FDA label 198f20a2-218e-4a0f-a4c1-ae7c3b62e1c6

WARNING: ASTHMA-RELATED DEATH Long-acting beta 2 -adrenergic agonists (LABA), such as salmeterol, the active ingredient in SEREVENT ® DISKUS ® , increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of salmeterol (SEREVENT ® Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 deaths out of 13,179 patients on placebo). 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 a concomitant 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. WARNING: ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning Long-acting beta 2 -adrenergic agonists (LABA), such as salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death. A US study showed an increase in asthma-related deaths in patients receiving salmeterol (13 deaths out of 13,176 patients treated for 28 weeks on salmeterol versus 3 out of 13,179 patients on placebo). 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. (5.1) Prescribe 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. (1.1, 5.1) Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. (5.1)

5 WARNINGS AND PRECAUTIONS Asthma-related death and asthma-related hospitalizations: Long-acting beta 2 -adrenergic agonists increase the risk. Prescribe for asthma only as concomitant therapy with an inhaled corticosteroid. (5.1) Deterioration of disease and acute episodes: Do not initiate during rapidly deteriorating asthma. Do not use to treat acute symptoms. (5.2) Corticosteroids: Not a substitute for corticosteroids. Patients with asthma must take a concomitant inhaled corticosteroid. (5.3) Use with additional long-acting beta 2 -agonist: Do not use in combination because of risk of overdose. (5.4) Paradoxical bronchospasm: Discontinue SEREVENT DISKUS and institute alternative therapy if paradoxical bronchospasm occurs. (5.5) Patients with cardiovascular or central nervous system disorders: Use with caution because of beta-adrenergic stimulation. (5.6) Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Risk of cardiovascular effects. Use not recommended with SEREVENT DISKUS. (5.8) Coexisting conditions: Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.9) Metabolic effects: Be alert to hypokalemia and hyperglycemia. (5.10) 5.1 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 Multi-center Asthma Research Trial (SMART) was a large 28-week placebo-controlled US study 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 patients receiving salmeterol [see Clinical Studies (14.1)] . Given the similar basic mechanisms of action of beta 2 -agonists, the findings seen in the SMART study are considered a class effect. A 16-week clinical study performed in the United Kingdom, the Salmeterol Nationwide Surveillance (SNS) study, showed results similar to the SMART study. In the SNS study, the rate of asthma-related death was numerically, though not statistically significantly, greater in patients 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 studies enrolled patients with asthma. No studies have been conducted that were adequate to determine whether the rate of death in patients with COPD is increased by LABA. 5.2 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 patients 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 beta 2 -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 beta 2 -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 (morning and evening) 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 beta 2 -agonist, not SEREVENT DISKUS, should be used to relieve acute symptoms such as shortness of breath. 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 acute symptoms. When beginning treatment with SEREVENT DISKUS, patients who have been taking oral or 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. 5.3 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. 5.4 Excessive Use of SEREVENT DISKUS and Use With Other Long-Acting Beta 2 -Agonists As with other inhaled beta 2 -adrenergic drugs, SEREVENT DISKUS should not be used more often or at higher doses than recommended, or in conjunction with other medications 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 an additional LABA (e.g., formoterol fumarate, arformoterol tartrate) for any reason. 5.5 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled 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 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. 5.6 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 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. 5.7 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of SEREVENT DISKUS, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm. There have been reports of anaphylactic reactions in patients with severe milk protein allergy; therefore, patients with severe milk protein allergy should not take SEREVENT DISKUS [see Contraindications (4)] . 5.8 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Because of the potential for drug interactions and the potential for increased risk of cardiovascular adverse events, the concomitant use of SEREVENT DISKUS with strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) is not recommended [see Drug Interactions (7.1)] . 5.9 Coexisting Conditions SEREVENT DISKUS, like all medications 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 beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.10 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medications 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 studies with SEREVENT DISKUS at recommended doses.

