FDA label e4c93201-2be3-2299-e053-2a95a90aaf2c

5 WARNINGS AND PRECAUTIONS LABA monotherapy increases the risk of serious asthma-related events. ( 5.1 ) Do not initiate in acutely deteriorating COPD or asthma. Do not use to treat acute symptoms. ( 5.2 ) Do not use in combination with an additional medicine containing a LABA because of risk of overdose. ( 5.3 ) Candida albicans infection of the mouth and pharynx may occur. Monitor patients periodically. Advise the patient to rinse his/her mouth with water without swallowing after inhalation to help reduce the risk. ( 5.4 ) Increased risk of pneumonia in patients with COPD. Monitor patients for signs and symptoms of pneumonia. ( 5.5 ) Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.6 ) Risk of impaired adrenal function when transferring from systemic corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. ( 5.7 ) Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly. ( 5.8 ) If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy. ( 5.10 ) Use with caution in patients with cardiovascular disorders because of beta-adrenergic stimulation. ( 5.12 ) Assess for decrease in bone mineral density initially and periodically thereafter. ( 5.13 ) Glaucoma and cataracts may occur with long-term use of ICS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREO ELLIPTA long term. ( 5.14 ) Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. ( 5.15 ) Increased blood glucose levels have been reported. Also, be alert to hypokalemia. ( 5.16 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)] . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma‑related events (hospitalizations, intubations, death) compared with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists) . Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta 2 -adrenergic Agonists Four (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma. Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder, and 1 trial compared mometasone furoate/formoterol with mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol inhalation powder with fluticasone propionate inhalation powder. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A blinded adjudication committee determined whether events were asthma related. The 3 adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk margin of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone ( Table 1 ). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist. a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related. ICS/LABA (n = 17,537) a ICS (n = 17,552) a ICS/LABA vs. ICS Hazard Ratio (95% CI) b Serious asthma-related event c 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24-hour stay) 115 105 The pediatric safety trial included 6,208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3,107 (0.9%) subjects randomized to ICS/LABA and 21/3,101 (0.7%) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared with ICS based on the pre-specified risk margin (2.7), with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled, U.S. trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. 5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD or asthma. BREO ELLIPTA has not been studied in subjects with acutely deteriorating COPD or asthma. The initiation of BREO ELLIPTA in this setting is not appropriate. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA 100/25 no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting, beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once. For COPD, increasing the daily dose of BREO ELLIPTA 100/25 is not appropriate in this situation. 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 replacing the current strength of BREO ELLIPTA with a higher strength, adding additional ICS, or initiating systemic corticosteroids. Patients should not use more than 1 inhalation once daily of BREO ELLIPTA. BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta 2 -agonist. When beginning treatment with BREO ELLIPTA, 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 and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient on how it should be used. 5.3 Excessive Use of BREO ELLIPTA and Use with Other Long-acting Beta 2 -agonists BREO ELLIPTA 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 BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason. 5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth with water without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis. 5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA 100/25 in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with moderate to severe COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving fluticasone furoate/vilanterol 50 mcg/25 mcg: 6% (48 of 820 subjects); BREO ELLIPTA 100/25: 6% (51 of 806 subjects); or BREO ELLIPTA 200/25: 7% (55 of 811 subjects) than in subjects receiving vilanterol 25 mcg: 3% (27 of 818 subjects). