RELENZA

5 WARNINGS AND PRECAUTIONS • Bronchospasm: Serious, sometimes fatal, cases have occurred. Not recommended in individuals with underlying airways disease. Discontinue RELENZA if bronchospasm or decline in respiratory function develops. ( 5.1 ) • Allergic Reactions: Discontinue RELENZA and initiate appropriate treatment if an allergic reaction occurs or is suspected. ( 5.2 ) • Neuropsychiatric Events: Patients with influenza, particularly pediatric patients, may be at an increased risk of seizures, confusion, or abnormal behavior early in their illness. Monitor for signs of abnormal behavior. ( 5.3 ) • High-Risk Underlying Medical Conditions: Safety and effectiveness have not been demonstrated in these patients. ( 5.4 ) 5.1 Bronchospasm RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease). Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess. RELENZA should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required. Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions. Bronchospasm was documented following administration of zanamivir in 1 of 13 subjects with mild or moderate asthma (but without acute influenza‑like illness) in a Phase 1 trial. In a Phase 3 trial in subjects with acute influenza‑like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of subjects on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in forced expiratory volume in 1 second (FEV 1 ) following treatment for 5 days. If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. If a decision is made to prescribe RELENZA for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation, and appropriate supportive care, including availability of fast‑acting bronchodilators. 5.2 Allergic Reactions Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected. 5.3 Neuropsychiatric Events Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. There have been postmarketing reports of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors (NAIs), including RELENZA. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon based on usage data for RELENZA. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RELENZA to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient. 5.4 Limitations of Populations Studied Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management. 5.5 Bacterial Infections Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications. 5.6 Importance of Proper Route of Administration RELENZA inhalation powder must not be made into an extemporaneous solution for administration by nebulization or mechanical ventilation. There have been reports of hospitalized patients with influenza who received a solution made with RELENZA inhalation powder administered by nebulization or mechanical ventilation, including a fatal case where it was reported that the lactose in this formulation obstructed the proper functioning of the equipment. RELENZA inhalation powder must only be administered using the device provided [see Dosage and Administration ( 2.1 )] . 5.7 Importance of Proper Use of DISKHALER Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully evaluate the ability of young children to use the delivery system if use of RELENZA is considered [see Use in Specific Populations ( 8.4 )].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Bronchospasm [see Warnings and Precautions ( 5.1 )] . • Safety information in patients with underlying airways disease [see Warnings and Precautions ( 5.1 )]. • Allergic-like reactions [see Warnings and Precautions ( 5.2 )] . The most common adverse events reported in greater than 1.5% of subjects treated with RELENZA and more commonly than in subjects treated with placebo are: • Treatment Trials – sinusitis, dizziness. ( 6.1 ) • Prophylaxis Trials – fever and/or chills, arthralgia, and articular rheumatism. ( 6.1 ) 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 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 placebo used in clinical trials consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation. Treatment of Influenza Clinical Trials in Adults and Adolescents: Adverse events that occurred with an incidence greater than or equal to 1.5% in treatment trials are listed in Table 1. This table shows adverse events occurring in subjects aged 12 years and older receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). Table 1. Summary of Adverse Events ≥1.5% Incidence during Treatment in Adults and Adolescents a Includes trials where RELENZA was administered intranasally (6.4 mg 2 to 4 times per day in addition to inhaled preparation) and/or inhaled more frequently (q.i.d.) than the currently recommended dose. Adverse Event RELENZA Placebo (Lactose Vehicle) (n = 1,520) 10 mg b.i.d. Inhaled (n = 1,132) All Dosing Regimens a (n = 2,289) Body as a whole Headaches 2% 2% 3% Digestive Diarrhea 3% 3% 4% Nausea 3% 3% 3% Vomiting 1% 1% 2% Respiratory Nasal signs and symptoms 2% 3% 3% Bronchitis 2% 2% 3% Cough 2% 2% 3% Sinusitis 3% 2% 2% Ear, nose, and throat infections 2% 1% 2% Nervous system Dizziness 2% 1% <1% Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria. The most frequent laboratory abnormalities in Phase 3 treatment trials included elevations of liver enzymes and creatine phosphokinase (CPK), lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza‑like illness. Clinical Trials in Pediatric Subjects: Adverse events that occurred with an incidence greater than or equal to 1.5% in children receiving treatment doses of RELENZA in 2 Phase 3 trials are listed in Table 2 . This table shows adverse events occurring in pediatric subjects aged 5 to 12 years receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). Table 2. Summary of Adverse Events ≥1.5% Incidence during Treatment in Pediatric Subjects a a Includes a subset of subjects receiving RELENZA for treatment of influenza in a prophylaxis trial. Adverse Event RELENZA 10 mg b.i.d. Inhaled (n = 291) Placebo (Lactose Vehicle) (n = 318) Respiratory Ear, nose, and throat infections 5% 5% Ear, nose, and throat hemorrhage <1% 2% Asthma <1% 2% Cough <1% 2% Digestive Vomiting 2% 3% Diarrhea 2% 2% Nausea <1% 2% In 1 of the 2 trials described in Table 2 , some additional information is available from children (aged 5 to 12 years) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients. Prophylaxis of Influenza Family/Household Prophylaxis Trials: Adverse events that occurred with an incidence of greater than or equal to 1.5% in the 2 prophylaxis trials are listed in Table 3 . This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 10 days. Table 3. Summary of Adverse Events ≥1.5% Incidence during 10-Day Prophylaxis Trials in Adults, Adolescents, and Children a a In prophylaxis trials, symptoms associated with influenza-like illness were captured as adverse events; subjects were enrolled during a winter respiratory season during which time any symptoms that occurred were captured as adverse events. Adverse Event Contact Cases RELENZA (n = 1,068) Placebo (n = 1,059) Lower respiratory Viral respiratory infections 13% 19% Cough 7% 9% Neurologic Headaches 13% 14% Ear, nose, and throat Nasal signs and symptoms 12% 12% Throat and tonsil discomfort and pain 8% 9% Nasal inflammation 1% 2% Musculoskeletal Muscle pain 3% 3% Endocrine and metabolic Feeding problems (decreased or increased appetite and anorexia) 2% 2% Gastrointestinal Nausea and vomiting 1% 2% Non-site specific Malaise and fatigue 5% 5% Temperature regulation disturbances (fever and/or chills) 5% 4% Community Prophylaxis Trials: Adverse events that occurred with an incidence of greater than or equal to 1.5% in 2 prophylaxis trials are listed in Table 4 . This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 28 days. Table 4. Summary of Adverse Events ≥1.5% Incidence during 28-Day Prophylaxis Trials in Adults, Adolescents, and Children a a In prophylaxis trials, symptoms associated with influenza-like illness were captured as adverse events; subjects were enrolled during a winter respiratory season during which time any symptoms that occurred were captured as adverse events. Adverse Event RELENZA (n = 2,231) Placebo (n = 2,239) Neurologic Headaches 24% 26% Ear, nose, and throat Throat and tonsil discomfort and pain 19% 20% Nasal signs and symptoms 12% 13% Ear, nose, and throat infections 2% 2% Lower respiratory Cough 17% 18% Viral respiratory infections 3% 4% Musculoskeletal Muscle pain 8% 8% Musculoskeletal pain 6% 6% Arthralgia and articular rheumatism 2% <1% Endocrine and metabolic Feeding problems (decreased or increased appetite and anorexia) 4% 4% Gastrointestinal Nausea and vomiting 2% 3% Diarrhea 2% 2% Non-site specific Temperature regulation disturbances (fever and/or chills) 9% 10% Malaise and fatigue 8% 8% 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of RELENZA. 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. Allergic Reactions Allergic or allergic-like reaction, including oropharyngeal edema [see Warnings and Precautions ( 5.2 )] . Psychiatric Delirium, including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares [see Warnings and Precautions ( 5.3 )]. Cardiac Arrhythmias, syncope. Neurologic Seizures. Vasovagal-like episodes have been reported shortly following inhalation of zanamivir. Respiratory Bronchospasm, dyspnea [see Warnings and Precautions ( 5.1 )] . Skin Facial edema; rash, including serious cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria [see Warnings and Precautions ( 5.2 )] .

