which means that [0.001).:<0.001). Safe usage with maintenance of efficacy for periods up to 1 year has been documented. SEREVENT DISKUS and SEREVENT (salmeterol xinafoate) Inhalation Aerosol were compared to placebo in 2 additional randomized, double-blind clinical trials in adolescent and adult patients with mild-to-moderate asthma. SEREVENT DISKUS 50 mcg and SEREVENT Inhalation Aerosol 42 mcg, both administered twice daily, produced significant improvements in pulmonary function compared with placebo over the 12-week period. While no statistically significant differences were observed between the active treatments for any of the efficacy assessments or safety evaluations performed, there were some efficacy measures on which the metered-dose inhaler appeared to provide better results. Similar findings were noted in 2 randomized, single-dose, crossover comparisons of SEREVENT DISKUS and SEREVENT Inhalation Aerosol for the prevention of exercise-induced bronchospasm (EIB). Therefore, while SEREVENT DISKUS was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate patients with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all patients. In a randomized, double-blind, controlled study (N = 449), 50 mcg of SEREVENT DISKUS was administered twice daily to pediatric patients with asthma who did and who did not receive concurrent inhaled corticosteroids. The efficacy of salmeterol inhalation powder was demonstrated over the 12-week treatment period with respect to periodic serial peak expiratory flow (PEF) (36% to 39% postdose increase from baseline) and FEV 1 (32% to 33% postdose increase from baseline). Salmeterol was effective in demographic subgroup analyses (gender and age) and was effective when coadministered with other inhaled asthma medications such as short-acting bronchodilators and inhaled corticosteroids. A second randomized, double-blind, placebo-controlled study (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS. Effects in Patients With Asthma on Concomitant Inhaled Corticosteroids : In 4 clinical trials in adult and adolescent patients with asthma (N = 1,922), the effect of adding salmeterol to inhaled corticosteroid therapy was evaluated. The studies utilized the inhalation aerosol formulation of salmeterol xinafoate for a treatment period of 6 months. They compared the addition of salmeterol therapy to an increase (at least doubling) of the inhaled corticosteroid dose. Two randomized, double-blind, controlled, parallel-group clinical trials (N = 997) enrolled patients (ages 18 to 82 years) with persistent asthma who were previously maintained but not adequately controlled on inhaled corticosteroid therapy. During the 2-week run-in period, all patients were switched to beclomethasone dipropionate 168 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalational Aerosol 42 mcg twice daily or an increase of beclomethasone dipropionate to 336 mcg twice daily. As compared to the doubled dose of beclomethasone dipropionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reduction in supplemental albuterol use. The percent of patients who experienced asthma exacerbations overall was not different between groups (i.e., 16.2% in the group receiving SEREVENT Inhalation Aerosol versus 17.9% in the higher dose beclomethasone dipropionate group). Two randomized, double-blind, parallel-group clinical trials (N = 925) enrolled patients (ages 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior therapy. During the 2- to 4-week run-in period, all patients were switched to fluticasone propionate 88 mcg twice daily. Patients still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of fluticasone propionate to 220 mcg twice daily. As compared to the increased (2.5 times) dose of fluticasone propionate, the addition of SEREVENT Inhalation Aerosol resulted in statistically significantly greater improvements in pulmonary function and asthma symptoms, and statistically significantly greater reductions in supplemental albuterol use. Fewer patients receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%). Exercise-Induced Bronchospasm : In 2 randomized, single-dose, crossover studies in adolescents and adults with EIB (N = 53), 50 mcg of SEREVENT DISKUS prevented EIB when dosed 30 minutes to exercise. For many patients, this protective effect against prior EIB was still apparent up to 8.5 hours following a single dose. Table 2. Results of 2 Exercise-Induced Bronchospasm Studies in Adolescents and Adults Placebo (N = 52) SEREVENT DISKUS (N = 52) n % Total n % Total 0.5-Hour % Fall in FEV 1 postdose> <10% 15 29 31 60 exercise> /=10%, <20% 3 6 11 21 challenge> /=20% 34 65 10 19 Mean maximal % fall in FEV 1 (SE) -25% (1.8) -11% (1.9) 8.5-Hour % Fall in FEV 1 postdose <10% 12 23 26 50 exercise> /=10%, <20% 