphocytes. In an in vivo rat micronucleus assay, salmeterol did not exhibit evidence of mutagenicity.

Dose-related increases in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, uterine leiomyomas, and ovarian cysts occurred in mice given oral salmeterol dosages of at least 1.4 mg/kg (approximately 20 times the maximum recommended daily inhalation dosage for adults and children based on comparisons of the plasma area under the curve [AUC]) in an 18-month carcinogenicity study. In a 24-month study in rats given salmeterol orally and/or by inhalation, mesovarian leiomyomas and ovarian cysts occurred at dosages of at least 0.68 mg/kg (approximately 55 or 25 times the maximum recommended daily inhalation dosage for adults or children respectively, on a mg/m basis). The findings of these studies in rodents are similar to those reported previously for other β-adrenergic agonist drugs; the relevance of these findings to human use is unknown. No carcinogenic effects were observed in mice given salmeterol in doses of 0.2 mg/kg (approximately 3 times the maximum recommended daily inhalation dosage for adults and children based on AUC comparisons) or in rats given 0.21 mg/kg (approximately 15 or 8 times the maximum recommended daily inhalation dosage for adults or children, respectively, on a mg/m basis).

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies of salmeterol in pregnant women. Because of the potential for β-agonist interference with uterine contractility, use of salmeterol during labor should be restricted to those patients in whom the benefits clearly outweigh the risks. The drug should be used during other stages of pregnancy only if the potential benefit justifies the potential risk to the fetus. Salmeterol in fixed combination with fluticasone propionate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Reproduction studies in male and female rats using oral salmeterol dosages of up to 2 mg/kg daily (representing 160 times the recommended clinical dosage on a mg/m basis) have not revealed evidence of harm to the fetus. Dutch rabbit fetuses exposed to oral salmeterol dosages of at least 1 mg/kg (representing 50 times the maximum recommended daily inhalation dosage based on comparison of AUC data) exhibited characteristic effects of β-receptor stimulation, including precocious eyelid openings, cleft palate, sternebral fusion, limb and paw flexures, and delayed ossification of the frontal cranial bones. No teratogenic effects were observed at oral salmeterol doses of 0.6 mg/kg (20 times the maximum recommended daily inhalation dosage based on comparison of AUC data). Delayed ossification of the frontal bones was seen in the fetuses of New Zealand White rabbits given oral salmeterol dosages of 10 mg/kg (representing 1600 times the maximum recommended daily inhalation dosage on a mg/m basis). Extensive use of other β-agonists has provided no evidence that these class effects in animals are relevant to use in humans.

In reproduction studies in mice and rats, no evidence of an increased toxicity was associated with the use of salmeterol combined with fluticasone propionate when compared with toxicity observed from the components administered separately. Teratogenicity (i.e., cleft palate), fetal death, or increased implantation loss has been observed in mice receiving a subcutaneous dosage of 150 mcg/kg of fluticasone propionate (representing approximately less than the maximum recommended daily inhalation dosage in adults on a mcg/m basis) combined with a 10 mg/kg oral dosage of salmeterol (representing approximately 410 times the maximum recommended daily inhalation dosage in adults on a mg/m basis), but these effects did not occur when lower dosages of fluticasone propionate (up to 40 mcg/kg subcutaneously, representing less than the maximum recommended daily inhalation dosage in adults on a mcg/m basis) were combined with lower dosages of salmeterol (up to 1.4 mg/kg orally, representing approximately 55 times the maximum recommended daily inhalation dosage in adults on a mg/m basis). Reproduction studies in rats receiving subcutaneous dosages of fluticasone propionate of up to 30 mcg/kg (representing less than the maximum recommended daily inhalation dosage in adults on a mcg/m basis) combined with dosages of up to 1 mg/kg of salmeterol (approximately 80 times the recommended daily inhalation dosage in adults on a mg/m basis) did not reveal evidence of teratogenicity. Delayed ossification, changes in the occipital bone, umbilical hernia, decreased placental or fetal weight, and maternal toxicity have been observed in rats receiving subcutaneous dosages of fluticasone propionate 100 mcg/kg (representing less than the maximum recommended daily inhalation dosage in adults on a mcg/m basis) combined with oral salmeterol dosages of 10 mg/kg (approximately 810 times the maximum recommended daily inhalation dosage in adults on a mg/m basis).