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving BREO ELLIPTA 100/25 and in 7 subjects receiving BREO ELLIPTA 200/25 (<1% for each treatment group). In a mortality trial with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease, the annualized incidence rate of pneumonia was 3.4 per 100 patient-years for BREO ELLIPTA 100/25, 3.2 for placebo, 3.3 for fluticasone furoate 100 mcg, and 2.3 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to pneumonia occurred in 13 subjects receiving BREO ELLIPTA 100/25, 9 subjects receiving placebo, 10 subjects receiving fluticasone furoate 100 mcg, and 6 subjects receiving vilanterol 25 mcg (<0.2 per 100 patient-years for each treatment group). 5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. ICS should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.7 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to ICS because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available ICS. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD or asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress, a severe COPD exacerbation, or a severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress, a severe COPD exacerbation, or a severe asthma attack. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (FEV 1 or peak expiratory flow), beta-agonist use, and COPD or asthma symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function. 5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic doses of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions ( 5.9 ), Drug Interactions ( 7.1 )] . Because of the possibility of significant systemic absorption of ICS in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD or asthma symptoms should be considered. 5.9 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]. 5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted. 5.11 Hypersensitivity Reactions, including Anaphylaxis Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of BREO ELLIPTA. Discontinue BREO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder medications containing lactose; therefore, patients with severe milk protein allergy should not use BREO ELLIPTA [see Contraindications ( 4 )] . 5.12 Cardiovascular Effects Vilanterol, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12- or 10-fold higher systemic exposure than seen in subjects with COPD or asthma, respectively) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. In a mortality trial with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease, the annualized incidence rate of adjudicated cardiovascular events (composite of myocardial infarction, stroke, unstable angina, transient ischemic attack, or on-treatment death due to cardiovascular events) was 2.5 per 100 patient-years for BREO ELLIPTA 100/25, 2.7 for placebo, 2.4 for fluticasone furoate 100 mcg, and 2.6 for vilanterol 25 mcg. Adjudicated, on-treatment deaths due to cardiovascular events occurred in 82 subjects receiving BREO ELLIPTA 100/25, 86 subjects receiving placebo, 80 subjects receiving fluticasone furoate 100 mcg, and 90 subjects receiving vilanterol 25 mcg (annualized incidence rate ranged from 1.2 to 1.3 per 100 patient-years for the treatment groups). 5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with moderate to severe COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) compared with <1% of subjects receiving vilanterol 25 mcg alone (8 of 818 subjects). Similar findings were seen in a mortality trial with a median treatment duration of 1.5 years in 16,568 subjects with moderate COPD and cardiovascular disease. 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD or asthma following the long-term administration of ICS. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use BREO ELLIPTA long term. 5.15 Coexisting Conditions BREO ELLIPTA, 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 beta 2 -adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16 Hyperglycemia and Hypokalemia There have been reports of increases in blood glucose levels with BREO ELLIPTA. This should be considered in patients with a history of, or with risk factors for, diabetes mellitus [see Adverse Reactions ( 6.3 )] . Beta-adrenergic agonist medicines 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. In clinical trials evaluating BREO ELLIPTA in subjects with COPD or asthma, there was no evidence of a treatment effect on serum potassium. 5.17 Effect on Growth Orally inhaled corticosteroids may cause a reduction in growth velocity when administered to children and adolescents. [See Use in Specific Populations ( 8.4 ).]

<table ID="_Reft1" width="100%"><caption>Table 1. Meta-analysis of Serious Asthma-Related Events in Subjects with Asthma Aged 12 Years and Older</caption><col width="42%"/><col width="16%"/><col width="16%"/><col width="26%"/><tfoot><tr><td align="left" colspan="4" styleCode="Botrule" valign="top">ICS = Inhaled Corticosteroid, LABA = Long-acting Beta ₂-adrenergic Agonist. </td></tr><tr><td align="left" colspan="4" styleCode="Botrule" valign="top">^a Randomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. </td></tr><tr><td align="left" colspan="4" styleCode="Botrule" valign="top">^b Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. </td></tr><tr><td align="left" colspan="4" styleCode="Botrule" valign="top">^c Number of subjects with event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma related. </td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ICS/LABA</content></paragraph><paragraph><content