7 13 12 23 challenge> /=20% 33 63 14 27 Mean maximal % fall in FEV 1 (SE) -27% (1.5) -16% (2.0) In 2 randomized studies in children 4 to 11 years old with asthma and EIB (N = 50), a single 50-mcg dose of SEREVENT DISKUS prevented EIB when dosed 30 minutes prior to exercise, with protection lasting up to 11.5 hours in repeat testing following this single dose in many patients. Salmeterol Multi-center Asthma Research Trial : The Salmeterol Multi-center Asthma Research Trial (SMART) was a randomized, double-blind study that enrolled long-acting beta 2 -agonist-naive patients with asthma (average age of 39 years, 71% Caucasian, 18% African American, 8% Hispanic) to assess the safety of salmeterol (SEREVENT Inhalation Aerosol, 42 mcg twice daily over 28 weeks) compared to placebo when added to usual asthma therapy. The primary endpoint was the combined number of respiratory-related deaths or respiratory-related life-threatening experiences (intubation and mechanical ventilation). Secondary endpoints included combined asthma-related deaths or life-threatening experiences and asthma-related deaths. A planned interim analysis was conducted when approximately half of the intended number of patients had been enrolled (N = 26,355). Due to the low rate of primary events in the study, the findings of the planned interim analysis were not conclusive. However, analyses of secondary endpoints suggested that patients receiving salmeterol may be at increased risk for some of these events compared to patients receiving placebo. The analysis for the total population showed a relative risk of 1.40 (95% CI 0.91, 2.14) for the primary endpoint in the salmeterol group relative to the placebo group (50 out of 13,176 vs. 36 out of 13,179, respectively). In the total population, a higher number of asthma-related deaths (13 vs. 3, RR 4.37, 95% CI 1.25, 15.34) and combined asthma-related deaths or life-threatening experiences (37 vs. 22, RR 1.71, 95% CI 1.01, 2.89) occurred in patients treated with salmeterol than those treated with placebo. The analysis of the African American subgroup showed a relative risk of 4.10 (95% CI 1.54, 10.90) for the primary endpoint in patients treated with salmeterol relative to those treated with placebo (20 out of 2,366 vs. 5 out of 2,319, respectively). In African Americans, a higher number of asthma-related deaths (7 vs. 1, RR 7.26, 95% CI 0.89, 58.94) and combined asthma-related deaths or life-threatening experiences (19 vs. 4, RR 4.92, 95% CI 1.68, 14.45) occurred in patients treated with salmeterol than those treated with placebo. Analysis of the Caucasian population showed a relative risk of 1.05 (95% CI 0.62, 1.76) for the primary endpoint for those treated with salmeterol relative to those treated with placebo (29 out of 9,281 vs. 28 out of 9,361, respectively). In Caucasians, a higher number of asthma-related deaths (6 vs. 1, RR 5.82, 95% CI 0.70, 48.37) occurred in patients treated with salmeterol than in patients treated with placebo. In Caucasians, the relative risk was 1.08 (17 vs. 16, 95% CI 0.55, 2.14) for combined asthma-related deaths or life-threatening experiences in patients treated with salmeterol relative to placebo. The numbers of patients from other ethnic groups were too small to draw any conclusions in these populations. Even through SMART did not reach predetermined stopping criteria for the total population, the study was stopped due to the findings in African American patients and difficulties in enrollment. Chronic Obstructive Pulmonary Disease: In 2 clinical trials evaluating twice-daily treatment with SEREVENT DISKUS 50 mcg (N = 336) compared to placebo (N = 366) in patients with chronic bronchitis with airflow limitation, with or without emphysema, improvements in pulmonary function endpoints were greater with salmeterol 50 mcg than with placebo. Treatment with SEREVENT DISKUS did not result in significant improvements in secondary endpoints assessing COPD symptoms in either clinical trial. Both trials were randomized, double-blind, parallel-group studies of 24 weeks' duration and were identical in design, patient entrance criteria, and overall conduct. Figure 2 displays the integrated 2-hour postdose FEV 1 results from the 2 clinical trials. The percent change in FEV 1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for patient withdrawals during the study, Endpoint (last evaluable FEV 1 ) data are provided. Patients receiving SEREVENT DISKUS 50 mcg had significantly greater improvements in 2-hour postdose FEV 1 at Endpoint (216 mL, 20%) compared to placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment. Onset of Action and Duration of Effect : The onset of action and duration of effect of SEREVENT DISKUS were evaluated in a subset of patients (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV 1 increase of 12% or more and at least 200 mL) occurred at 2 hours. The mean time to peak bronchodilator effect was 4.75 hours. As seen in Figure 3, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 3 also demonstrates that the bronchodilating effect after 12 weeks of treatment was similar to that observed after the first dose. The mean time to peak bronchodilator effect after 12 weeks of treatment was 3.27 hours. Indications and Usage Asthma: SEREVENT DISKUS is indicated for long-term, twice-daily (morning and evening) administration in the maintenance treatment of asthma and in the prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease, including patients with symptoms of nocturnal asthma, who require regular treatment with inhaled, short-acting beta 2 -agonists. It is not indicated for patients whose asthma can be managed by occasional use of inhaled, short-acting beta 2 -agonists. SEREVENT DISKUS is also indicated for prevention of exercise-induced bronchospasm in patients 4 years of age and older. SEREVENT DISKUS may be used alone or in combination with inhaled or systemic corticosteroid therapy. Chronic Obstructive Pulmonary Disease: SEREVENT DISKUS is indicated for the long-term, twice-daily (morning and evening) administration in the maintenance treatment of bronchospasm associated with COPD (including emphysema and chronic bronchitis). Contraindications SEREVENT DISKUS is contraindicated in patients with a history of hypersensitivity to salmeterol or any other component of the drug product (see DESCRIPTION and ADVERSE REACTIONS : Observed During Clinical Practice : Non-Site Specific ). Warnings DATA FROM A LARGE PLACEBO-CONTROLLED SAFETY STUDY THAT WAS STOPPED EARLY SUGGEST THAT SALMETEROL MAY BE ASSOCIATED WITH RARE SERIOUS ASTHMA EPISODES OR ASTHMA-RELATED DEATHS. Data from this study, called the Salmeterol Multi-center Asthma Research Trial (SMART), further suggest that the risk might be greater in African American patients. These results led to stopping the study prematurely (see CLINICAL TRIALS : Asthma : Salmeterol Multi-center Asthma Research Trial ). The data from the SMART study are not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk. Given the similar basic mechanisms of action of beta 2 -agonists, it is possible that the findings seen in the SMART study may be consistent with a class effect. Findings similar to the SMART study findings were reported in a prior 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study. In the SNS study, the incidence of asthma-related death was numerically, though not statistically, greater in patients with asthma treated with salmeterol (42 mcg twice daily) versus albuterol (180 mcg 4 times daily) added to usual asthma therapy. SEREVENT DISKUS SHOULD NOT BE INITIATED IN PATIENTS WITH SIGNIFICANTLY WORSENING OR ACUTELY DETERIORATING ASTHMA, WHICH MAY BE A LIFE-THREATENING CONDITION. Serious acute respiratory events, including fatalities, have been reported both in the United States and worldwide when SEREVENT has been initiated in this situation. Although it is not possible from these reports to determine whether SEREVENT contributed to these adverse events or simply failed to relieve the deteriorating asthma, the use of SEREVENT DISKUS in this setting is inappropriate. SEREVENT DISKUS SHOULD NOT BE USED TO TREAT ACUTE SYMPTOMS. It is crucial to inform patients of this and prescribe an inhaled, short-acting beta 2 -agonist for this purpose as well as warn them that increasing inhaled beta 2 -agonist use is a signal of deteriorating asthma. SEREVENT DISKUS IS NOT A SUBSTITUTE FOR INHALED OR ORAL CORTICOSTEROIDS. Corticosteroids should not be stopped or reduced when SEREVENT DISKUS is initiated. (See PRECAUTIONS : Information for Patients and the Patient's Instructions for Use accompanying the product.) Do Not Introduce SEREVENT DISKUS as a Treatment for Acutely Deteriorating Asthma: SEREVENT DISKUS is intended for the maintenance treatment of asthma (see INDICATIONS AND USAGE ) and should not be introduced in acutely deteriorating asthma, which is a potentially life-threatening condition. There are no data demonstrating that SEREVENT DISKUS provides greater efficacy than or additional efficacy to inhaled, short-acting beta 2 -agonists in patients with worsening asthma. Serious acute respiratory events, including fatalities, have been reported both in the United States and worldwide in patients receiving SEREVENT. In most cases, these have occurred in patients with severe asthma (e.g., patients with a history of corticosteroid dependence, low pulmonary function, intubation, mechanical ventilation, frequent hospitalizations, or previous life-threatening acute asthma exacerbations) and/or in some