Salmeterol xinafoate, a synthetic sympathomimetic amine, is a relatively selective, long-acting β2-adrenergic agonist.1, 2, 3, 5, 270 The drug is structurally and pharmacologically similar to the short-acting β2-adrenergic agonist albuterol.2, 3
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.156, 222, 263, 267, 268, 269, 270 Monotherapy with long-acting β2-adrenergic agonists, such as salmeterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.248, 266, 267, 268, 269, 270 (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 .248, 270 (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.222, 263, 270 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 warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.267, 268, 269 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), if possible without loss of asthma control, and the patient should be maintained on long-term asthma controller therapy, such as inhaled corticosteroids.248, 270 Salmeterol is not a substitute for corticosteroids; corticosteroid therapy should not be stopped or reduced in dosage when salmeterol is initiated .1, 226, 270 (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 a low or medium dosage of inhaled corticosteroids.267, 268, 270
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.188, 270 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.188 If compliance cannot be ensured, a fixed-combination preparation containing both an inhaled corticosteroid and a long-acting β2-adrenergic agonist is recommended.188
Salmeterol also is used for the prevention of exercise-induced bronchospasm.12, 21, 91, 105, 172, 188, 263 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.188 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.188
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.1, 182, 183, 188, 238, 239 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.267 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.267
Salmeterol alone or in fixed combination with fluticasone propionate is not indicated for the relief of acute bronchospasm.154, 257, 267, 268, 269, 270 A short-acting inhaled β2-adrenergic agonist should be used intermittently (as needed) for acute symptoms of asthma or COPD.134, 222, 238, 239, 263, 264
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)263 and also by response to treatment (i.e., asthma control).222, 263 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.222, 263 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.222, 263 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).263 These 2 components of asthma control (i.e., current impairment and future risk) may respond differently to treatment.263
The National Asthma Education and Prevention Program (NAEPP) classifies the levels of asthma control as well controlled, not well controlled, or very poorly controlled.263 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.222, 263 Stepwise therapy is meant to assist, not replace, the clinical decision-making process in selecting therapy for individual patients.263 Once initiated, treatment is adjusted continuously according to changes in asthma control.263 Patients should be monitored every 2-6 weeks following initiation of therapy to ensure that asthma control is achieved.263 If asthma symptoms are not controlled with the current treatment regimen, treatment is stepped up until control is achieved.263 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.263 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.263 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.263
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).222, 263 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).42, 134, 214, 222 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.222, 263 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.222 Oral β2-adrenergic agonist therapy is suggested for use principally in patients unable to use inhaled bronchodilators (e.g., young children).222 Other experts do not recommend oral β2-agonists for relief of acute asthma symptoms.263 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.222, 263
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.1, 2, 40, 42, 78, 81, 106, 134, 144, 156, 188, 214, 222 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.222, 263 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.263 Low-dose inhaled corticosteroids also are recommended as the preferred initial therapy in such children.222, 263 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.263 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.222
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.222, 263 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.263 (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).222, 263 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).222, 263
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.222, 263 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.222, 263 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.263 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).222, 263 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).263
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).222, 263 Such recommendations in children 5-11 years of age are based on expert opinion and extrapolation from studies in adolescents and adults.263 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.222, 263 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.263 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.263 Recommendations for care of infants and children with severe asthma are based on expert opinion and extrapolation from studies in older children.263
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.222, 263 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.263
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.263 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.263 However, other experts do not consider regular use of oral corticosteroid therapy to be appropriate therapy in children with severely uncontrolled asthma.222 (See Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.)
When asthma symptoms at any stage are not controlled with maintenance therapy (e.g., inhaled corticosteroids) plus supplemental short-acting inhaled β2-agonist bronchodilator therapy as needed (e.g., if there is a need to increase the dose or frequency of administration of the short-acting sympathomimetic agent), prompt reevaluation is required to adjust dosage of the maintenance regimen or institute an alternative maintenance regimen.1, 8, 61, 113, 134, 156, 214, 222 For additional details on the stepped-care approach to drug therapy in asthma, see Asthma under Uses: Bronchospasm, in Albuterol 12:12.08.12 and see also Asthma under Uses: Respiratory Diseases, in the Corticosteroids General Statement 68:04.
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.188 However, for the treatment of asthma, salmeterol currently is indicated only as concomitant therapy with long-term asthma controller therapy, such as inhaled corticosteroids.188 (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).188 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).1, 154, 257 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.244 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.245 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.25, 49, 50, 90, 94, 99, 104, 106
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).7, 188, 193, 194 However, the manufacturer states that clinical equivalence of salmeterol oral inhalation powder and oral inhalation aerosol should not be assumed in all patient populations.188 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).154, 188, 194
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,20, 46, 78, 141 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.10 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.1, 10, 16, 17, 43, 58, 102, 162
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.10, 13, 16, 17, 25, 52, 102, 214 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.1, 10, 16, 17, 49, 52, 90, 94, 99, 102, 106, 171, 244, 245 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.244
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.148, 155, 159, 188, 221, 222 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.180, 181
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).148, 159, 181, 188
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).188 In addition, fewer patients receiving combined therapy experienced asthma exacerbations in these trials.188
In several randomized, double-blind, placebo-controlled clinical trials in patients with mild to severe asthma,221, 229, 230, 231 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 alone1, 229, 230, 231 and similar efficacy as concurrent therapy with both agents given separately.1, 221, 231 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.134, 257, 259, 260, 261 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.134, 257
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).1, 2, 3, 5, 8, 25, 42, 61, 63, 72, 114, 135, 154, 156, 188, 214, 267, 268, 269 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.1, 8, 13, 61, 63, 89, 188, 267, 268, 269 (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.2, 19, 42, 108, 135, 156, 188, 253, 267, 268, 269 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.188, 267, 268, 269 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.222, 263 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.1, 8, 113, 156, 188, 222 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.267, 268, 269 Patients should not increase the frequency of administration of the fixed combination.267, 268, 269 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.188, 254, 258, 267, 268, 269 (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).60, 64, 143, 167, 168, 170 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.44, 60, 64, 137 However, the design and interpretation of these study findings suggesting increased morbidity and mortality have been criticized,70, 71, 110, 135 and reanalysis of these data158 demonstrated that the differences between treatment periods were small and unlikely to be clinically important.135, 167, 168 Data from case-control studies have been conflicting and have not demonstrated a causal relationship between inhaled β2-agonist therapy and asthma mortality.61, 136, 143, 150, 168, 169, 170 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.136, 150, 167, 168 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,16, 17, 143, 150, 215, 263 such use does not appear to have demonstrable advantages compared with intermittent use16, 143, 214, 215 and does not adequately control asthmatic symptoms.263 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.222, 263
Monotherapy with long-acting β2-adrenergic agonists, such as salmeterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.266, 267, 268, 269, 270 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.1, 221, 226, 227, 241, 242, 270 (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects and see Uses: Bronchospasm.)