6 ADVERSE REACTIONS LABA, including salmeterol, the active ingredient in SEREVENT DISKUS, increase the risk of asthma-related death. Data from a large 28-week placebo-controlled US study that compared the safety of salmeterol (SEREVENT Inhalation Aerosol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients 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. The most common adverse reactions (incidence ≥5%) are: Asthma: Headache, influenza, nasal/sinus congestion, pharyngitis, rhinitis tracheitis/bronchitis. (6.1) COPD: Cough, headache, musculoskeletal pain, throat irritation, viral respiratory infection. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience in Asthma Adult and Adolescent Patients Aged 12 Years and Older: Two multicenter, 12-week, controlled studies evaluated twice-daily doses of SEREVENT DISKUS in patients aged 12 years and older with asthma. Table 1 reports the incidence of adverse reactions in these 2 studies. Table 1. Adverse Reaction Incidence in Two 12-Week Clinical Trials in Adult and Adolescent Patients With Asthma Adverse Event Percent of Patients Placebo (N = 152) SEREVENT DISKUS 50 mcg Twice Daily (N = 149) Albuterol Inhalation Aerosol 180 mcg 4 Times Daily (N = 150) Ear, nose, and throat Nasal/sinus congestion, pallor 6 9 8 Rhinitis 4 5 4 Neurological Headache 9 13 12 Respiratory Asthma 1 3 <1 Tracheitis/bronchitis 4 7 3 Influenza 2 5 5 Table 1 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common than in the placebo group. Pharyngitis, sinusitis, upper respiratory tract infection, and cough occurred at ≥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 patients with asthma treated with SEREVENT DISKUS compared with patients 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 Patients Aged 4 to 11 Years: Two multicenter, 12-week, controlled studies have evaluated twice-daily doses of SEREVENT DISKUS in patients 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 3% or greater 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 Patients With Asthma Adverse Event Percent of Patients Placebo (N = 215) SEREVENT DISKUS 50 mcg Twice Daily (N = 211) Albuterol Inhalation Aerosol 200 mcg 4 Times Daily (N = 115) Ear, nose, and throat Ear signs and symptoms 3 4 9 Pharyngitis 3 6 3 Neurological Headache 14 17 20 Respiratory Asthma 2 4 <1 Skin Skin rashes 3 4 2 Urticaria 0 3 2 The following events were reported at an incidence of >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 ≥1% of patients in clinical trials. The elevations were transient and did not lead to discontinuation from the studies. In addition, there were no clinically relevant changes noted in glucose or potassium. 6.2 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease Two multicenter, 24-week, controlled studies have evaluated twice-daily doses of SEREVENT DISKUS in patients with COPD. For presentation (Table 3), the placebo data from a third trial, identical in design, patient entrance criteria, and overall conduct but comparing fluticasone propionate with placebo, were integrated with the placebo data from these 2 studies (total N = 341 for salmeterol and 576 for placebo). Table 3. Adverse Reactions With ≥3% Incidence in US Controlled Clinical Trials With SEREVENT DISKUS in Patients With Chronic Obstructive Pulmonary Disease a Adverse Event Percent of Patients Placebo (N = 576) SEREVENT DISKUS 50 mcg Twice Daily (N = 341) Cardiovascular Hypertension 2 4 Ear, nose, and throat Throat irritation 6 7 Nasal congestion/blockage 3 4 Sinusitis 2 4 Ear signs and symptoms 1 3 Gastrointestinal Nausea and vomiting 3 3 Lower respiratory Cough 4 5 Rhinitis 2 4 Viral respiratory infection 4 5 Musculoskeletal Musculoskeletal pain 10 12 Muscle cramps and spasms 1 3 Neurological Headache 11 14 Dizziness 2 4 Average duration of exposure (days) 128.9 138.5 a Table 3 includes all events (whether considered drug-related or nondrug-related by the investigator) that occurred at a rate of 3% or greater in the group receiving SEREVENT DISKUS and were more common in the group receiving SEREVENT DISKUS than in the placebo group. Additional Adverse Reactions: Other events occurring in the group receiving SEREVENT DISKUS that occurred at a frequency of ≥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 beta 2 -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. 6.3 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 US 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.