Fertility

Reproduction studies in rats given oral salmeterol dosages up to 2 mg/kg (approximately 160 times the maximum recommended daily inhalation dosage for adults on a mg/m basis) have not revealed evidence of impaired fertility.

Lactation

It is not known whether salmeterol xinafoate is distributed into human milk. However, salmeterol is distributed into milk in rats. Because of the potential for serious adverse reactions to salmeterol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

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

Monoamine Oxidase Inhibitors and Tricyclic Antidepressants

The manufacturer states that the effects of salmeterol xinafoate on the vascular system may be potentiated in patients receiving concomitant therapy with monoamine oxidase (MAO) inhibitors or tricyclic antidepressants; therefore, salmeterol should be administered with extreme caution to patients being treated with these agents or to patients receiving salmeterol within 2 weeks of discontinuance of these agents.

Drugs Affecting Hepatic Microsomal Enzymes

Salmeterol is a substrate for cytochrome P-450 (CYP) isoenzyme 3A4. The manufacturer of SereventDiskus, Advair Diskus, and Advair HFA states that the use of potent CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) with salmeterol is not recommended because of the increased potential for systemic adverse effects (e.g., cardiovascular effects such as QTc prolongation, palpitations, or sinus tachycardia).

Supplemental Short-Acting β2-Adrenergic Agonists

In several 3-month clinical trials, adults and adolescents with asthma receiving therapy with salmeterol inhalation powder required an average of approximately 1.5 inhalations daily of a supplemental, short-acting β2-adrenergic agonist. In patients receiving salmeterol inhalation powder, 26% required 8-24 inhalations daily of a supplemental, short-acting β2-agonist on at least one occasion. Consistent use of greater than 4 inhalations daily of supplemental, short-acting β2-agonist therapy was required in 9% of patients receiving orally inhaled salmeterol over the course of these trials. In trials that evaluated salmeterol inhalation powder and as-needed short-acting β2-agonists, a few patients required an average of 8-11 inhalations of short-acting β2-agonists daily; no increase in cardiovascular effects were noted. However, the safety of concomitant use of more than 8 inhalations of supplemental, short-acting β2-agonist therapy daily with salmeterol inhalation therapy has not been established. In a moderate number of patients who experienced a worsening of asthma with salmeterol inhalation powder therapy, administration of albuterol by metered-dose inhaler or nebulizer (one dose in most patients) led to improvement in FEV1 with no increase in the occurrence of cardiovascular adverse effects.

In two 6-month clinical trials, patients with chronic obstructive pulmonary disease (COPD) receiving therapy with salmeterol inhalation powder alone or in fixed combination with fluticasone propionate required an average of approximately 4 inhalations daily of a supplemental, rapid-acting β2-adrenergic agonist. In COPD patients receiving salmeterol inhalation powder alone or in fixed combination with fluticasone propionate, 24 or 26%, respectively, required an average of 6 or more inhalations daily of a supplemental, rapid-acting β2-agonist over the course of these trials; no increase in the frequency of adverse cardiovascular effects was noted.

Cromolyn Sodium

In clinical studies, inhaled cromolyn sodium did not alter the safety profile of salmeterol oral inhalation when these drugs were administered concurrently.

Theophyllines

There is some evidence from studies in animals that concomitant administration of sympathomimetic agents (e.g., isoproterenol) and aminophylline may produce increased cardiotoxic effects (e.g., arrhythmias and sudden death, with histologic evidence of myocardial necrosis). Although such an interaction has not been established in humans, a few reports have suggested that such a combination may have the potential for producing cardiac arrhythmias and death. However, in one study in patients receiving theophylline therapy, no evidence of increased cardiotoxic effects was noted when salmeterol aerosol (no longer commercially available) was added to theophylline therapy. In a number of clinical trials in patients with COPD, concurrent therapy with theophylline did not alter the adverse effect profile of salmeterol given alone or in fixed combination with fluticasone propionate.

β-Adrenergic Blocking Agents

β-Adrenergic blocking agents not only block the pulmonary effects of β-adrenergic agonists, but also may produce severe bronchospasm in patients with asthma or COPD. Patients with asthma or COPD usually should not be treated with β-adrenergic blocking agents. However, under certain circumstances, there may be no acceptable alternatives to the use of β-adrenergic blocking agents in these patients; the use of cardioselective β-adrenergic blocking agents may be considered but should be used concomitantly with caution.