Salmeterol is used for the prevention of exercise-induced bronchospasm.1, 12, 21, 91, 105, 172, 188, 214, 222 However, most experts consider short-acting inhaled β2-adrenergic agonists to be drugs of choice for prevention of exercise-induced bronchospasm.214, 222 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.188 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.188 Experts from the NAEPP state that frequent or chronic use of a long-acting inhaled β2-agonist for exercise-induced bronchospasm should be discouraged.263 Such use may disguise poorly controlled persistent asthma, which should be managed with daily anti-inflammatory therapy.214
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.188 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.188 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 patients1, 105, 191 or a decreased duration of such protection.212, 213, 263
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.1, 182, 183, 188, 223, 224, 225 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.267 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.267 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;1 a drug with a shorter onset of action (e.g., a short-acting β2-adrenergic agonist) may be preferred in such cases.185, 224, 225
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.185, 197, 209, 223, 240 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)238, 240 can be added and a short-acting, selective inhaled β2-agonist used as needed for immediate symptom relief.237, 238, 239, 240 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.237, 238, 239, 240
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.237, 240, 262 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-agonist237, 239 (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).185, 202, 203, 237, 238, 239, 262 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.239, 240
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.238, 239, 240 A short-acting bronchodilator may be used as needed for relief of acute symptoms that occur despite regular use of long-acting bronchodilators.238, 240 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.238, 239, 240 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.237, 239, 240 For additional details on the stepped-care approach for drug therapy in COPD, see Chronic Obstructive Pulmonary Disease under Uses: Bronchospasm, in Ipratropium Bromide 12:08.08.
Orally inhaled salmeterol therapy in patients with COPD generally has produced increases in peak FEV1 averaging 7-20%.1, 182, 188 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.188
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.233, 234, 235 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.233, 234, 235 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.236
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.221, 232 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.221 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.221 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.221 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.221 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.221
Salmeterol xinafoate is administered by oral inhalation using a special preloaded oral inhaler (Serevent® or Advair® Diskus®, or AirDuo® RespiClick®) that delivers powdered drug alone or in fixed combination with fluticasone propionate.188, 189, 267, 269 The manufacturer of the Diskus® devices states that spacer devices should not be used with Serevent® or Advair® Diskus®.253, 254, 267, 270 The manufacturer of the RespiClick® device states that spacers or volume holding chambers should not be used with AirDuo® RespiClick®.269
Salmeterol/fluticasone propionate inhalation aerosol (Advair® HFA) should only be used with the actuator supplied with the product.258 Before each inhalation, the inhaler must be shaken well for 5 seconds.257, 258 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.257, 258 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.257, 258
The cap covering the mouthpiece should be slipped off the mouthpiece; the strap on the cap will stay attached to the mouthpiece.258 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.258 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.258 Then the patient should inhale deeply through the mouth while actuating the inhaler.258 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.258 It is recommended that 30 seconds elapse between inhalations.258 Rinsing the mouth after inhalation of salmeterol/fluticasone propionate inhalation aerosol and spitting out the water are advised.257, 258 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.257, 258 The actuator should be allowed to air-dry overnight.258 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.257 The inhaler should be discarded when the dose counter reads “000.”257 The counter should never be altered or removed from the canister.257
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.189, 253, 254, 255 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.189, 253, 254, 255 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.189, 253, 254 A dose counter will advance each time the lever is depressed.189, 253, 254, 255 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.189, 190, 253, 254, 255, 267 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.188, 189, 190, 253, 254, 255 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.189, 253, 254, 255 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.253, 254 Rinsing the mouth after inhalation of salmeterol in fixed combination with fluticasone propionate is advised.254, 255, 267 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.189, 253, 254, 255 The inhaler should not be washed but should be stored in a dry place away from direct heat or sunlight.188, 189, 253, 254, 255 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.188, 190, 253, 254 The inhaler should not be taken apart.188, 190, 253, 254, 255, 267
For instructions on use of the AirDuo® RespiClick® oral inhaler, the manufacturer's labeling should be consulted.269
To obtain optimal benefit, the patient should be given a copy of the product-specific patient instructions and medication guide provided by the manufacturer.253, 254, 258, 267, 268, 269, 270 (See Asthma-related Death and Life-threatening Events under Cautions: Respiratory Effects.)
Dosage of salmeterol xinafoate is expressed in terms of salmeterol.1 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.188 (See Chemistry and Stability: Chemistry.)
Each blister of the 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.267 (See Chemistry and Stability: Chemistry.)
Each actuation of the AirDuo® RespiClick® device contains 14 mcg of salmeterol as salmeterol xinafoate and 55, 113, or 232 mcg of fluticasone propionate; however, the precise amount of each drug delivered to the lungs with each actuation of the RespiClick® device depends on factors such as the patient's inspiratory flow.269
Each actuation of the oral aerosol inhaler of the fixed combination of salmeterol and fluticasone propionate (Advair® HFA) delivers 50, 125, or 250 mcg of fluticasone propionate and 25 mcg of salmeterol from the valve.268 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.268 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.268
The manufacturer states that adjustment of salmeterol dosage alone or in fixed combination with fluticasone propionate is not necessary in geriatric patients.1, 257, 267, 270
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.270 If a dose of salmeterol is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.253 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;1, 23, 25 however, such dosages are more likely to be associated with adverse effects,1, 15, 23, 37 and the manufacturer states that patients should not use more than 50 mcg (1 inhalation) twice daily of salmeterol.270 Patients receiving salmeterol should not use additional long-acting β2-adrenergic agonists for any reason.270
Patients should contact a clinician if asthma symptoms do not improve after 1 week of therapy.253, 267, 268, 269, 270 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.111, 112, 267, 268, 269, 270 If symptoms arise in the period between doses, a short-acting, inhaled β2-agonist should be used for immediate relief.267, 268, 269, 270 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.270 Extra/increased doses of salmeterol should not be used in such situations.1, 156, 253, 270 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.267, 268, 269, 270 Patients should adhere to dosing schedules, including not altering the dose or frequency of use of salmeterol unless otherwise instructed by a clinician.188, 253 (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.1, 2, 5, 16, 20, 40, 42, 43, 45, 61, 62, 63, 72, 85, 97, 270 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.270 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.270 Patients also should be advised not to discontinue salmeterol without medical supervision because symptoms may recur after treatment discontinuance.270 (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.267
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 and current asthma therapy, including the dosage of inhaled corticosteroids, as well as the patient's current control of asthma symptoms and risk of future exacerbations.267 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.265, 267 The maximum recommended dosage of salmeterol in fixed combination is 50 mcg of salmeterol with 500 mcg of fluticasone propionate twice daily.267 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.267
When the fixed combination of salmeterol and fluticasone propionate is administered via the AirDuo® RespiClick® device in asthmatic patients 12 years of age or older, the recommended initial dosage is based on the patient's current asthma therapy and asthma severity.269 For patients with asthma not previously receiving inhaled corticosteroid therapy, the usual recommended initial dosage is 14 mcg of salmeterol and 55 mcg of fluticasone propionate (1 inhalation) twice daily, given approximately 12 hours apart at approximately the same time every day.269 For patients with asthma switching from another inhaled corticosteroid or fixed-combination therapy, the dosage strength should be selected based on the dosage strength of the previously inhaled corticosteroid alone or in combination as well as disease severity.269 For patients who do not respond to AirDuo® RespiClick® containing 14 mcg of salmeterol and 55 mcg of fluticasone propionate after 2 weeks of therapy, increasing the dosage may provide additional asthma control.269 If the dosage regimen does not provide adequate control of asthma, the regimen should be reevaluated and additional therapeutic options (e.g., replacing the current strength of the fixed combination with a higher strength [higher strengths contain higher dosages of fluticasone propionate only], using additional asthma controller therapy) should be considered.269 The maximum recommended dosage of salmeterol in fixed combination with fluticasone is 14 mcg of salmeterol and 232 mcg of fluticasone propionate twice daily.269 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.269
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, including the dosage of inhaled corticosteroids, as well as the patient's current control of asthma symptoms and risk of future exacerbations.268 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.258, 265, 268 The maximum recommended dosage of salmeterol is 42 mcg in fixed combination with 460 mcg of fluticasone propionate (2 inhalations) twice daily.268 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.268
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.267, 268, 269 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.254, 258, 267, 268, 269 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.254, 258, 267, 268, 269 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.258, 267, 268, 269 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).267, 268, 269 (See Cautions: Precautions and Contraindications.)
