Serevent Diskus

Medications can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Serevent Diskus, there are no specific foods that you must exclude from your diet when receiving this medication.

If you take too much this medication, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

If this medication is administered by a healthcare provider in a medical setting, it is unlikely that an overdose will occur. However, if overdose is suspected, seek emergency medical attention.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Inhalation Powder. Inhaler containing a foil blister strip of powder formulation for oral inhalation. The strip contains salmeterol 50 mcg per blister.

Asthma-Related Death

LABA, such as salmeterol, the active ingredient in Serevent Diskus, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA.

Because of this risk, use of Serevent Diskus for the treatment of asthma without concomitant use of a long-term asthma control medication, such as an inhaled corticosteroid, is contraindicated. Use Serevent Diskus only as additional therapy for patients with asthma who are currently taking but are inadequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue Serevent Diskus) if possible without loss of asthma control and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use Serevent Diskus for patients whose asthma is adequately controlled on low- or medium-dose inhaled corticosteroids.

Pediatric and Adolescent Patients

Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. For pediatric and adolescent patients with asthma who require addition of a LABA to an inhaled corticosteroid, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA should ordinarily be used to ensure adherence with both drugs. In cases where use of a separate long-term asthma control medication (e.g., inhaled corticosteroid) and a LABA is clinically indicated, appropriate steps must be taken to ensure adherence with both treatment components. If adherence cannot be assured, a fixed-dose combination product containing both an inhaled corticosteroid and a LABA is recommended.

The Salmeterol Multicenter Asthma Research Trial (SMART) was a large 28-week placebo-controlled U.S. trial comparing the safety of salmeterol (SEREVENT® Inhalation Aerosol) with placebo, each added to usual asthma therapy, that showed an increase in asthma-related deaths in subjects receiving salmeterol [see Clinical Studies (14.1)]. Given the similar basic mechanisms of action of beta2-agonists, the findings seen in the SMART trial are considered a class effect.

A 16-week clinical trial performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) trial, showed results similar to the SMART trial. In the SNS trial, the rate of asthma-related death was numerically, though not statistically significantly, greater in subjects with asthma treated with salmeterol (42 mcg twice daily) than those treated with albuterol (180 mcg 4 times daily) added to usual asthma therapy.

The SNS and SMART trials enrolled subjects with asthma. No trials have been conducted that were primarily designed to determine whether the rate of death in patients with COPD is increased by LABA.

Deterioration of Disease and Acute Episodes

Serevent Diskus should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma or COPD. Serevent Diskus has not been studied in subjects with acutely deteriorating asthma or COPD. The initiation of Serevent Diskus in this setting is not appropriate.

Serious acute respiratory events, including fatalities, have been reported when salmeterol has been initiated in patients with significantly worsening or acutely deteriorating asthma. 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, previous life-threatening acute asthma exacerbations) and in some patients with acutely deteriorating asthma (e.g., patients with significantly increasing symptoms; increasing need for inhaled, short-acting beta2-agonists; decreasing response to usual medications; increasing need for systemic corticosteroids; recent emergency room visits; deteriorating lung function). However, these events have occurred in a few patients with less severe asthma as well. It was not possible from these reports to determine whether salmeterol contributed to these events.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate reevaluation with reassessment of the treatment regimen, giving special consideration to the possible need for adding additional inhaled corticosteroid or initiating systemic corticosteroids. Patients should not use more than 1 inhalation twice daily of Serevent Diskus.

Serevent Diskus should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not Serevent Diskus, should be used to relieve acute symptoms such as shortness of breath. When prescribing Serevent Diskus, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms.

When beginning treatment with Serevent Diskus, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.

Serevent Diskus is Not a Substitute for Corticosteroids

There are no data demonstrating that Serevent Diskus has a clinical anti-inflammatory effect such as that associated with corticosteroids. When initiating and throughout treatment with Serevent Diskus 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 feel better as a result of initiating Serevent Diskus. Any change in corticosteroid dosage should be made ONLY after clinical evaluation.