<table border="single" width="465.000" ID="id_a3770fd7-40f0-456f-a710-267d44cecdf9"> <caption ID="id_ae1fa906-0378-46d9-8620-07f593f7e79f">Table 1. Adverse Reaction Incidence in Two 12-Week Clinical Trials in Adult and Adolescent Patients With Asthma</caption> <col width="35.7%"/> <col width="19.4%"/> <col width="22.4%"/> <col width="22.6%"/> <tbody> <tr ID="id_0b2e5091-de90-4bb8-aaf7-1000367ea33f"> <td align="center" valign="bottom" rowspan="2" styleCode="Botrule Toprule Rrule Lrule">Adverse Event</td> <td align="center" valign="bottom" colspan="3" styleCode="Rrule">Percent of Patients</td> </tr> <tr ID="id_bf7ca0f5-44c5-4198-ae91-fea473d92863"> <td align="center" valign="bottom" styleCode="Lrule Botrule Rrule"> <paragraph>Placebo</paragraph>(N = 152)</td> <td align="center" valign="bottom" styleCode="Botrule Rrule"> <paragraph>SEREVENT DISKUS</paragraph> <paragraph>50 mcg</paragraph> <paragraph>Twice Daily</paragraph>(N = 149)</td> <td align="center" valign="bottom" styleCode="Botrule Rrule"> <paragraph>Albuterol Inhalation Aerosol</paragraph> <paragraph>180 mcg</paragraph> <paragraph>4 Times Daily</paragraph>(N = 150)</td> </tr> <tr ID="id_9f34290d-c686-489a-abc9-42b8a3155ebd"> <td align="left" valign="top" styleCode="Lrule Rrule">Ear, nose, and throat</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_da10ab05-c977-45a5-a8b6-5e2dc0a0acff"> <td align="left" valign="top" styleCode="Lrule Rrule"> Nasal/sinus congestion, pallor</td> <td align="center" valign="top" styleCode="Rrule">6</td> <td align="center" valign="top" styleCode="Rrule">9</td> <td align="center" valign="top" styleCode="Rrule">8</td> </tr> <tr ID="id_1b7f98ab-f467-44d4-99c9-dce91dbfd8e2"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Rhinitis</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> </tr> <tr ID="id_a6313023-c658-4d56-bcdb-c409a90f14ee"> <td align="left" valign="top" styleCode="Lrule Rrule">Neurological</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_1f025f6c-8457-442d-bf0d-7f93602ce760"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Headache</td> <td align="center" valign="top" styleCode="Botrule Rrule">9</td> <td align="center" valign="top" styleCode="Botrule Rrule">13</td> <td align="center" valign="top" styleCode="Botrule Rrule">12</td> </tr> <tr ID="id_2327788f-d87c-44c1-b387-33555598098d"> <td align="left" valign="top" styleCode="Lrule Rrule">Respiratory</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_60d72da6-19dc-4a68-ab6c-e36dd8317cf0"> <td align="left" valign="top" styleCode="Lrule Rrule"> Asthma</td> <td align="center" valign="top" styleCode="Rrule">1</td> <td align="center" valign="top" styleCode="Rrule">3</td> <td align="center" valign="top" styleCode="Rrule">&lt;1</td> </tr> <tr ID="id_a8ac15e7-94e9-4dbc-97df-c46f609814c5"> <td align="left" valign="top" styleCode="Lrule Rrule"> Tracheitis/bronchitis</td> <td align="center" valign="top" styleCode="Rrule">4</td> <td align="center" valign="top" styleCode="Rrule">7</td> <td align="center" valign="top" styleCode="Rrule">3</td> </tr> <tr ID="id_a52b2618-af98-4905-9768-c2d6c0099454"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Influenza</td> <td align="center" valign="top" styleCode="Rrule">2</td> <td align="center" valign="top" styleCode="Rrule">5</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> </tr> </tbody> </table>

<table border="single" width="465.000" ID="id_f2bb029d-9de8-4f6c-8091-175465ea0384"> <caption ID="id_c3614afb-4374-4969-a9c9-7d130272867f">Table 2. Adverse Reaction Incidence in Two 12-Week Pediatric Clinical Trials in Patients With Asthma</caption> <col width="35.7%"/> <col width="19.4%"/> <col width="22.4%"/> <col width="22.6%"/> <tbody> <tr ID="id_043c10cc-83b4-48f9-ad39-af2db6fe287a"> <td align="center" valign="bottom" rowspan="2" styleCode="Botrule Toprule Rrule Lrule">Adverse Event</td> <td align="center" valign="bottom" colspan="3" styleCode="Rrule">Percent of Patients</td> </tr> <tr ID="id_cf2aa14a-0be7-4f5e-a929-dd39680d8a04"> <td align="center" valign="bottom" styleCode="Lrule