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.270 Additional doses of salmeterol should not be used for 12 hours. 270 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.270 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.267, 268, 269, 270
Chronic Obstructive Pulmonary Disease
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.188, 270 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.188 Patients should not discontinue salmeterol without medical supervision because symptoms may recur after treatment discontinuance.188, 253
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.267 If shortness of breath occurs between doses, an inhaled, short-acting β2-adrenergic agonist may be administered for immediate relief.267 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.267 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, indacaterol) for any reason, including the treatment of COPD.267 Patients should not discontinue salmeterol in fixed combination with fluticasone propionate without medical supervision because symptoms may recur.254, 267
Dosage in Renal and/or Hepatic Impairment
The pharmacokinetics of salmeterol or salmeterol in fixed combination with fluticasone have not been studied in patients with hepatic impairment.188, 267, 268, 269 Since salmeterol and fluticasone propionate are cleared predominantly by hepatic metabolism, impaired liver function theoretically may lead to accumulation of the drugs in plasma.188, 267, 268, 269 Therefore, the manufacturers recommend that patients with hepatic disease be monitored closely while receiving salmeterol therapy.188, 267, 268, 269
The pharmacokinetics of salmeterol in fixed combination with fluticasone have not been studied in patients with renal impairment.267, 268, 269 Therefore, there are no specific dosage recommendations for such patients.267, 268, 269
Salmeterol xinafoate oral inhalation appears to be well tolerated when administered in recommended doses.25, 49, 50, 77, 81, 104, 114, 154, 156 However, monotherapy with long-acting β2-adrenergic agonists, such as salmeterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.266, 267, 268, 269, 270 (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.1, 2, 16, 17, 25, 52, 56, 81, 102, 107, 111, 114, 188 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.188 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.188 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).188 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.188 For adverse effects reported with salmeterol therapy in the Cautions section, a causal relationship to the drug has not always been established.1, 154, 188
Usual doses of salmeterol oral inhalation generally produce no apparent cardiovascular effects.1, 15, 16, 17, 52, 102, 154, 156 However, salmeterol may produce a clinically important cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or cardiovascular symptoms.188 Although such effects are uncommon after administration of salmeterol at recommended dosages, if they occur, discontinuance of the drug may be needed.13, 188, 210 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.188 Hypertension was reported in 4% of patients with COPD receiving salmeterol inhalation powder during clinical trials and also has been reported during postmarketing surveillance.188 Supraventricular tachycardia or atrial fibrillation has been reported with salmeterol inhalation powder during postmarketing surveillance.188 Pallor has been reported in 9% of adults and adolescents with asthma receiving salmeterol inhalation powder in clinical trials.188
Nonsustained ventricular tachycardia among patients with COPD receiving salmeterol inhalation powder was reported in an incidence similar to that with placebo and fluticasone propionate.221 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.188, 221 ECG changes, including extrasystoles (supraventricular and ventricular premature complexes), also have been noted with salmeterol inhalation powder.17, 187, 188 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.19, 33, 37, 188 Fatalities also have been reported in association with excessive use of inhaled sympathomimetic drugs.188 (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.210 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.110, 115, 116, 117, 118, 120, 154
In clinical trials with salmeterol inhalation powder, headache188 was reported in 14% of patients with COPD,188 13% of adults and adolescents with asthma,188 and 17% of children with asthma.188 Migraine has been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 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.188 Dizziness has been reported in 4% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 Unrest,14 depression,17 anxiety,152 and vertigo138 also have been reported rarely156 with salmeterol oral inhalation therapy. Anxiety has been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188
Asthma-related Death and Life-threatening Events
Monotherapy with long-acting β2-adrenergic agonists, such as salmeterol, increases the risk of asthma-related death.188, 248, 266, 267, 268, 269, 270 In addition, available data from controlled clinical trials suggest that monotherapy with long-acting β2-adrenergic agonists increases the risk of asthma-related hospitalization in pediatric and adolescent patients.248, 267, 268, 269, 270 Because of these risks, the use of long-acting 2-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 .248, 270 (See Cautions: Precautions and Contraindications.) However, FDA has concluded that there is no clinically important increased risk of serious asthma-related events, including hospitalization, intubation, or death, associated with concomitant use of long-acting β2-adrenergic agonists (e.g., salmeterol) and inhaled corticosteroids compared with inhaled corticosteroids alone based on the results of several large clinical studies.266, 267, 268, 269, 271, 272 In addition, these studies showed that combination therapy with long-acting β2-adrenergic agonists and inhaled corticosteroids was more effective in reducing the incidence of asthma exacerbations (i.e., events requiring use of systemic corticosteroids for at least 3 outpatient days or an asthma-related hospitalization or emergency department visit requiring use of systemic corticosteroids) compared with use of inhaled corticosteroids alone.266, 271, 272
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.248, 267, 268, 269, 270 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 warrants initiation of treatment with both an inhaled corticosteroid and a long-acting β2-adrenergic agonist.267, 268, 269 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.221, 248, 257, 270 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 a low or medium dosage of inhaled corticosteroids.248, 267, 268, 270 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.248, 270 (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.1, 226, 227, 267, 268, 269, 270 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.1, 226, 241, 242, 267, 268, 269, 270 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).226 Secondary end points included asthma-related deaths and combined asthma-related deaths or life-threatening experiences.241, 242 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.242 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.242, 267, 268, 269, 270 Results of a post hoc analysis also revealed a greater risk for asthma-related death (relative risk: 7.26) with salmeterol therapy in African-American patients (18% of study patients)270 and in patients not receiving concomitant inhaled corticosteroid therapy (53% of study patients) compared with placebo.226, 227, 246 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.221, 270 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).226 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).221, 257, 270 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.246, 267, 268, 269, 270
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).1, 188, 221
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.270
In 4 randomized, double-blind, active-controlled clinical trials mandated by FDA, the risk of serious asthma-related events from use of inhaled corticosteroids alone compared with combined use of long-acting β2-adrenergic agonists and inhaled corticosteroids was evaluated over 26 weeks in 41,297 patients with asthma (3 trials in adults and adolescents 12 years of age or older and one trial in children 4-11 years of age).266, 267, 268, 269, 271, 272 The primary safety end point in all of these trials was serious asthma-related events, including hospitalization, intubation, and death; these events were reviewed by a blinded committee to determine if the events were asthma related.266, 267, 268, 269, 271, 272 The 3 trials performed in adults and adolescents were designed to rule out a hazard ratio of 2, and the pediatric trial was designed to rule out a hazard ratio of 2.7; this objective was met in all 4 individual trials.266, 267, 268, 269, 271 The trials were not designed to rule out all risk for serious asthma-related events associated with long-acting β2-adrenergic agonists in combination with inhaled corticosteroids compared with inhaled corticosteroids alone.266, 267, 268, 269
The safety studies in adults and adolescents included one trial comparing salmeterol and fluticasone propionate in fixed combination as the inhalation powder (Advair® Diskus®) with fluticasone propionate inhalation powder alone, one trial comparing formoterol and mometasone furoate in fixed combination with mometasone furoate alone, and one trial comparing formoterol and budesonide in fixed combination with budesonide alone.266, 267, 268, 269, 271, 272 In a meta-analysis combining data from these 3 trials, a hazard ratio of 1.1 for serious asthma-related events in patients receiving fixed-combination therapy with long-acting β2-adrenergic agonists and inhaled corticosteroids compared with patients receiving inhaled corticosteroids alone was reported.266, 268, 269, 271 Subgroup analyses for gender, adolescents 12-17 years of age, Asian and African-American patients, and obese patients also showed no substantial increase in the risk of serious asthma-related events or asthma exacerbations in these populations.266, 271