Excessive Use of Serevent Diskus and Use with Other Long-acting Beta2-agonists

Serevent Diskus should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using Serevent Diskus should not use another medicine containing a LABA (e.g., formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Paradoxical Bronchospasm and Upper Airway Symptoms

As with other inhaled medicines, Serevent Diskus can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Serevent Diskus, it should be treated immediately with an inhaled, short-acting bronchodilator; Serevent Diskus should be discontinued immediately; and alternative therapy should be instituted. Upper airway symptoms of laryngeal spasm, irritation, or swelling, such as stridor and choking, have been reported in patients receiving Serevent Diskus.

Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia [see Overdosage (10)]. Therefore, Serevent Diskus, like all products containing sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Salmeterol 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 salmeterol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (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. 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. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of Serevent Diskus. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of powder products containing lactose; therefore, patients with severe milk protein allergy should not use Serevent Diskus [see Contraindications (4)].

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with Serevent Diskus is not recommended because increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Coexisting Conditions

Serevent Diskus, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Hypokalemia and Hyperglycemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant and dose-related changes in blood glucose and/or serum potassium were seen infrequently during clinical trials with Serevent Diskus at recommended doses.

LABA, including salmeterol, the active ingredient in Serevent Diskus, increase the risk of asthma-related death. Data from a large 28-week placebo-controlled U.S. trial that compared the safety of salmeterol or placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1), Clinical Studies (14.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience in Asthma

Adult and Adolescent Subjects Aged 12 Years and Older

Two multicenter, 12-week, placebo-controlled clinical trials evaluated twice-daily doses of Serevent Diskus in subjects aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 trials.

Table 1. Adverse Reactions with Serevent Diskus with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects with Asthma

Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of greater than or equal to 3% in the group treated with Serevent Diskus and were more common than in the placebo group.

Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at greater than or equal to 3% but were more common in the placebo group. However, throat irritation has been described at rates exceeding that of placebo in other controlled clinical trials.

Additional Adverse Reactions: Other adverse reactions not previously listed, whether considered drug-related or not by the investigators, that were reported more frequently by subjects with asthma treated with Serevent Diskus compared with subjects treated with placebo include the following: contact dermatitis, eczema, localized aches and pains, nausea, oral mucosal abnormality, pain in joint, paresthesia, pyrexia of unknown origin, sinus headache, and sleep disturbance.

Pediatric Subjects Aged 4 to 11 Years

Two multicenter, 12-week, controlled trials have evaluated twice-daily doses of Serevent Diskus in subjects aged 4 to 11 years with asthma. Table 2 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of greater than or equal to 3% in the group receiving Serevent Diskus and were more common than in the placebo group.

Table 2. Adverse Reaction Incidence in Two 12-Week Pediatric Clinical Trials in Subjects with Asthma

The following events were reported at an incidence of greater than 1% in the salmeterol group and with a higher incidence than in the albuterol and placebo groups: gastrointestinal signs and symptoms, lower respiratory signs and symptoms, photodermatitis, and arthralgia and articular rheumatism.

In clinical trials evaluating concurrent therapy of salmeterol with inhaled corticosteroids, adverse events were consistent with those previously reported for salmeterol, or with events that would be expected with the use of inhaled corticosteroids.

Laboratory Test Abnormalities

Elevation of hepatic enzymes was reported in greater than or equal to 1% of subjects in clinical trials. The elevations were transient and did not lead to discontinuation from the trials. In addition, there were no clinically relevant changes noted in glucose or potassium.

Clinical Trials Experience in Chronic Obstructive Pulmonary Disease

Two multicenter, 24-week, placebo-controlled U.S. trials evaluated twice-daily doses of Serevent Diskus in subjects with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, subject entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 trials (total N = 341 for salmeterol and 576 for placebo).

Table 3. Adverse Reactions with Serevent Diskus with ≥3% Incidence in U.S. Controlled Clinical Trials in Subjects with Chronic Obstructive Pulmonary Diseasea

Additional Adverse Reactions

Other adverse reactions occurring in the group receiving Serevent Diskus that occurred at a frequency of greater than or equal to 1% and were more common than in the placebo group were as follows: anxiety; arthralgia and articular rheumatism; bone and skeletal pain; candidiasis mouth/throat; dental discomfort and pain; dyspeptic symptoms; edema and swelling; gastrointestinal infections; hyperglycemia; hyposalivation; keratitis and conjunctivitis; lower respiratory signs and symptoms; migraines; muscle pain; muscle stiffness, tightness, and rigidity; musculoskeletal inflammation; pain; and skin rashes.