patients in whom asthma has been acutely deteriorating (e.g., unresponsive to usual medications; increasing need for inhaled, short-acting beta 2 -agonists; increasing need for systemic corticosteroids; significant increase in symptoms; recent emergency room visits; sudden or progressive deterioration in pulmonary function). However, they have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether SEREVENT contributed to these events or simply failed to relieve the deteriorating asthma. Do Not Use SEREVENT DISKUS to Treat Acute Symptoms: An inhaled, short-acting beta 2 -agonist, not SEREVENT DISKUS, should be used to relieve acute asthma or COPD symptoms. When prescribing SEREVENT DISKUS, the physician must also provide the patient with an inhaled, short-acting beta 2 -agonist (e.g., albuterol) for treatment of symptoms that occur acutely, despite regular twice-daily (morning and evening) use of SEREVENT DISKUS. When beginning treatment with SEREVENT DISKUS, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute asthma or COPD symptoms (see PRECAUTIONS : Information for Patients ). Watch for Increasing Use of Inhaled, Short-Acting Beta 2 -Agonists, Which Is a Marker of Deteriorating Asthma or COPD: The patient's condition may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient's inhaled, short-acting beta 2 -agonist becomes less effective, the patient needs more inhalations than usual, or the patient develops a significant decrease in PEF or lung function, these may be markers of destabilization of their disease. In this setting, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for corticosteroids. If the patient uses 4 or more inhalations per day of an inhaled, short-acting beta 2 -agonist for 2 or more consecutive days, or if more than 1 canister (200 inhalations per canister) of inhaled, short-acting beta 2 -agonist is used in an 8-week period in conjunction with SEREVENT DISKUS, then the patient should consult the physician for reevaluation. Increasing the daily dosage of SEREVENT DISKUS in this situation is not appropriate. SEREVENT DISKUS should not be used more frequently than twice daily (morning and evening) at the recommended dose of 1 inhalation. Do Not Use SEREVENT DISKUS as a Substitute for Oral or Inhaled Corticosteroids: The use of beta-adrenergic agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids. There are no data demonstrating that SEREVENT DISKUS has a clinical anti-inflammatory effect and could be expected to take the place of corticosteroids. Patients who already require oral or inhaled corticosteroids for treatment of asthma should be continued on a suitable dose to maintain clinical stability even if they feel better as a result of initiating SEREVENT DISKUS. Any change in corticosteroid dosage should be made ONLY after clinical evaluation (see PRECAUTIONS : Information for Patients ). Do Not Exceed Recommended Dosage: As with other inhaled beta 2 -adrenergic drugs, SEREVENT DISKUS should not be used more often or at higher doses than recommended. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Large doses of inhaled or oral salmeterol (12 to 20 times the recommended dose) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Paradoxical Bronchospasm: As with other inhaled asthma and COPD medications, SEREVENT DISKUS can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with SEREVENT DISKUS, it should be treated with a short-acting, inhaled bronchodilator; SEREVENT DISKUS should be discontinued immediately; and alternative therapy should be instituted. Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of SEREVENT DISKUS, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. Upper Airway Symptoms: Symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving SEREVENT DISKUS. Cardiovascular Disorders: SEREVENT DISKUS, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. SEREVENT DISKUS, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of SEREVENT DISKUS at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-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 significance of these findings is unknown. Precautions General: 1. Cardiovascular and Other Effects: No effect on the cardiovascular system is usually seen after the administration of inhaled salmeterol at recommended doses, but the cardiovascular and central nervous system effects seen with all sympathomimetic drugs (e.g., increased blood pressure, heart rate, excitement) can occur after use of salmeterol and may require discontinuation of SEREVENT DISKUS. SEREVENT DISKUS, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. As has been described with other beta-adrenergic agonist bronchodilators, clinically significant changes in systolic and/or diastolic blood pressure, pulse rate, and ECGs have been seen infrequently in individual patients in controlled clinical studies with salmeterol. 