The trial comparing salmeterol and fluticasone propionate in fixed combination as the inhalation powder (Advair® Diskus) with fluticasone propionate inhalation powder alone included 11,679 adults and adolescents 12 years of age or older with moderate to severe persistent asthma who had a history of asthma-related hospitalization or at least one asthma exacerbation in the previous year requiring treatment with systemic corticosteroids.267, 272 Patients with a history of life-threatening or unstable asthma were excluded from the study.267, 272 In this trial, serious asthma-related events were reported in 0.6% of patients in each treatment group, with a hazard ratio for first event for the combination therapy compared with fluticasone alone of approximately 1.267, 271, 272
The safety study in children 4-11 years of age included 6208 patients who were randomized to receive salmeterol and fluticasone propionate in fixed combination as the inhalation powder (Advair® Diskus) or fluticasone propionate inhalation powder alone.266, 267, 268, 269 Patients had a diagnosis of asthma and a history of at least one asthma exacerbation in the previous year requiring treatment with systemic corticosteroids; patients with life-threatening asthma were excluded from the study.267 Serious asthma-related events were reported in 0.9% of patients receiving salmeterol and fluticasone in fixed combination and in 0.7% of patients receiving fluticasone alone, with an estimated hazard ratio for first event of 1.29 for the combination therapy compared with fluticasone alone.266, 267, 268, 269 No asthma-related deaths or intubations were reported in either group of pediatric patients.266, 267, 268, 269
Cough was reported in 5% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 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.188 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.188, 190 Tracheitis/bronchitis or influenza occurred in 7 or 5%, respectively, of adults and adolescents receiving salmeterol inhalation powder.188 Nasal/sinus congestion or rhinitis occurred in 9 or 5%, respectively, of adults and adolescents with asthma receiving salmeterol inhalation powder.188 Nasal congestion or blockage, rhinitis, or sinusitis occurred in 4% of patients with COPD receiving salmeterol inhalation powder in clinical trials.188 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.188 However, throat irritation has been reported in 7% of patients with COPD receiving salmeterol inhalation powder in controlled clinical trials.188 Pharyngitis was reported in 6% of children with asthma receiving salmeterol inhalation powder in clinical trials.188 Lower respiratory tract signs and symptoms occurred in greater than 1% of children with asthma receiving salmeterol inhalation powder.188 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.188
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.188 As with other inhaled drugs, paradoxical bronchospasm, a potentially life-threatening event, also has occurred with salmeterol therapy.56, 188 (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.60, 61, 63, 65, 66, 69, 89, 136, 137, 141, 142, 188 Such detrimental effects may be related to down-regulation of β-adrenergic receptors (tolerance),136, 144 increased responsiveness of airways to allergens and exercise,137, 145, 263 genetic changes in β2-agonist receptor gene,263 or increased airway accessibility to inhaled allergens, which may lead to increased airway inflammation and reactivity and worsening of asthma symptoms.2, 44, 142, 263 However, increased airway accessibility to inhaled allergens theoretically also would occur with long-acting bronchodilators such as extended-release theophylline.168
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.188 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.188 Nausea and vomiting have been reported in 3% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 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.188
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.111, 119, 188
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.25, 154, 188 No clinically important changes in glucose or potassium concentrations were reported in clinical studies in patients with asthma receiving salmeterol oral inhalation powder.188 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.188 Patients should inform their clinician of the presence of diabetes mellitus prior to initiation of therapy.253, 254 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.2, 42, 43, 188 Although such reductions potentially may cause adverse cardiovascular effects, the decreases usually are transient and supplemental potassium therapy generally is not required.188 Hyperglycemia occurred in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 The potential for hyperglycemia or hypokalemia with salmeterol therapy appears to be dose related.2, 15, 19, 25, 33, 37, 188 Tolerance to the hypokalemic effects of albuterol has been demonstrated but has not been reported to date with salmeterol therapy.2, 33, 44
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.188 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.188 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.188
Dermatologic and Sensitivity Reactions
Immediate hypersensitivity reactions, including urticaria, angioedema, rash, and bronchospasm may occur following administration of salmeterol alone or salmeterol and fluticasone propionate in fixed combination.267, 268, 269, 270 Anaphylactic reactions have been reported very rarely in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not receive such products containing salmeterol or salmeterol and fluticasone in fixed combination.188, 267, 269 (See Cautions: Precautions and Contraindications.) Anaphylaxis also has been reported during postmarketing surveillance studies with the drug.267, 269, 270
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.188 Rash, photodermatitis, or urticaria was reported in 4, greater than 1, or 3%, respectively, of children receiving salmeterol inhalation powder in clinical trials.188 Rash was reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188
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).56, 59, 153, 156 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.114
Dental discomfort and pain have been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 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.188 Otic manifestations have been reported in 3% of patients with COPD receiving salmeterol inhalation powder in clinical trials.188 Edema and swelling have been reported in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 Keratitis and conjunctivitis occurred in at least 1% of patients receiving salmeterol inhalation powder for the treatment of COPD.188 Pain also has been reported in at least 1% of such patients.188 Herniated disk has been reported in at least one patient receiving inhaled salmeterol, but a causal relationship to the drug has not been established.17 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.43 Elevation of hepatic enzymes was reported in at least 1% of patients with asthma receiving salmeterol oral inhalation powder in clinical studies.188 However, these elevations were transient and did not lead to discontinuance from the studies.188
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.267, 268, 269
Patients should be advised to read the product-specific medication guide, patient information, and/or instructions for use prior to initiating therapy with the drug and each time the prescription is refilled.253, 254, 258, 267, 268, 269, 270
Patients should be informed that monotherapy with long-acting β2-adrenergic agonists, such as salmeterol, increases the risk of asthma-related death and may increase the risk of asthma-related hospitalization in pediatric and adolescent patients.266, 267, 268, 269, 270 (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.267, 268, 269, 270 Patients should be advised that when salmeterol is added to their treatment regimen they must continue to use their long-term asthma controller drugs.270 (See Uses: Bronchospasm.)
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.267, 268, 269, 270 Salmeterol alone or in fixed combination has not been studied in patients with acutely deteriorating asthma or COPD.267, 268, 269, 270 Initiation of salmeterol in this setting is not appropriate.267, 268, 269, 270 Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with substantially worsening or acutely deteriorating asthma.267, 268, 269, 270 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).61, 63, 89, 267, 268, 269, 270 However, such events also have occurred in patients with less severe asthma.1, 267, 268, 269, 270 It was not possible from these reports to determine whether salmeterol contributed to these events.267, 268, 269, 270
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.154, 222, 267, 268, 269, 270 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.267, 268, 269, 270 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.267, 268, 269 However, extra/increased doses of salmeterol alone or in fixed combination with fluticasone propionate should not be used in such situations.1, 8, 113, 267, 268, 269, 270 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.267, 268, 269, 270 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.267, 268, 269, 270
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).1, 2, 42, 61, 267, 268, 269, 270 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.267, 268, 269, 270 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.97, 267, 268, 269, 270 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.267, 268, 269, 270
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.2, 5, 16, 20, 40, 42, 43, 45, 61, 62, 63, 72, 85, 97, 270 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.270 The manufacturer states that there are no data demonstrating that salmeterol has a clinical anti-inflammatory effect such as that associated with corticosteroids.188 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;188 any change in corticosteroid dosage should be made only after clinical evaluation.188 Salmeterol in fixed combination with fluticasone as the inhalation aerosol (Advair® HFA) should not be used to transfer patients from systemic corticosteroid therapy.257 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.267, 268, 269 (See Cautions: Precautions and Contraindications, in Beclomethasone Dipropionate 68:04.)