Other Drugs

Since salmeterol may decrease serum potassium concentration, care should be taken in patients also receiving other drugs that can lower serum potassium concentration, such as non-potassium-sparing diuretics (loop or thiazide diuretics). ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics may be aggravated by concomitant β-agonist therapy, especially when the recommended dosage of the β-agonist is exceeded. Although the clinical importance of these effects is not known, caution is advised when administering salmeterol with non-potassium-sparing diuretics.

Pharmacokinetics

Limited data are available on the pharmacokinetics of salmeterol xinafoate after oral inhalation. Salmeterol xinafoate dissociates in solution to salmeterol and xinafoate moieties that are absorbed, distributed, metabolized, and excreted independently. The xinafoate moiety has no intrinsic pharmacologic activity. While commercially available salmeterol is administered as salmeterol xinafoate, dosages and drug concentrations are expressed in terms of salmeterol.

Absorption

The absorption of salmeterol xinafoate from the respiratory tract following oral inhalation has not been fully characterized. Although it has been suggested that most of an orally inhaled drug actually is swallowed, the bronchodilating action of orally inhaled sympathomimetic agents is believed to result from a local action of the portion of the dose that reaches the bronchial tree. Systemic concentrations of salmeterol are low or undetectable after inhalation of the recommended dosage of the powder (50 mcg) twice daily and are not predictive of therapeutic effects. Delayed absorption was noted following oral administration of 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) in a few healthy individuals; peak plasma salmeterol concentrations of about 600-650 pg/mL occurred at 45-75 minutes. Following repeated, twice-daily administration of 50 mcg of salmeterol as the oral inhalation powder in patients with asthma, salmeterol was detected in the plasma within 5-45 minutes; mean peak plasma concentrations of the drug were 167 pg/mL, and no accumulation was noted with repeated dosing.

Compared with short-acting β-agonists such as albuterol or isoproterenol, the onset and duration of bronchodilation with orally inhaled salmeterol are longer. Following administration of a single dose (50 mcg) of salmeterol oral inhalation powder in patients with asthma, most patients experienced clinically important improvement (as measured by a 15% improvement in FEV1) within 1 hour. Maximum improvement in FEV1 generally occurred within 3 hours, and clinically important improvement was maintained for 12 hours in most patients. Following administration of a single dose (50 mcg) of salmeterol oral inhalation powder in patients with chronic obstructive pulmonary disease (COPD), improvement in lung function (as measured by a 12% improvement in FEV1 and at least 200 mL) occurred in 2 hours. Mean time to maximum improvement in FEV1 occurred at 4.75 hours, and improvement was maintained for 12 hours. In the prevention of exercised-induced bronchospasm, salmeterol oral inhalation powder provided protection for up to about 9 hours in adolescents and adults and up to about 12 hours in children 4 to 11 years of age following a single 50- mcg dose 30 minutes prior to exercise.

Distribution

Binding of salmeterol averages 96% in vitro to human plasma proteins over the concentration range of 8 ng/mL to 7.7 mcg/mL, which are concentrations greatly exceeding those achieved following usual doses of the drug. Salmeterol is bound to albumin and α1-acid glycoprotein; the xinafoate moiety also is highly protein bound (exceeding 99%) to albumin.

The distribution of salmeterol into various human organs and tissues following oral inhalation has not been fully characterized. Results of studies in rats indicate that salmeterol crosses the blood-brain barrier in trace amounts.

It is not known if salmeterol and/or its metabolites cross the placenta in humans. Salmeterol crossed the placenta following oral administration in mice and rats. It also is not known if salmeterol is distributed into milk in humans; however the drug is distributed into milk in rats.

Elimination

Salmeterol is extensively metabolized in the liver by hydroxylation and is eliminated predominantly in feces. In a few healthy individuals who received radiolabeled salmeterol 1 mg orally, approximately 25 and 60% of the dose were eliminated in urine and feces, respectively, 1-7 days after administration. Negligible amounts of unchanged salmeterol are detectable in urine or feces. A minor metabolite is formed by o-dealkylation of the phenylalkyl side chain. Following oral administration of salmeterol in healthy individuals, the terminal elimination half-lives of salmeterol and the xinafoate moiety are about 5.5 hours and 11-15 days, respectively.

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