2. Metabolic Effects: Doses of the related beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. Beta-adrenergic agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen rarely during clinical studies with long-term administration of SEREVENT DISKUS at recommended doses. Information for Patients: Patients being treated with SEREVENT DISKUS should receive the following information and instructions. This information is intended to aid them in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. It is important that patients understand how to use the DISKUS appropriately and how to use SEREVENT DISKUS in relation to other asthma or COPD medications they are taking. Patients should be given the following information: The action of SEREVENT DISKUS may last up to 12 hours or longer. The recommended dosage (1 inhalation twice daily, morning and evening) should not be exceeded. Most patients are able to taste or feel a dose delivered from SEREVENT DISKUS. However, whether or not patients are able to sense delivery of a dose, you should instruct them not to exceed the recommended dose of 1 inhalation twice daily, morning and evening. You should instruct them to contact you or the pharmacist if they have questions. SEREVENT DISKUS is not meant to relieve acute asthma or COPD symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting bronchodilator (the physician should provide the patient with such medication and instruct the patient in how it should be used). Patients should not stop therapy with SEREVENT DISKUS for asthma or COPD without physician/provider guidance since symptoms may worsen after discontinuation. When used for the treatment of EIB, 1 inhalation of SEREVENT DISKUS should be taken 30 minutes before exercise. Additional doses of SEREVENT should not be used for 12 hours. Patients who are receiving SEREVENT DISKUS twice daily should not use additional SEREVENT for prevention of EIB. The physician should be notified immediately if any of the following situations occur, which may be a sign of seriously worsening asthma or COPD: Decreasing effectiveness of inhaled, short-acting beta 2 -agonists Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists Significant decrease in PEF or lung function as outlined by the physician Use of 4 or more inhalations per day of a short-acting beta 2 -agonist for 2 or more days consecutively Use of more than 1 canister (200 inhalations per canister) of an inhaled, short-acting beta 2 -agonist in an 8-week period. SEREVENT DISKUS should not be used as a substitute for oral or inhaled corticosteroids. The dosage of these medications should not be changed and they should not be stopped without consulting the physician, even if the patient feels better after initiating treatment with SEREVENT DISKUS. Patients should be cautioned regarding adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. When patients are prescribed SEREVENT DISKUS, other medications for asthma and COPD should be used only as directed by the physician. SEREVENT DISKUS should not be used with a spacer device. Patients who are pregnant or nursing should contact the physician about the use of SEREVENT DISKUS. Effective and safe use of SEREVENT DISKUS includes an understanding of the way that it should be used: Never exhale into the DISKUS. Never attempt to take the DISKUS apart. Always activate and use the DISKUS in a level, horizontal position. Never wash the mouthpiece or any part of the DISKUS. KEEP IT DRY. Always keep the DISKUS in a dry place. Discard 6 weeks after removal from the moisture-protective foil overwrap pouch or after all blisters have been used (when the dose indicator reads "0"), whichever comes first. For the proper use of SEREVENT DISKUS and to attain maximum benefit, the patient should read and follow carefully the Patient's Instructions for Use accompanying the product. Drug Interactions Short-Acting Beta 2 -Agonists: In two 12-week, repetitive-dose adolescent and adult clinical trials in patients with asthma (N = 149), the mean daily need for additional beta 2 -agonist in patients using SEREVENT DISKUS was approximately 1 inhalations/day. Twenty-six percent (26%) of the patients in these trials used between 8 and 24 inhalations of short-acting beta-agonist per day on 1 or more occasions. Nine percent (9%) of the patients in these trials averaged over 4 inhalations/day over the course of the 12-week trials. No increase in frequency of cardiovascular events was observed among the 3 patients who averaged 8 to 11 inhalations/day; however, the safety of concomitant use of more than 8 inhalations/day of short-acting beta 2 -agonist with SEREVENT DISKUS has not been established. In 29 