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.267, 268, 269, 270 Clinically important cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.64, 81, 110, 111, 112, 115, 119, 270 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, indacaterol) for any reason, including prevention of exercise-induced bronchospasm or treatment of asthma or COPD.267, 268, 269, 270
Rarely, a patient may develop acute bronchospasm immediately upon inhalation of a sympathomimetic drug preparation.56, 59, 111, 112, 116, 153, 154, 156, 188 Acute bronchospasm probably represents a hypersensitivity reaction to the active drug57 or an ingredient in the formulation.17, 20, 56, 59, 114 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.1, 153, 156, 267, 268, 269, 270 Paradoxical bronchospasm should immediately be treated with a short-acting inhaled bronchodilator, and alternative therapy should be instituted.267, 268, 269, 270 Patients should inform their clinicians of allergic reactions to salmeterol-containing preparations, other agents, or foods (including milk proteins).253, 254, 258, 267, 268, 269, 270
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.111, 119, 187, 188 (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).267, 268, 269, 270 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.1, 187, 210, 267, 268, 269, 270 Patients should be informed of adverse effects associated with β2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.154, 156, 267, 268, 269, 270 Patients should inform their clinician of heart problems, hypertension, seizures, thyroid disorders, or diabetes mellitus prior to initiation of salmeterol-containing therapy.253, 254, 258 Patients receiving salmeterol oral inhalation should use other inhaled medications only as directed by their clinician.1
The pharmacokinetics of salmeterol or salmeterol in fixed combination with fluticasone propionate have not been studied in patients with hepatic impairment.267, 268, 269, 270 Because salmeterol and fluticasone propionate are 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 such therapy.267, 268, 269, 270 Patients should inform their clinician of liver dysfunction prior to initiation of therapy.253, 254, 258
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.267 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.267, 268
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 .270 (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®, AirDuo® RespiClick®) is contraindicated in patients with severe hypersensitivity to milk proteins.267, 269, 270 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.268 Patients should inform their clinician of allergies to drugs or food prior to initiation of therapy.253, 254 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.267, 268, 269, 270
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.270 However, monotherapy with long-acting β2-adrenergic agonists, such as salmeterol, increases the risk of asthma-related death.267, 268, 269, 270 In addition, available data from controlled clinical trials suggest that monotherapy with long-acting β2-adrenergic agonists increases the risk of asthma-related hospitalization in pediatric and adolescent patients.267, 268, 269, 270 (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.270 (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.270 Pediatric patients should receive salmeterol therapy under adult supervision.253 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.243, 267 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.243, 267
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.267 Safety and efficacy of salmeterol in fixed combination with fluticasone propionate inhalation powder (AirDuo® RespiClick®) in children younger than 12 years of age have not been established.269 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.268 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.268
Data from trials in patients with COPD receiving salmeterol inhalation powder suggested a greater effect on FEV1 in younger adults compared with geriatric patients.270 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.1, 77, 82, 92, 257, 270 No overall differences in safety or efficacy were observed in geriatric patients receiving salmeterol in fixed combination with fluticasone propionate inhalation powder (AirDuo® RespiClick®) compared with younger adults.269 Clinical studies of salmeterol in fixed combination with fluticasone inhalation powder (Advair® Diskus®) or inhalation aerosol (Advair® HFA) 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.267, 268 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.267 The possibility of greater sensitivity of some older patients cannot be ruled out.257 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.188, 267, 268 (See Cautions: Precautions and Contraindications.) Adjustment of salmeterol dosage alone or in combination with fluticasone propionate in geriatric patients solely on the basis of age is not necessary.1, 154, 156, 257, 267, 270
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.1, 188 In an in vivo rat micronucleus assay, salmeterol did not exhibit evidence of mutagenicity.1, 188
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.188 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/m2 basis).154, 188 The findings of these studies in rodents are similar to those reported previously for other β-adrenergic agonist drugs;1, 111, 112, 188 the relevance of these findings to human use is unknown.1, 188 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/m2 basis).154, 188
Pregnancy, Fertility, and Lactation
There are no adequate and well-controlled studies of salmeterol in pregnant women.1, 267, 268, 269, 270 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.1, 188, 268 The drug should be used during other stages of pregnancy only if the potential benefit justifies the potential risk to the fetus.1, 270 Salmeterol in fixed combination with fluticasone propionate inhalation aerosol (Advair® HFA) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.268 In pregnant women with poorly or moderately controlled asthma, there is an increased risk of adverse perinatal events such as preeclampsia in the mother, and prematurity, low birth weight, and small size for gestational age in the neonate.267, 269 Pregnant women with asthma should be closely monitored and dosage of medications should be adjusted as needed to maintain optimal asthma control.267, 269
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/m2 basis) have not revealed evidence of harm to the fetus.1, 154, 188, 221 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.154, 188 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).188 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/m2 basis).188 Extensive use of other β-agonists has provided no evidence that these class effects in animals are relevant to use in humans.1
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.221 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/m2 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/m2 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/m2 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/m2 basis).221 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/m2 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/m2 basis) did not reveal evidence of teratogenicity.221 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/m2 basis) combined with oral salmeterol dosages of 10 mg/kg (approximately 810 times the maximum recommended daily inhalation dosage in adults on a mg/m2 basis).221
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/m2 basis) have not revealed evidence of impaired fertility.188, 221
It is not known whether salmeterol xinafoate or fluticasone propionate is distributed into human milk.253, 267, 268, 269 However, salmeterol is distributed into milk in rats.38, 267, 268, 269, 270 Corticosteroids, other than fluticasone propionate, are distributed into human milk.267, 268, 269 Effects of salmeterol xinafoate or fluticasone propionate on breast-fed infants or milk production also are not known.267, 269 The benefits of breast-feeding and the woman's clinical need for salmeterol xinafoate or fluticasone propionate should be considered along with any potential adverse effects on the breast-fed infant from the drugs or from the underlying maternal condition.267, 269 Since no data from controlled trials are available on the use of such preparations in nursing women, caution is advised if salmeterol alone or salmeterol in fixed combination with fluticasone propionate is administered in nursing women.268, 270