Adverse reactions to salmeterol are similar in nature to those seen with other selective beta2-adrenoceptor agonists, e.g., tachycardia; palpitations; immediate hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm; headache; tremor; nervousness; and paradoxical bronchospasm.

Laboratory Abnormalities

There were no clinically relevant changes in these trials. Specifically, no changes in potassium were noted.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of salmeterol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to salmeterol or a combination of these factors.

In extensive U.S. and worldwide postmarketing experience with salmeterol, serious exacerbations of asthma, including some that have been fatal, have been reported. In most cases, these have occurred in patients with severe asthma and/or in some patients in whom asthma has been acutely deteriorating [see Warnings and Precautions (5.2)], but they have also occurred in a few patients with less severe asthma. It was not possible from these reports to determine whether salmeterol contributed to these events.

Cardiovascular

Arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles) and anaphylaxis.

Non-Site Specific

Very rare anaphylactic reaction in patients with severe milk protein allergy.

Respiratory

Reports of upper airway symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking; oropharyngeal irritation.

Asthma

The initial trials supporting the approval of Serevent Diskus for the treatment of asthma did not require the regular use of inhaled corticosteroids. However, for the treatment of asthma, Serevent Diskus is currently indicated only as concomitant therapy with an inhaled corticosteroid [see Indications and Usage (1.1)].

Adult and Adolescent Subjects Aged 12 Years and Older

In 2 randomized double-blind trials, Serevent Diskus was compared with albuterol inhalation aerosol and placebo in adolescent and adult subjects with mild-to-moderate asthma (protocol defined as 50% to 80% predicted FEV1, actual mean of 67.7% at baseline), including subjects who did and who did not receive concurrent inhaled corticosteroids. The efficacy of Serevent Diskus was demonstrated over the 12-week period with no change in effectiveness over this time period (Figure 1). There were no gender- or age-related differences in safety or efficacy. No development of tachyphylaxis to the bronchodilator effect was noted in these trials. FEV1 measurements (mean change from baseline) from these two 12-week trials are shown in Figure 1 for both the first and last treatment days.

Figure 1. Serial 12-Hour FEV1 from Two 12-Week Clinical Trials in Subjects with Asthma

First Treatment Day

Last Treatment Day (Week 12)

Table 4 shows the treatment effects seen during daily treatment with Serevent Diskus for 12 weeks in adolescent and adult subjects with mild-to-moderate asthma.

Table 4. Daily Efficacy Measurements in Two 12-Week Clinical Trials (Combined Data)

Maintenance of efficacy for periods up to 1 year has been documented.

Serevent Diskus and SEREVENT Inhalation Aerosol were compared with placebo in 2 additional randomized double-blind clinical trials in adolescent and adult subjects 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 EIB. Therefore, while Serevent Diskus was comparable to SEREVENT Inhalation Aerosol in clinical trials in mild-to-moderate subjects with asthma, it should not be assumed that they will produce clinically equivalent outcomes in all subjects.

Subjects on Concomitant Inhaled Corticosteroids: In 4 clinical trials in adult and adolescent subjects with asthma (N = 1,922), the effect of adding SEREVENT Inhalation Aerosol to inhaled corticosteroid therapy was evaluated over a 24-week treatment period. The trials 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 subjects (aged 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 subjects were switched to beclomethasone dipropionate (BDP) 168 mcg twice daily. Subjects still not adequately controlled were randomized to either the addition of SEREVENT Inhalation Aerosol 42 mcg twice daily or an increase of BDP to 336 mcg twice daily. As compared with the doubled dose of BDP, 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 subjects 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, controlled, parallel-group clinical trials (N = 925) enrolled subjects (aged 12 to 78 years) with persistent asthma who were previously maintained but not adequately controlled on prior asthma therapy. During the 2- to 4-week run-in period, all subjects were switched to fluticasone propionate 88 mcg twice daily. Subjects 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 with 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 subjects receiving SEREVENT Inhalation Aerosol experienced asthma exacerbations than those receiving the higher dose of fluticasone propionate (8.8% versus 13.8%).

Table 5 shows the treatment effects seen during daily treatment with SEREVENT Inhalation Aerosol for 24 weeks in adolescent and adult subjects with mild-to-moderate asthma.