styleCode="bold">(n = 17,537) ^a</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ICS</content></paragraph><paragraph><content styleCode="bold">(n = 17,552) ^a</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ICS/LABA vs. ICS</content></paragraph><paragraph><content styleCode="bold">Hazard Ratio (95% CI) ^b</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Serious asthma-related event ^c</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>116</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>105</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1.10 (0.85, 1.44)</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Asthma-related death</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>0</paragraph></td><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Asthma-related intubation (endotracheal)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Lrule " valign="top"><paragraph>2</paragraph></td><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Asthma-related hospitalization (&#x2265;24-hour stay)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>115</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>105</paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"/></tr></tbody></table>

6 ADVERSE REACTIONS Use of LABA may result in the following: Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] Cardiovascular effects [see Warnings and Precautions ( 5.12 )] Systemic and local corticosteroid use may result in the following: Candida albicans infection [see Warnings and Precautions ( 5.4 )] Increased risk of pneumonia in COPD [see Warnings and Precautions ( 5.5 )] Immunosuppression [see Warnings and Precautions ( 5.6 )] Hypercorticism and adrenal suppression [see Warnings and Precautions ( 5.8 )] Reduction in bone mineral density [see Warnings and Precautions ( 5.13 )] 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. COPD: Most common adverse reactions (incidence ≥3%) are nasopharyngitis, upper respiratory tract infection, headache, oral candidiasis, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, and pyrexia. ( 6.1 ) Asthma: Most common adverse reactions (incidence ≥2%) are nasopharyngitis, oral candidiasis, headache, influenza, upper respiratory tract infection, bronchitis, sinusitis, oropharyngeal pain, dysphonia, and cough. ( 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 Chronic Obstructive Pulmonary Disease The clinical program for BREO ELLIPTA included more than 24,000 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, 1 mortality trial, and 6 other trials of shorter duration. A total of 6,174 subjects with COPD received at least 1 dose of BREO ELLIPTA 100/25, and 1,087 subjects received a higher strength of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6- and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials. 6-Month Trials The incidence of adverse reactions associated with BREO ELLIPTA 100/25 in Table 2 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were white. They had a mean age of 62 years and an average smoking history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV 1 /forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo. Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with ≥3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis. Adverse Reaction BREO ELLIPTA 100/25 (n = 410) % Vilanterol 25 mcg (n = 408) % Fluticasone Furoate 100 mcg (n = 410) % Placebo (n = 412) % Infections and infestations Nasopharyngitis 9 10 8 8 Upper respiratory tract infection 7 5 4 3 Oropharyngeal candidiasis a 5 2 3 2 Nervous system disorders Headache 7 9 7 5 12-Month Trials Long-term safety data are based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were white. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV 1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV 1 /FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, fluticasone furoate/vilanterol 50 mcg/25 mcg, or vilanterol 25 mcg. In addition to the reactions shown in Table 2 , adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA 100/25 (n = 806) for 12 months included back pain, pneumonia [see Warnings and Precautions ( 5.5 )] , bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, influenza, pharyngitis, and pyrexia. Mortality Trial Safety data are available from a mortality trial in subjects with moderate COPD (moderate airflow limitation [≥50% and ≤70% predicted FEV 1 ]) who either had a history of, or were at risk of, cardiovascular disease and were treated for up to 4 years (median treatment duration of 1.5 years). The trial included 16,568 subjects, 4,140 of whom received BREO ELLIPTA 100/25. In addition to the events in COPD trials shown in Table 2, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA 100/25 and more common than placebo included pneumonia, back pain, hypertension, and influenza. 6.2 Clinical Trials Experience in Asthma BREO ELLIPTA for the treatment of asthma was studied in 18 double-blind, parallel-group, controlled trials (11 with placebo) of 4 to 76 weeks’ duration, which enrolled 9,969 subjects with asthma. BREO ELLIPTA 100/25 was studied in 2,369 subjects and BREO ELLIPTA 200/25 was studied in 956 subjects. While subjects aged 12 to 17 years were included in these trials, BREO ELLIPTA is not approved for use in this age group [see Use in Specific Populations ( 8.4 )] . The safety data described below are based on two 12-week efficacy trials, one 24-week efficacy trial, and 2 long-term trials. 