The following information addresses potential interactions with salmeterol.188 When salmeterol is used in fixed combination with fluticasone propionate, interactions associated with fluticasone propionate should be considered.267, 268, 269 No formal drug interaction studies have been performed to date with the fixed-combination preparations containing salmeterol and fluticasone propionate.267, 268, 269
Monoamine Oxidase Inhibitors and Tricyclic Antidepressants
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.267, 268, 269, 270
Drugs Affecting Hepatic Microsomal Enzymes
Salmeterol and fluticasone propionate are substrates for cytochrome P-450 (CYP) isoenzyme 3A4.267, 268, 269, 270 The manufacturers state 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).267, 268, 269, 270
Supplemental Short-Acting 2-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.188 In patients receiving salmeterol inhalation powder, 26% required 8-24 inhalations daily of a supplemental, short-acting β2-agonist on at least one occasion.188 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.188 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.188 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.1, 188 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.188
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.188, 221 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.188, 221
In clinical studies, inhaled cromolyn sodium did not alter the safety profile of salmeterol oral inhalation when these drugs were administered concurrently.16, 17, 25, 45, 52, 102, 188
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).1, 123, 124 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.1, 121, 122, 123, 124 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.1, 154 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.188, 221
Beta-Adrenergic Blocking Agents
β-Adrenergic blocking agents not only block the pulmonary effects of β-adrenergic agonists (e.g., salmeterol), but also may produce severe bronchospasm in patients with asthma or COPD.154, 156, 267, 268, 269, 270 Patients with asthma or COPD usually should not be treated with β-adrenergic blocking agents.267, 268, 269, 270 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.267, 268, 269, 270
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).1, 267, 268, 269, 270 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.1, 267, 268, 269, 270 Although the clinical importance of these effects is not known, caution is advised when administering salmeterol with non-potassium-sparing diuretics.267, 268, 269, 270
Rats and dogs survived inhalation doses of 2.9 and 0.7 mg/kg of salmeterol, respectively, representing approximately 240 or 190 times the maximum daily adult inhalation powder dosage, and 110 or 90 times the maximum daily pediatric inhalation powder dosage, respectively, on a mg/m2 basis.1, 188, 221 No deaths occurred in mice and rats given oral salmeterol doses of 150 and 1000 mg/kg, respectively, representing 6100 or 81,000 times the maximum recommended human daily inhalation powder dosage in adults, and 2900 or 38,000 times the maximum recommended daily pediatric inhalation powder dosage, respectively, on a mg/m2 basis.1, 188
In humans, single orally inhaled doses as high as 400 mcg have been studied and appeared to be relatively safe in short-term use.2, 37 However, in a dose-response study in healthy men, single orally inhaled 400-mcg doses of salmeterol were associated with tremor, headache, increases in heart rate and blood glucose, and decreases in plasma potassium concentrations.37 Nonspecific T-wave changes and prolonged QT interval also were observed at this dose; patients receiving lower doses did not display ECG changes.37
The expected signs and symptoms associated with overdosage of orally inhaled salmeterol xinafoate are those of excessive β-adrenergic stimulation and/or occurrence or exaggeration of any of the following: tachycardia (with rates up to 200 beats/minute) and/or arrhythmia, nervousness, palpitation, nausea, dizziness, fatigue, malaise, seizures, angina, hypertension or hypotension, insomnia, dry mouth, tremor, headache, hypokalemia, hyperglycemia, and muscle cramps.188 Large IV doses of albuterol (dosage form currently not commercially available in the US) have been reported to exacerbate preexisting diabetes mellitus and ketoacidosis; the potential for salmeterol to cause such effects has not been determined.1 Large oral or inhaled doses of salmeterol (12-20 times the recommended dosage) have produced clinically important prolongation of the QTc interval, which increases the risk for ventricular arrhythmias.37, 188 Cardiac arrest and fatalities have occurred following excessive use of sympathomimetic pressurized aerosol medications, and may occur with overuse of salmeterol.1, 154, 188 However, cardiorespiratory arrest has been reported in at least one patient with chronic obstructive pulmonary disease (COPD) and pre-existing alcoholic cardiomyopathy receiving the recommended dosage of inhaled salmeterol in conjunction with usual dosages of ipratropium and albuterol.210 No cases of overdosage of salmeterol were reported during controlled studies with the orally inhaled drug.114 The safety of concomitant therapy with salmeterol and more than 8 inhalations per day of a short-acting β2-agonist has not been established.1
The manufacturer suggests that in case of salmeterol overdosage, therapy with salmeterol and all other β-adrenergic agonists be discontinued and appropriate symptomatic therapy initiated.1, 114, 188 The judicious use of a β-adrenergic blocking agent may be considered but only with extreme caution in asthmatic patients because such agents may induce an asthmatic attack.1, 154, 156, 188 (See Drug Interactions: β-Adrenergic Blocking Agents.) Cardiac monitoring is recommended in cases of overdosage with salmeterol.1, 114, 188 The manufacturer states that there is insufficient evidence to determine if dialysis is effective for the treatment of salmeterol overdosage.1, 154, 188
Salmeterol xinafoate has pharmacologic actions similar to those of other selective β2-adrenergic receptor agonists (e.g., albuterol).1, 2, 5, 188 Salmeterol stimulates β2-adrenergic receptors and apparently has little or no effect on α-, β1-, or β3-adrenergic receptors.1, 5, 24, 45, 84, 86, 188 In vitro and in vivo pharmacologic studies indicate that the selectivity of salmeterol for β2- versus β1-adrenergic receptors is greater than that of albuterol (e.g., approximately 50-60 times).1, 2, 5, 25, 86, 154, 156, 188 It is believed that β-adrenergic effects result from stimulation of the production of cyclic adenosine-3',5'-monophosphate (cAMP) by activation of the enzyme adenyl cyclase.1, 2, 3, 44, 93, 129, 130, 131, 188 Cyclic AMP appears to mediate numerous cellular responses, and increased concentrations of cAMP are associated with relaxation of bronchial smooth muscle, suppression of some aspects of inflammation, and stimulation of lung ciliary function.2, 5, 26, 111, 129, 130, 131, 133, 154
The principal effect following oral inhalation of salmeterol and other β2-adrenergic agonists is bronchodilation resulting from relaxation of smooth muscles of the bronchial tree.4 The delayed onset and prolonged duration of action of salmeterol may be the result of its slow cellular uptake and/or membrane translocation to the β2 receptor,5, 84, 154 lipophilicity,3, 5, 25, 83, 84, 86, 114 and protracted binding at the β2 receptor.2, 3, 5, 15, 45, 84, 86 Some evidence suggests that salmeterol binds reversibly to an active site on the β2 receptor and irreversibly to an exosite, which may be a domain adjacent to the active site within the β2 receptor in the lipid bilayer of the cell membrane.3, 5, 15, 25, 35, 44, 45, 84, 154 The persistence of salmeterol at the β2 receptor is thought to be related to the binding of the oxyalkyl side chain of salmeterol to the exosite while the saligenin end of the molecule is free to dissociate from the active receptor site in the presence of β-adrenergic blocking agents.2, 3, 5, 15, 45, 84, 86, 154 It has been suggested that the slow waning of the bronchodilatory effect of salmeterol is related to slow dissociation from the receptor or to turnover of the occupied β2-adrenergic receptor protein.3, 154