Botrule Rrule"> <paragraph>Placebo</paragraph>(N = 215)</td> <td align="center" valign="bottom" styleCode="Botrule Rrule"> <paragraph>SEREVENT DISKUS</paragraph> <paragraph>50 mcg</paragraph> <paragraph>Twice Daily</paragraph>(N = 211)</td> <td align="center" valign="bottom" styleCode="Botrule Rrule"> <paragraph>Albuterol</paragraph> <paragraph>Inhalation Aerosol</paragraph> <paragraph>200 mcg</paragraph> <paragraph>4 Times Daily</paragraph>(N = 115)</td> </tr> <tr ID="id_bd553c30-0e07-4de0-83aa-e838b28b7612"> <td align="left" valign="top" styleCode="Lrule Rrule">Ear, nose, and throat</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_4338ca8a-c6c5-4ef7-aa29-68b74b4813c3"> <td align="left" valign="top" styleCode="Lrule Rrule"> Ear signs and symptoms</td> <td align="center" valign="top" styleCode="Rrule">3</td> <td align="center" valign="top" styleCode="Rrule">4</td> <td align="center" valign="top" styleCode="Rrule">9</td> </tr> <tr ID="id_f52d0901-ad0f-4e34-8224-a15352338a46"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Pharyngitis</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">6</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_f35a42e9-3fd6-4379-9a6d-853cee180ab2"> <td align="left" valign="top" styleCode="Lrule Rrule">Neurological</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_870d3859-025f-4f49-845c-c290be8f51d0"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Headache</td> <td align="center" valign="top" styleCode="Botrule Rrule">14</td> <td align="center" valign="top" styleCode="Botrule Rrule">17</td> <td align="center" valign="top" styleCode="Botrule Rrule">20</td> </tr> <tr ID="id_78e771b1-de6d-4fa7-a396-313dd94e4c99"> <td align="left" valign="top" styleCode="Lrule Rrule">Respiratory</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_61aad828-2cc3-48ab-ae48-292a25eaebf0"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Asthma</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">&lt;1</td> </tr> <tr ID="id_8f6e3b24-75fb-4292-9e8e-e3dbf6598cf6"> <td align="left" valign="top" styleCode="Lrule Rrule">Skin</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_a16a91be-40f2-48e5-9656-ebea2cacdd04"> <td align="left" valign="top" styleCode="Lrule Rrule"> Skin rashes</td> <td align="center" valign="top" styleCode="Rrule">3</td> <td align="center" valign="top" styleCode="Rrule">4</td> <td align="center" valign="top" styleCode="Rrule">2</td> </tr> <tr ID="id_2b5a2f85-1fa3-496b-a225-598f6eb93eab"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Urticaria</td> <td align="center" valign="top" styleCode="Rrule">0</td> <td align="center" valign="top" styleCode="Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> </tr> </tbody> </table>

<table border="single" width="459.000" ID="id_bde9aed2-4ec4-453c-802d-5d85ceea95b0"> <caption ID="id_bc28aa50-4723-4cfb-b004-563db910fa3d">Table 3. Adverse Reactions With &#x2265;3% Incidence in US Controlled Clinical Trials With SEREVENT DISKUS in Patients With Chronic Obstructive Pulmonary Disease^a </caption> <col width="49.9%"/> <col width="23.5%"/> <col width="26.6%"/> <tbody> <tr ID="id_0c12ca54-71b7-4502-a903-4c6d28e56139"> <td align="center" valign="bottom" rowspan="2" styleCode="Botrule Toprule Rrule Lrule">Adverse Event</td> <td align="center" valign="top" colspan="2" styleCode="Botrule Rrule">Percent of Patients</td> </tr> <tr ID="id_d4b56ee3-d6b9-4b2e-ae10-f7eb9b788103"> <td align="center" valign="bottom" styleCode="Lrule Botrule Rrule"> <paragraph>Placebo</paragraph>(N = 576)</td> <td align="center" valign="bottom" styleCode="Botrule Rrule"> <paragraph>SEREVENT DISKUS</paragraph> <paragraph>50 mcg Twice Daily</paragraph>(N = 341)</td> </tr> <tr ID="id_4f30118c-6dee-4aee-bd04-ffc16d4bb99c"> <td align="left" valign="top" styleCode="Lrule Rrule">Cardiovascular</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_83063a88-12b1-4c0a-9bf1-fe920d2969b4"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Hypertension</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> </tr> <tr