12-Week Trials Trial 1 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25 in adult and adolescent subjects with asthma compared with fluticasone furoate 100 mcg and placebo. Of the 609 subjects, 58% were female and 84% were white; the mean age was 40 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 is shown in Table 3 . Table 3. Adverse Reactions with BREO ELLIPTA 100/25 with ≥2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1) a Includes oral candidiasis and oropharyngeal candidiasis. Adverse Reaction BREO ELLIPTA 100/25 (n = 201) % Fluticasone Furoate 100 mcg (n = 205) % Placebo (n = 203) % Infections and infestations Nasopharyngitis 10 7 7 Oral candidiasis a 2 2 0 Nervous system disorders Headache 5 4 4 Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 2 2 1 Dysphonia 2 1 0 Trial 2 was a 12-week trial that evaluated the efficacy of BREO ELLIPTA 100/25, BREO ELLIPTA 200/25, and fluticasone furoate 100 mcg in adult and adolescent subjects with asthma. This trial did not have a placebo arm. Of the 1,039 subjects, 60% were female and 88% were white; the mean age was 46 years. The incidence of adverse reactions associated with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 is shown in Table 4 . Table 4. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with ≥2% Incidence in Subjects with Asthma (Trial 2) Adverse Reaction BREO ELLIPTA 200/25 (n = 346) % BREO ELLIPTA 100/25 (n = 346) % Fluticasone Furoate 100 mcg (n = 347) % Nervous system disorders Headache 8 8 9 Infections and infestations Nasopharyngitis 7 6 7 Influenza 3 3 1 Upper respiratory tract infection 2 2 3 Sinusitis 2 1 <1 Bronchitis 2 <1 2 Respiratory, thoracic and mediastinal disorders Oropharyngeal pain 2 2 1 Cough 1 2 1 24-Week Trial Trial 3 was a 24-week trial that evaluated the efficacy of BREO ELLIPTA 200/25 once daily, fluticasone furoate 200 mcg once daily, and fluticasone propionate 500 mcg twice daily in adult and adolescent subjects with asthma. Of the 586 subjects, 59% were female and 84% were white; the mean age was 46 years. This trial did not have a placebo arm. In addition to the reactions shown in Tables 3 and 4 , adverse reactions occurring in ≥2% of subjects treated with BREO ELLIPTA 200/25 included viral respiratory tract infection, pharyngitis, pyrexia, and arthralgia. 12-Month Trial Long-term safety data are based on a 12-month trial that evaluated the safety of BREO ELLIPTA 100/25 once daily (n = 201), BREO ELLIPTA 200/25 once daily (n = 202), and fluticasone propionate 500 mcg twice daily (n = 100) in adult and adolescent subjects with asthma (Trial 4). Overall, 63% were female and 67% were white. The mean age was 39 years; adolescents (aged 12 to 17 years) made up 16% of the population. In addition to the reactions shown in Tables 3 and 4, adverse reactions occurring in ≥2% of the subjects treated with BREO ELLIPTA 100/25 or BREO ELLIPTA 200/25 for 12 months included pyrexia, back pain, extrasystoles, upper abdominal pain, respiratory tract infection, allergic rhinitis, pharyngitis, rhinitis, arthralgia, supraventricular extrasystoles, ventricular extrasystoles, acute sinusitis, and pneumonia. Exacerbation Trial In a 24- to 76-week trial, subjects received BREO ELLIPTA 100/25 (n = 1,009) or fluticasone furoate 100 mcg (n = 1,010) (Trial 5). Subjects participating in this trial had a history of 1 or more asthma exacerbations that required treatment with oral/systemic corticosteroids or emergency department visit or in-patient hospitalization for the treatment of asthma in the year prior to trial entry. Overall, 67% were female and 73% were white; the mean age was 42 years (adolescents aged 12 to 17 years made up 14% of the population). While subjects aged 12 to 17 years were included in this trial, BREO ELLIPTA is not approved for use in this age group [see Use in Specific Populations ( 8.4 )] . Asthma-related hospitalizations occurred in 10 subjects (1%) treated with BREO ELLIPTA 100/25 compared with 7 subjects (0.7%) treated with fluticasone furoate 100 mcg. Among subjects aged 12 to 17 years, asthma-related hospitalizations occurred in 4 subjects (2.6%) treated with BREO ELLIPTA 100/25 (n = 151) compared with 0 subjects treated with fluticasone furoate 100 mcg (n = 130). There were no asthma-related deaths or asthma-related intubations observed in this trial. 6.3 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of BREO ELLIPTA. 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 BREO ELLIPTA or a combination of these factors. Cardiac Disorders Palpitations, tachycardia. Immune System Disorders Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Metabolism and Nutrition Disorders Hyperglycemia. Musculoskeletal and Connective Tissue Disorders Muscle spasms. Nervous System Disorders Tremor. Psychiatric Disorders Nervousness. Respiratory, Thoracic, and Mediastinal Disorders Paradoxical bronchospasm.