Onset of Action: During the initial treatment day in several multiple-dose clinical trials with Serevent Diskus in subjects with asthma, the median time to onset of clinically significant bronchodilatation (≥15% improvement in FEV1) ranged from 30 to 48 minutes after a 50-mcg dose.

One hour after a single dose of 50 mcg of Serevent Diskus, the majority of subjects had ≥15% improvement in FEV1. Maximum improvement in FEV1 generally occurred within 180 minutes, and clinically significant improvement continued for 12 hours in most subjects.

Pediatric Subjects

In a randomized, double-blind, controlled trial (N = 449), 50 mcg of Serevent Diskus was administered twice daily to pediatric subjects 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 PEF (36% to 39% postdose increase from baseline) and FEV1 (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 trial (N = 207) with 50 mcg of salmeterol inhalation powder via an alternate device supported the findings of the trial with the DISKUS.

Salmeterol Multicenter Asthma Research Trial

The SMART trial was a randomized double-blind trial that enrolled LABA-naive subjects 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 with placebo when added to usual asthma therapy.

A planned interim analysis was conducted when approximately half of the intended number of subjects had been enrolled (N = 26,355), which led to premature termination of the trial. The results of the interim analysis showed that subjects receiving salmeterol were at increased risk for fatal asthma events (Table 5 and Figure 2). In the total population, a higher rate of asthma-related death occurred in subjects treated with salmeterol than those treated with placebo (0.10% versus 0.02%, relative risk: 4.37 [95% CI: 1.25, 15.34]).

Post-hoc subpopulation analyses were performed. In Caucasians, asthma-related death occurred at a higher rate in subjects treated with salmeterol than in subjects treated with placebo (0.07% versus 0.01%, relative risk: 5.82 [95% CI: 0.70, 48.37]). In African Americans also, asthma-related death occurred at a higher rate in subjects treated with salmeterol than those treated with placebo (0.31% versus 0.04%, relative risk: 7.26 [95% CI: 0.89, 58.94]). Although the relative risks of asthma-related death were similar in Caucasians and African Americans, the estimate of excess deaths in subjects treated with salmeterol was greater in African Americans because there was a higher overall rate of asthma-related death in African American subjects (Table 5).

Post-hoc analyses in pediatric subjects aged 12 to 18 years were also performed. Pediatric subjects accounted for approximately 12% of subjects in each treatment arm. Respiratory-related death or life-threatening experience occurred at a similar rate in the salmeterol group (0.12% [2/1,653]) and the placebo group (0.12% [2/1,622]; relative risk: 1.0 [95% CI: 0.1, 7.2]). All-cause hospitalization, however, was increased in the salmeterol group (2% [35/1,653]) versus the placebo group (less than 1% [16/1,622]; relative risk: 2.1 [95% CI: 1.1, 3.7]).

The data from the SMART trial are not adequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control therapy mitigates the risk of asthma-related death.

Table 5: Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART)

aLife-table 28-week estimate, adjusted according to the subjects’ actual lengths of exposure to study treatment to account for early withdrawal of subjects from the study.

bRelative risk is the ratio of the rate of asthma-related death in the salmeterol group and the rate in the placebo group. The relative risk indicates how many more times likely an asthma-related death occurred in the salmeterol group than in the placebo group in a 28-week treatment period.

cEstimate of the number of additional asthma-related deaths in subjects treated with salmeterol in SMART, assuming 10,000 subjects received salmeterol for a 28-week treatment period. Estimate calculated as the difference between the salmeterol and placebo groups in the rates of asthma-related death multiplied by 10,000.

dThe Total Population includes the following ethnic origins listed on the case report form: Caucasian, African American, Hispanic, Asian, and “Other.” In addition, the Total Population includes those subjects whose ethnic origin was not reported. The results for Caucasian and African American subpopulations are shown above. No asthma-related deaths occurred in the Hispanic (salmeterol n = 996, placebo n = 999), Asian (salmeterol n = 173, placebo n = 149), or “Other” (salmeterol n = 230, placebo n = 224) subpopulations. One asthma-related death occurred in the placebo group in the subpopulation whose ethnic origin was not reported (salmeterol n = 130, placebo n = 127).