ID="id_6116822c-f5ea-4053-9a84-22454e5c5fb4"> <td align="left" valign="top" styleCode="Lrule Rrule">Ear, nose, and throat</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_41edd67f-cc20-40e8-a9af-5603372678c4"> <td align="left" valign="top" styleCode="Lrule Rrule"> Throat irritation</td> <td align="center" valign="top" styleCode="Rrule">6</td> <td align="center" valign="top" styleCode="Rrule">7</td> </tr> <tr ID="id_89705b0a-18f6-4ad8-9673-a19500a4d1fd"> <td align="left" valign="top" styleCode="Lrule Rrule"> Nasal congestion/blockage</td> <td align="center" valign="top" styleCode="Rrule">3</td> <td align="center" valign="top" styleCode="Rrule">4</td> </tr> <tr ID="id_5efc0c6c-e814-4429-8d50-37c902b49ee7"> <td align="left" valign="top" styleCode="Lrule Rrule"> Sinusitis</td> <td align="center" valign="top" styleCode="Rrule">2</td> <td align="center" valign="top" styleCode="Rrule">4</td> </tr> <tr ID="id_d2cb79bc-0297-4044-b1c8-07af9b7c67e1"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Ear signs and symptoms</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_aef80b8a-dc6d-40e8-9cb6-4684aa292126"> <td align="left" valign="top" styleCode="Lrule Rrule">Gastrointestinal</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_4f0d1c51-eb2f-4899-8afe-f4fc4ff2292c"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Nausea and vomiting</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_fca03da5-c3b2-4aa2-895c-e859cbac32fa"> <td align="left" valign="top" styleCode="Lrule Rrule">Lower respiratory</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_0d0d4574-0f9f-41e4-ace0-395f58197203"> <td align="left" valign="top" styleCode="Lrule Rrule"> Cough</td> <td align="center" valign="top" styleCode="Rrule">4</td> <td align="center" valign="top" styleCode="Rrule">5</td> </tr> <tr ID="id_108a9d04-c041-45de-bb51-b782477e5289"> <td align="left" valign="top" styleCode="Lrule Rrule"> Rhinitis</td> <td align="center" valign="top" styleCode="Rrule">2</td> <td align="center" valign="top" styleCode="Rrule">4</td> </tr> <tr ID="id_bea02ef1-ca25-49fb-b1de-aed7c34412ce"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Viral respiratory infection</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> <td align="center" valign="top" styleCode="Botrule Rrule">5</td> </tr> <tr ID="id_fb2dfcd7-40ba-46e7-811c-c13667f0b3fc"> <td align="left" valign="top" styleCode="Lrule Rrule">Musculoskeletal</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_a4ccd6ec-5941-48fa-9030-421b62bf292b"> <td align="left" valign="top" styleCode="Lrule Rrule"> Musculoskeletal pain</td> <td align="center" valign="top" styleCode="Rrule">10</td> <td align="center" valign="top" styleCode="Rrule">12</td> </tr> <tr ID="id_a62d8083-f380-43c4-9dd9-abf2b6fbe76a"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Muscle cramps and spasms</td> <td align="center" valign="top" styleCode="Botrule Rrule">1</td> <td align="center" valign="top" styleCode="Botrule Rrule">3</td> </tr> <tr ID="id_bfc141ac-3d4e-45ea-a99b-270ebc4a00c0"> <td align="left" valign="top" styleCode="Lrule Rrule">Neurological</td> <td align="center" valign="top" styleCode="Rrule"/> <td align="center" valign="top" styleCode="Rrule"/> </tr> <tr ID="id_092d2085-6add-4dff-8916-aa5e1aa971fa"> <td align="left" valign="top" styleCode="Lrule Rrule"> Headache</td> <td align="center" valign="top" styleCode="Rrule">11</td> <td align="center" valign="top" styleCode="Rrule">14</td> </tr> <tr ID="id_40c50f34-d684-4cfe-8df7-9ef2681de6cd"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule"> Dizziness</td> <td align="center" valign="top" styleCode="Botrule Rrule">2</td> <td align="center" valign="top" styleCode="Botrule Rrule">4</td> </tr> <tr ID="id_87860807-9974-42ac-914c-d8fabe9b5e2e"> <td align="left" valign="top" styleCode="Lrule Botrule Rrule">Average duration of exposure (days)</td> <td align="center" valign="top" styleCode="Rrule">128.9</td> <td align="center" valign="top" styleCode="Botrule Rrule">138.5</td> </tr> </tbody> </table>