Salmeterol relaxes bronchial smooth muscle by stimulating β2-adrenergic receptors when administered by oral inhalation.1, 2, 44, 86, 154, 188 In isolated bronchial smooth muscle tissue in which muscle tone was increased by a spasmogen (e.g., methacholine, prostaglandin F2α) or by electrical stimulation, salmeterol generally was more potent than albuterol and at least as potent as isoproterenol in relaxing smooth muscle.2, 5, 6, 83, 84, 86 In patients with reversible airway obstruction, salmeterol decreases airway resistance (as measured by forced expiratory volume in 1 second [FEV1], peak expiratory flow rate [PEFR], and vital capacity) and airway reactivity to histamine.9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 Residual elevation of morning PEFR has been maintained for up to at least 1-6 days following completion of salmeterol therapy.10, 43 In addition to bronchodilator activity, salmeterol and other inhaled β2-agonists may affect clearance of pulmonary secretions by increasing the ciliary activity of airway epithelial cells.5, 26, 45, 93, 154
Salmeterol inhibits the release of proinflammatory mediators associated with early-phase inflammatory response to allergen challenge (e.g., histamine, leukotrienes C4and D4, prostaglandin D2) in human lung tissue and may thereby attenuate early- and late-phase-associated bronchoconstriction.1, 2, 4, 5, 79, 87, 91, 93, 188 Salmeterol also attenuates late-phase-associated vascular permeability, and inflammatory cell activation, migration, and recruitment.1, 2, 4, 5, 79, 87, 91, 93 However, the extent of salmeterol's anti-inflammatory activity is not well characterized, and the lack of a consistent effect of the drug on inflammatory processes suggests that anti-inflammatory effects are of secondary or negligible importance in producing the clinical improvement noted in patients with asthma receiving the drug.1, 2, 4, 5, 28, 30, 31, 32, 34, 41, 43, 51, 79, 91, 154, 156 Studies in animals and humans indicate that orally inhaled salmeterol inhibits extravasation of plasma proteins, neutrophils, and eosinophils associated with late-phase response to challenge with histamine, leukotriene B4, antigen, endotoxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), and platelet-activating factor.1, 5, 28, 29, 30, 32, 41, 43, 85, 91, 155, 188 Some evidence indicates that salmeterol is as potent as isoproterenol and more potent than albuterol in inhibiting the release of these mediators2, 5, 25, 87, 91 and has a longer duration of anti-inflammatory action, including late-phase response to allergen challenge than either of these drugs.2, 5, 87 In addition, these anti-inflammatory effects have been reversed by pretreatment with β-adrenergic blocking agents (e.g., propranolol), suggesting that such effects may be mediated by β-adrenergic receptors.2, 5, 87 As inflammatory changes occur during periods of increased bronchial hyperresponsiveness, the degree of response to bronchoconstrictor stimuli has been used as an indirect measure of inflammation.2, 22, 27, 34, 40, 41, 48, 85, 127 In a few single-dose, placebo-controlled or comparative studies with albuterol, salmeterol decreased the degree of airway responsiveness to bronchoconstrictor stimuli (e.g., allergens, cold air).4, 9, 14, 22, 41, 75 Whether these bronchoprotective effects of salmeterol are associated with sustained bronchodilation or anti-inflammatory effects has not been fully determined.1, 9, 11, 22, 41, 75, 127, 156 The lack of activity of other β-adrenergic agonists on the late-phase response to allergen challenge may be related to their short duration of action.22, 25, 29, 40, 85, 87, 127, 133
Current evidence and experience indicate that prolonged therapy with salmeterol does not appear to be associated with development of tolerance to the bronchodilatory effects of the drug.1, 10, 16, 17, 20, 43, 58, 102, 154, 188, 213, 214, 216 However, conflicting data exist with regard to the development of tolerance to the drug's protective effects against bronchoconstrictor stimuli, and further study is needed to clarify the potential for development of tolerance to these effects of salmeterol.20, 45, 54, 105, 154, 156, 174, 175, 176, 177, 178, 179, 181, 191
Salmeterol, like other β2-adrenergic agonists, can produce changes in heart rate and blood pressure.1, 15, 16, 19, 25, 33, 37, 52, 107, 188 In several studies in asthmatic patients or healthy individuals receiving escalating doses of inhaled salmeterol (up to 84 mcg)1, 2 or usual doses of inhaled albuterol (180 mcg), dose-related increases in heart rate of 3-16 beats/minute were noted with salmeterol but did not exceed those observed with albuterol therapy.1, 15, 16, 19, 33, 37, 52, 107, 188 The increase in heart rate observed in patients with asthma with salmeterol or albuterol therapy probably results either indirectly from peripheral vasodilation or directly from a chronotropic effect via β2-receptors in the heart.2, 37, 44, 154 In patients with chronic obstructive pulmonary disease (COPD) receiving orally inhaled salmeterol (50 mcg/dose) inhalation powder alone or in combination with fluticasone propionate, pulse rate or systolic or diastolic blood pressure was not affected.188, 221
In several studies in patients with asthma in which continuous electrocardiographic monitoring during 12- or 24-hour periods was performed during therapy with orally inhaled salmeterol (42 or 50 mcg twice daily) or albuterol (180 mcg 4 times daily), no clinically important dysrhythmias were noted.1, 15, 17, 188 In several studies (24 weeks' duration) in patients with COPD in whom electrocardiographic monitoring was performed at weeks 12 and 24 of therapy with orally inhaled salmeterol inhalation powder (50 mcg twice daily) or placebo, the incidence of clinically important dysrhythmias was similar.188 In a clinical trial in patients with COPD who were receiving salmeterol inhalation powder, fluticasone inhalation powder, salmeterol in fixed combination with fluticasone propionate, or placebo, continuous ECG monitoring for 24 hours (prior to the first dose and after 4 weeks of therapy) did not reveal appreciable differences in ventricular or supraventricular arrhythmias or heart rate.221 The incidence of ventricular premature complexes with salmeterol, albuterol, or placebo in clinical studies generally has been similar. 15, 16, 17 However at higher dosages, both salmeterol1, 19, 33, 37, 188 and albuterol administration37 have been associated with prolongation of the QTc interval.1, 19, 33, 154, 188 Tolerance to the effects of salmeterol on the QTc interval has been reported in healthy individuals receiving high dosages of the drug.19, 33
Administration of salmeterol and other β-adrenergic agonists may cause dose-related increases in blood glucose and/or decreases in serum potassium concentrations.2, 19, 33, 37, 93, 166 (See Cautions: Metabolic and Electrolyte Effects.) Increases in blood glucose concentration may be caused by stimulation of glycogenolysis or gluconeogenesis through activation of β2-receptors in skeletal muscle and liver;2, 37, 55, 93, 128 tolerance to this effect may occur with regular salmeterol treatment.2, 33, 37 Reductions in serum potassium concentration that occur during therapy with salmeterol and other β-adrenergic agonists may be related to β-adrenergic stimulation of cell membrane Na+- K+-ATPase, with increased intracellular shunting of potassium from blood into liver, skeletal muscle, and myocardium.2, 33, 37, 44, 93, 100, 126 Limited data in healthy individuals suggest that tolerance to the hypokalemic effects of high-dose salmeterol does not occur.33
Like other sympathomimetic amines, salmeterol may cause CNS stimulation and adverse nervous system effects.1, 2, 13, 15, 19, 188 (See Cautions: Nervous System Effects.)