<table ID="_RefTOC_END" width="100%"><caption>Table 1. Summary of Adverse Events &#x2265;1.5% Incidence during Treatment in Adults and Adolescents</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tfoot><tr><td align="left" colspan="4" valign="top">^a Includes trials where RELENZA was administered intranasally (6.4 mg 2 to 4 times per day in addition to inhaled preparation) and/or inhaled more frequently (q.i.d.) than the currently recommended dose.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">RELENZA</content></paragraph></td><td align="center" rowspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(Lactose Vehicle)</content></paragraph><paragraph><content styleCode="bold">(n = 1,520)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">10 mg b.i.d. <content styleCode="underline">Inhaled</content></content></paragraph><paragraph><content styleCode="bold">(n = 1,132)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Dosing Regimens^a</content></paragraph><paragraph><content styleCode="bold">(n = 2,289)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Body as a whole</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Headaches</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Digestive</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nasal signs and symptoms</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Bronchitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Sinusitis</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Ear, nose, and throat infections</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Nervous system</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Dizziness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr></tbody></table>

<table ID="_Reftable_2" width="100%"><caption>Table 2. Summary of Adverse Events &#x2265;1.5% Incidence during Treatment in Pediatric Subjects^a</caption><col width="46%"/><col width="29%"/><col width="25%"/><tfoot><tr><td align="left" colspan="3" valign="top">^a Includes a subset of subjects receiving RELENZA for treatment of influenza in a prophylaxis trial.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">RELENZA</content></paragraph><paragraph><content styleCode="bold">10 mg b.i.d. Inhaled</content></paragraph><paragraph><content styleCode="bold">(n = 291)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(Lactose Vehicle)</content></paragraph><paragraph><content styleCode="bold">(n = 318)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Ear, nose, and throat infections</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Ear, nose, and throat hemorrhage</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Asthma</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Digestive</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>

<table ID="_Reftable_3" width="100%"><caption>Table 3. Summary of Adverse Events &#x2265;1.5% Incidence during 10-Day Prophylaxis Trials in Adults, Adolescents, and Children^a</caption><col width="33%"/><col width="33%"/><col width="33%"/><tfoot><tr><td align="left" colspan="3" valign="top">^a In prophylaxis trials, symptoms associated with influenza-like illness were captured as adverse events; subjects were enrolled during a winter respiratory season during which time any symptoms that occurred were captured as adverse events.</td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Contact Cases</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">RELENZA</content></paragraph><paragraph><content styleCode="bold">(n = 1,068)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 1,059)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Lower respiratory</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Viral respiratory infections</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Neurologic</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Headaches</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Ear, nose, and throat</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nasal signs and symptoms</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>12%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Throat and tonsil discomfort and pain</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nasal inflammation</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Muscle pain</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Endocrine and metabolic</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Feeding problems (decreased or increased appetite and anorexia)</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea and vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Non-site specific</content></paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Malaise and fatigue</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Temperature regulation disturbances (fever and/or chills)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>