<table ID="_Ref517173642" width="100%"><caption>Table 2. Adverse Reactions with BREO ELLIPTA 100/25 with &#x2265;3% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease</caption><col width="33%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="17%"/><tfoot><tr><td align="left" colspan="5" styleCode="Botrule" valign="top">^a Includes oral candidiasis, oropharyngeal candidiasis, candidiasis, and fungal oropharyngitis. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">BREO ELLIPTA</content></paragraph><paragraph><content styleCode="bold">100/25</content></paragraph><paragraph><content styleCode="bold">(n = 410)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Vilanterol</content></paragraph><paragraph><content styleCode="bold">25 mcg</content></paragraph><paragraph><content styleCode="bold">(n = 408)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Fluticasone Furoate</content></paragraph><paragraph><content styleCode="bold">100 mcg</content></paragraph><paragraph><content styleCode="bold">(n = 410)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 412)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Infections and infestations</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Nasopharyngitis </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Upper respiratory tract infection </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item> Oropharyngeal candidiasis ^a</item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nervous system disorders</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item> Headache </item></list></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>5</paragraph></td></tr></tbody></table>

<table ID="_Reftable_3" width="100%"><caption>Table 3. Adverse Reactions with BREO ELLIPTA 100/25 with &#x2265;2% Incidence and More Common than Placebo in Subjects with Asthma (Trial 1)</caption><col width="46%"/><col width="20%"/><col width="19%"/><col width="14%"/><tfoot><tr><td align="left" colspan="4" styleCode="Botrule" valign="top">^a Includes oral candidiasis and oropharyngeal candidiasis. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">BREO ELLIPTA</content></paragraph><paragraph><content styleCode="bold">100/25</content></paragraph><paragraph><content styleCode="bold">(n = 201)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Fluticasone Furoate</content></paragraph><paragraph><content styleCode="bold">100 mcg</content></paragraph><paragraph><content styleCode="bold">(n = 205)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 203)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Infections and infestations</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Nasopharyngitis </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item> Oral candidiasis ^a</item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nervous system disorders</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item> Headache </item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Respiratory, thoracic, and mediastinal disorders</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Oropharyngeal pain </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item> Dysphonia </item></list></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

<table ID="_Reftable_4" width="100%"><caption>Table 4. Adverse Reactions with BREO ELLIPTA 100/25 and BREO ELLIPTA 200/25 with &#x2265;2% Incidence in Subjects with Asthma (Trial 2)</caption><col width="43%"/><col width="19%"/><col width="19%"/><col width="19%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">BREO ELLIPTA</content></paragraph><paragraph><content styleCode="bold">200/25</content></paragraph><paragraph><content styleCode="bold">(n = 346)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">BREO ELLIPTA</content></paragraph><paragraph><content styleCode="bold">100/25</content></paragraph><paragraph><content styleCode="bold">(n = 346)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Fluticasone Furoate</content></paragraph><paragraph><content styleCode="bold">100 mcg</content></paragraph><paragraph><content styleCode="bold">(n = 347)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nervous system disorders</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item> Headache </item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Infections and infestations</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Nasopharyngitis </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Influenza </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Upper respiratory tract infection </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Sinusitis </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item> Bronchitis </item></list></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Respiratory, thoracic and mediastinal disorders</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item> Oropharyngeal pain </item></list></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><list listType="unordered"><item> Cough </item></list></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>