patients who experienced worsening of asthma while receiving SEREVENT DISKUS during these trials, albuterol therapy administered via either nebulizer or inhalation aerosol (1 dose in most cases) led to improvement in FEV 1 and no increase in occurrence of cardiovascular adverse events. In 2 clinical trials in patients with COPD, the mean daily need for additional beta 2 -agonist for patients using SEREVENT DISKUS was approximately 4 inhalations/day. Twenty-four percent (24%) of the patients using SEREVENT DISKUS in these trials averaged 6 or more inhalations of albuterol per day over the course of the 24-week trials. No increase in frequency of cardiovascular events was observed among patients who averaged 6 or more inhalations per day. Monoamine Oxidase Inhibitors and Tricyclic Antidepressants : Salmeterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol on the vascular system may be potentiated by these agents. Corticosteroids and Cromoglycate : In clinical trials, inhaled corticosteroids and/or inhaled cromolyn sodium did not alter the safety profile of salmeterol when administered concurrently. Methylxanthines : The concurrent use of intravenously or orally administered methylxanthines (e.g., aminophylline, theophylline) by patients receiving salmeterol has not been completely evaluated. In 1 clinical asthma trial, 87 patients receiving SEREVENT Inhalation Aerosol 42 mcg twice daily concurrently with a theophylline product had adverse event rates similar to those in 71 patients receiving SEREVENT Inhalation Aerosol without theophylline. Resting heart rates were slightly higher in the patients on theophylline but were little affected by therapy with SEREVENT Inhalation Aerosol. In 2 clinical trials in patients with COPD, 39 subjects receiving SEREVENT DISKUS concurrently with a theophylline product had adverse event rates similar to those in 302 patients receiving SEREVENT DISKUS without theophylline. Based on the available data, the concomitant administration of methylxanthines with SEREVENT DISKUS did not alter the observed adverse event profile. Beta-Adrenergic Receptor Blocking Agents : Beta-blockers not only block the pulmonary effect of beta-agonists, such as SEREVENT DISKUS, but may also produce severe bronchospasm in patients with asthma or COPD. Therefore, patients with asthma or COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma or COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. Diuretics : The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics. Carcinogenesis, Mutagenesis, Impairment of Fertility: In an 18-month oral carcinogenicity study in CD-mice, salmeterol xinafoate caused a dose-related increase in the incidence of smooth muscle hyperplasia, cystic glandular hyperplasia, leiomyomas of the uterus, and ovarian cysts at doses of 1.4 mg/kg and above (approximately 20 times the maximum recommended daily inhalation dose in adults and children based on comparison of the area under the plasma concentration versus time curves [AUCs]). The incidence of leiomyosarcomas was not statistically significant. No tumors were seen at 0.2 mg/kg (approximately 3 times the maximum recommended daily inhalation doses in adults and children based on comparison of the AUCs). In a 24-month oral and inhalation carcinogenicity study in Sprague Dawley rats, salmeterol caused a dose-related increase in the incidence of mesovarian leiomyomas and ovarian cysts at doses of 0.68 mg/kg and above (approximately 55 times the maximum recommended daily inhalation dose in adults and approximately 25 times the maximum recommended daily inhalation dose in children on a mg/m 2 basis). No tumors were seen at 0.21 mg/kg (approximately 15 times the maximum recommended daily inhalation dose in adults and approximately 8 times the maximum recommended daily inhalation dose in children on a mg/m 2 basis). These findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Salmeterol produced no detectable or reproducible increases in microbial and mammalian gene mutation in vitro. No clastogenic activity occurred in vitro in human lymphocytes or in vivo in a rat micronucleus test. No effects on fertility were identified in male and female rats treated with salmeterol at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). Pregnancy: Teratogenic Effects : Pregnancy Category C. No teratogenic effects occurred in rats at oral doses up to 2 mg/kg (approximately 160 times the maximum recommended daily inhalation dose in adults on a mg/m 2 basis). In pregnant Dutch rabbits administered oral doses of 1 mg/kg and above (approximately 50 times the maximum recommended daily inhalation dose in adults based on comparison of the AUCs), salmeterol exh this college
pictures in most cases Serevent diskus the child
EmoticonEmoticon