Figure 2. Cumulative Incidence of Asthma-Related Deaths in the 28-Week Salmeterol Multicenter Asthma Research Trial (SMART), by Duration of Treatment

Exercise-Induced Bronchospasm

In 2 randomized, single-dose, crossover trials in adolescents and adults with EIB (N = 52), 50 mcg of Serevent Diskus prevented EIB when dosed 30 minutes prior to exercise. For some subjects, this protective effect against EIB was still apparent up to 8.5 hours following a single dose (Table 6).

Table 6. Results of 2 Exercise-Induced Bronchospasm Trials in Adolescents and Adults

In 2 randomized trials in children aged 4 to 11 years 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 subjects.

Chronic Obstructive Pulmonary Disease

In 2 clinical trials evaluating twice-daily treatment with Serevent Diskus 50 mcg (n = 336) compared with placebo (n = 366) in subjects 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 trials of 24 weeks’ duration and were identical in design, subject entrance criteria, and overall conduct.

Figure 3 displays the integrated 2-hour postdose FEV1 results from the 2 clinical trials. The percent change in FEV1 refers to the change from baseline, defined as the predose value on Treatment Day 1. To account for subject withdrawals during the trial, Endpoint (last evaluable FEV1) data are provided. Subjects receiving Serevent Diskus 50 mcg had significantly greater improvements in 2-hour postdose FEV1 at Endpoint (216 mL, 20%) compared with placebo (43 mL, 5%). Improvement was apparent on the first day of treatment and maintained throughout the 24 weeks of treatment.

Figure 3. Mean Percent Change from Baseline in Postdose FEV1 Integrated Data from 2 Trials of Subjects with Chronic Bronchitis and Airflow Limitation

Onset of Action and Duration of Effect

The onset of action and duration of effect of Serevent Diskus were evaluated in a subset of subjects (n = 87) from 1 of the 2 clinical trials discussed above. Following the first 50-mcg dose, significant improvement in pulmonary function (mean FEV1 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 4, evidence of bronchodilatation was seen throughout the 12-hour period. Figure 4 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.

Figure 4. Serial 12-Hour FEV1 on the First Day and at Week 12 of Treatment

SEREVENT DISKUS (salmeterol xinafoate inhalation powder) contains salmeterol xinafoate as the racemic form of the 1-hydroxy-2-naphthoic acid salt of salmeterol. The active component of the formulation is salmeterol base, a highly selective beta 2 -adrenergic bronchodilator. The chemical name of salmeterol xinafoate is 4-hydroxy-(alpha) 1 -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol, 1-hydroxy-2-naphthalenecarboxylate.

Salmeterol xinafoate is a white to off-white powder with a molecular weight of 603.8, and the empirical formula is C 25 H 37 NO 4 ·C 11 H 8 O 3 . It is freely soluble in methanol; slightly soluble in ethanol, chloroform, and isopropanol; and sparingly soluble in water.

SEREVENT DISKUS is a specially designed plastic inhalation delivery system containing a double-foil blister strip of a powder formulation of salmeterol xinafoate intended for oral inhalation only. The DISKUS , which is the delivery component, is an integral part of the drug product. Each blister on the double-foil strip within the unit contains 50 mcg of salmeterol administered as the salmeterol xinafoate salt in 12.5 mg of formulation containing lactose (which contains milk proteins). After a blister containing medication is opened by activating the DISKUS, the medication is dispersed into the airstream created by the patient inhaling through the mouthpiece.

Under standardized in vitro test conditions, SEREVENT DISKUS delivers 47 mcg when tested at a flow rate of 60 L/min for 2 seconds. In adult patients with obstructive lung disease and severely compromised lung function (mean forced expiratory volume in 1 second [FEV 1 ] 20% to 30% of predicted), mean peak inspiratory flow (PIF) through a DISKUS was 82.4 L/min (range, 46.1 to 115.3 L/min).

The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile.

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).

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:

1. 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.
2. 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.
3. 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).
4. Patients should not stop therapy with SEREVENT DISKUS for asthma or COPD without physician/provider guidance since symptoms may worsen after discontinuation.
5. ·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.
6. 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.
7. 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.
8. Patients should be cautioned regarding adverse effects associated with beta 2 -agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.
9. When patients are prescribed SEREVENT DISKUS, other medications for asthma and COPD should be used only as directed by the physician.
10. SEREVENT DISKUS should not be used with a spacer device.
11. Patients who are pregnant or nursing should contact the physician about the use of SEREVENT DISKUS.
12. 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.
13. 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.