Limited data are available on the pharmacokinetics of salmeterol xinafoate after oral inhalation.1, 2, 25 Salmeterol xinafoate dissociates in solution to salmeterol and xinafoate moieties that are absorbed, distributed, metabolized, and excreted independently.1, 188 The xinafoate moiety has no intrinsic pharmacologic activity.1, 25, 188 While commercially available salmeterol is administered as salmeterol xinafoate, dosages and drug concentrations are expressed in terms of salmeterol.1, 188
The absorption of salmeterol xinafoate from the respiratory tract following oral inhalation has not been fully characterized.2, 25 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.1, 2, 38, 39 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.39, 188 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.1, 38 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.188
Compared with short-acting β-agonists such as albuterol or isoproterenol, the onset and duration of bronchodilation with orally inhaled salmeterol are longer.25 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.188 Maximum improvement in FEV1 generally occurred within 3 hours, and clinically important improvement was maintained for 12 hours in most patients.188 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.188 Mean time to maximum improvement in FEV1 occurred at 4.75 hours, and improvement was maintained for 12 hours.188 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.188
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.1, 25, 188 Salmeterol is bound to albumin25 and α1-acid glycoprotein;154 the xinafoate moiety also is highly protein bound (exceeding 99%) to albumin.1, 25, 188
The distribution of salmeterol into various human organs and tissues following oral inhalation has not been fully characterized.2, 25, 38 Results of studies in rats indicate that salmeterol crosses the blood-brain barrier in trace amounts.13, 38
It is not known if salmeterol and/or its metabolites cross the placenta in humans.154 Salmeterol crossed the placenta following oral administration in mice and rats.267, 268, 269, 270 It also is not known if salmeterol is distributed into milk in humans;1 however the drug is distributed into milk in rats.38, 267, 268, 269, 270
Salmeterol is extensively metabolized in the liver by hydroxylation and is eliminated predominantly in feces.1, 2, 25, 38 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.1, 2, 25, 38, 188 Negligible amounts of unchanged salmeterol are detectable in urine or feces.1, 2, 38, 154, 188 A minor metabolite is formed by o -dealkylation of the phenylalkyl side chain.25, 38 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.1, 25, 188
Salmeterol xinafoate is a long-acting, synthetic, sympathomimetic amine.1, 2, 3, 5, 188 The drug is structurally and pharmacologically similar to the short-acting β2-adrenergic agonist albuterol.2, 3 The pharmacologically active moiety of salmeterol contains a saligenin nucleus identical to that in albuterol.3, 17, 25 This polar nucleus reversibly attaches to the classic β2-receptor binding site.2, 3, 5, 18 Salmeterol differs structurally from albuterol in part by the presence of a long, N -substituted, phenylalkyl side chain.1, 2, 3, 5, 16, 25, 35 This substitution contributes to increased lipophilicity; greater bronchial tissue penetration; increased resistance to metabolism by catechol- o -methyltransferase (COMT); prolonged and selective binding to a second, nonpolar domain (exosite) on the β2-receptor; and decreased clearance from the airways.1, 2, 3, 5, 15, 16, 17, 18, 22, 25, 35, 38, 40, 44, 85, 86, 91 The ether oxygen on the N -substituent facilitates binding of the substituent to the exosite portion of the β2-adrenergic receptor protein.3
Salmeterol is commercially available as the xinafoate salt, the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol.1, 25, 154, 188, 256 Both the R - and S - enantiomers of salmeterol are long acting.256 Available data suggest that the S -enantiomer of salmeterol does not antagonize the effects of the R -enantiomer and does not have pharmacologic effects that are different from those of the racemic mixture.256 Salmeterol xinafoate occurs as an off-white powder and has solubilities of approximately 40 mg/mL in methanol, 7 mg/mL in ethanol, 3 mg/mL in chloroform, 2-3 mg/mL in isopropanol, and 0.07-0.11 mg/mL in water.154
Salmeterol xinafoate powder for oral inhalation is a powdered mixture of drug and lactose and is contained in a foil blister strip for use in a special oral inhaler device (Serevent® Diskus®).270 Salmeterol xinafoate also is commercially available in fixed combination with fluticasone propionate as a powder for oral inhalation (Advair® Diskus® or AirDuo® RespiClick®).267, 269 With commercially available salmeterol inhalation powder delivered via the Serevent® Diskus®, Advair® Diskus®, or AirDuo® RespiClick® device, the amount of drug delivered to the lungs depends on factors such as the patient's inspiratory flow.267, 269, 270 Using standardized in vitro testing at a flow rate of 60 L per minute for 2 seconds, the Serevent® Diskus® device delivered 47 mcg of salmeterol per activation.270 Under similar conditions, the Advair®Diskus® device delivered 93, 233, and 465 mcg of fluticasone propionate and 45 mcg of salmeterol per activation from a Diskus® labeled as containing 100, 250, or 500 mcg of fluticasone propionate and 50 mcg of salmeterol.267 In adult patients with obstructive lung disease and severely compromised lung function (FEV1 of 0.65 L or 20-30% of the predicted value), mean peak inspiratory flow through the Diskus® device was 82.4 L per minute for Serevent® and 82.4 L per minute for Advair®.267, 270 In adults and adolescents with asthma, mean peak inspiratory flow through the Diskus® device was 122.2 L per minute.267 In a group of children 4 years of age, mean peak inspiratory flow through the Diskus®device averaged 75.5 L per minute; in children 8 years of age, mean peak inspiratory flow averaged 107.3 L per minute.267 Based on in vitro modeling of these flow rates, a dose of approximately 46 mcg of salmeterol is emitted per activation of the Diskus® device.154 Results of standardized in vitro testing at a flow rate of 85 L per minute for 1.4 seconds indicated that the AirDuo® RespiClick® device delivered 49, 100, or 202 mcg of fluticasone propionate and 12.75 mcg of salmeterol per actuation from an oral inhaler labeled as containing 55, 113, or 232 mcg of fluticasone propionate and 14 mcg of salmeterol.269 In adult and adolescent patients with asthma, mean peak inspiratory flow through the RespiClick® device was 108.3 and 106.7 L per minute, respectively.269
The commercially available inhalation powder containing salmeterol xinafoate alone (Serevent®) or in fixed combination with fluticasone propionate (Advair® Diskus®) should be stored at room temperature (20-25°C) in a dry place away from direct heat and sunlight.253, 254, 267, 270 The Serevent® Diskus® inhaler should be discarded 6 weeks after removal from the foil pouch or when every blister has been used (when the dose counter reads “0”), whichever comes first.270 The Advair® Diskus® inhaler should be discarded 1 month after removal from the foil pouch or when every blister has been used, whichever comes first.254, 255, 267
The commercially available inhalation powder containing salmeterol in fixed combination with fluticasone propionate (AirDuo® RespiClick®) should be stored at 15-25°C in a dry place away from extreme heat, cold, and humidity.269 The inhaler should be discarded 30 days after opening the foil pouch or when the dose counter reads “0,” whichever comes first.269
The commercially available inhalation aerosol of salmeterol in fixed combination with fluticasone propionate (Advair® HFA) should be stored (with the mouthpiece down) at 20-25°C but may be exposed to temperatures ranging from 15-30°C.257, 258, 268 Because the contents of the aerosol oral inhaler are under pressure, the aerosol container should not be punctured, used or stored near heat or an open flame, or placed into a fire or an incinerator for disposal.258, 268 Exposure of the canister to temperatures exceeding 49°C may cause the canister to burst.268 The inhaler should be discarded when the dose counter reads “0.”268
Salmeterol xinafoate oral inhalation powder (Serevent® Diskus®) is stable for 18 months from the date of manufacture.154
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral Inhalation | Powder | 50 mcg (of salmeterol) per inhalation | Serevent® Diskus® |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral Inhalation | Aerosol | 21 mcg (of salmeterol) with Fluticasone Propionate 45 mcg per metered spray (from the actuator) | Advair® HFA (with hydrofluoroalkane propellant) | GlaxoSmithKline |
21 mcg (of salmeterol) with Fluticasone Propionate 115 mcg per metered spray (from the actuator) | Advair® HFA (with hydrofluoroalkane propellant) | GlaxoSmithKline | ||
21 mcg (of salmeterol) with Fluticasone Propionate 230 mcg per metered spray (from the actuator) | Advair® HFA (with hydrofluoroalkane propellant) | GlaxoSmithKline | ||
Powder | 14 mcg (of salmeterol) with Fluticasone Propionate 55 mcg per inhalation | AirDuo® RespiClick® | ||
14 mcg (of salmeterol) with Fluticasone Propionate 113 mcg per inhalation | AirDuo® RespiClick® | Teva | ||
14 mcg (of salmeterol) with Fluticasone Propionate 232 mcg per inhalation | AirDuo® RespiClick® | Teva | ||
50 mcg (of salmeterol) with Fluticasone Propionate 100 mcg per inhalation | Advair® Diskus® | GlaxoSmithKline | ||
50 mcg (of salmeterol) with Fluticasone Propionate 250 mcg per inhalation | Advair® Diskus® | GlaxoSmithKline | ||
50 mcg (of salmeterol) with Fluticasone Propionate 500 mcg per inhalation | Advair® Diskus® | GlaxoSmithKline |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions July 10, 2024. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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