FDA label 6622d6db-adf4-4e36-b243-c23f3d4ba08e

WARNING : ASTHMA-RELATED DEATH L ong-acting beta 2 -adrenergic agonist s (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US study that compared the safety of another long-acting beta 2 -adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including indacaterol, the active ingredient in ARCAPTA NEOHALER . The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. A RCAPTA NEOHALER is not indicated for the treatment of asthma. [See C ontraindications (4), W arnings and Precautions (5.1) ] . WARNING : ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning L ong -acting beta 2 -adrenergic agonist s (LABA) increase the risk of asthma-related death ( 5.1 ) . A placebo-controlled study with another long-acting beta 2 -adrenergic agonist (salmeterol) showed an increase in asthma-related deaths in patients receiving salmeterol. ( 5.1 ) This finding of an increased risk of asthma-related death with salmeterol is considered a class effect of LABA, including indacaterol , the active ingredient in ARCAPTA NEOHALER . The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established . A RCAPTA NEOHALER is not indicated for the treatment of asthma. ( 4 , 5.1 )

5 WARNINGS AND PRECAUTIONS Do not initiate in acutely deteriorating COPD patients ( 5.2 ) Do not use for relief of acute symptoms. Concomitant short-acting beta 2 -agonists can be used as needed for acute relief ( 5.2 ) Do not exceed the recommended dose. Excessive use or use in conjunction with other medications containing LABA can result in clinically significant cardiovascular effects and may be fatal ( 5.3 ) Immediate hypersensitivity reactions may occur. Discontinue immediately. ( 5.4 ) Life-threatening paradoxical bronchospasm can occur. Discontinue immediately. ( 5.5 ) Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis or sensitivity to sympathomimetic drugs. ( 5.6 , 5.7 ) 5.1 Asthma-Related Death [See Boxed Warning] Data from a large placebo-controlled study in asthma patients showed that long-acting beta 2 -adrenergic agonists may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by long-acting beta 2 -adrenergic agonists. A 28-week, placebo-controlled US study comparing the safety of another long-acting beta 2 -adrenergic agonist ( salmeterol ) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). The increased risk of asthma-related death is considered a class effect of the long-acting beta 2 -adrenergic agonists, including ARCAPTA NEOHALER . No study adequate to determine whether the rate of asthma-related death is increased in patients treated with ARCAPTA NEOHALER has been conducted. The safety and efficacy of ARCAPTA NEOHALER in patients with asthma have not been established. ARCAPTA NEOHALER is not indicated for the treatment of asthma. [ see Contraindications (4 )]. Serious asthma-related events, including death, were reported in clinical studies with ARCAPTA NEOHALER. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups . [see Adverse Reactions ( 6.2 )] . 5.2 Deterioration of Disease and Acute Episodes ARCAPTA NEOHALER should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. ARCAPTA NEOHALER has not been studied in patients with acutely deteriorating COPD. The use of ARCAPTA NEOHALER in this setting is inappropriate. ARCAPTA NEOHALER should not be used for the relief of acute symptoms, i.e. as rescue therapy for the treatment of acute episodes of bronchospasm. ARCAPTA NEOHALER 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 ARCAPTA NEOHALER, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing ARCAPTA NEOHALER, the healthcare provider should also prescribe an inhaled, short-acting beta 2 - agonist and instruct the patient on how it should be used. Increasing inhaled beta 2 -agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If ARCAPTA NEOHALER no longer controls the symptoms of bronchoconstriction, or the patient’s inhaled, short-acting beta 2 -agonist becomes less effective or the patient needs more inhalation of short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of ARCAPTA NEOHALER beyond the recommended dose is not appropriate in this situation. 5.3 Excessive Use of ARCAPTA NEOHALER and Use with Other Long-Acting Beta 2 -Agonists As with other inhaled beta 2 -adrenergic drugs, ARCAPTA NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta 2 -agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.4 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of ARCAPTA NEOHALER. If signs suggesting allergic reactions (in particular, difficulties in breathing or swallowing, swelling of tongue, lips and face, urticaria, skin rash) occur, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted. 5.5 Paradoxical Bronchospasm As with other inhaled beta 2 -agonists, ARCAPTA NEOHALER may produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, ARCAPTA NEOHALER should be discontinued immediately and alternative therapy instituted. 5.6 Cardiovascular Effects ARCAPTA NEOHALER, 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, or symptoms. If such effects occur, ARCAPTA NEOHALER 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, although the clinical significance of these findings is unknown. Therefore, ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.7 Coexisting Conditions ARCAPTA NEOHALER, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. 5.8 Hypokalemia and Hyperglycemia Beta 2 -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. Inhalation of high doses of beta 2 -adrenergic agonists may produce increases in plasma glucose. Clinically notable decreases in serum potassium or changes in blood glucose were infrequent during clinical studies with long-term administration of ARCAPTA NEOHALER with the rates similar to those for placebo controls. ARCAPTA NEOHALER has not been investigated in patients whose diabetes mellitus is not well controlled.

6 ADVERSE REACTIONS L ong - acting beta 2 -adrenergic agonists , such as A RCAPTA NEOHALER , increase the risk of asthma-related death . ARCAPTA NEOHALER is not indicated for the treatment of asthma [See B oxed Warning and W arning and Precautions (5.1) ]. Most common adverse reactions (>2% and more common than placebo) are cough, oropharyngeal pain, nasopharyngitis, headache and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience in Chronic Obstructive Pulmonary Disease Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The ARCAPTA NEOHALER safety database reflects exposure of 2516 patients to ARCAPTA NEOHALER at doses of 75 mcg or greater for at least 12 weeks in six confirmatory randomized, double-blind, placebo and active-controlled clinical trials (see Section 14). In these trials, 449 patients were exposed to the recommended dose of 75 mcg for up to 3 months, and 144, 583 and 425 COPD patients were exposed to a dose of 150, 300 or 600 mcg for one year, respectively. Overall, patients had a mean pre-bronchodilator forced expiratory volume in one second (FEV 1 ) percent predicted of 54%. The mean age of patients was 64 years, with 47% of patients aged 65 years or older, and the majority (88%) was Caucasian. In these six clinical trials, 48% of patients treated with any dose of ARCAPTA NEOHALER reported an adverse reaction compared with 43% of patients treated with placebo. The proportion of patients who discontinued treatment due to adverse reaction was 5% for ARCAPTA NEOHALER-treated patients and 5% for placebo-treated patients. The most common adverse reactions that lead to discontinuation of ARCAPTA NEOHALER were COPD and dyspnea. The most common serious adverse reactions were COPD exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar rates across treatment groups. Table 1 displays adverse drug reactions reported by at least 2% of patients (and higher than placebo) during a 3 month exposure at the recommended 75 mcg once daily dose. Adverse drug reactions are listed according to MedDRA (version 13.0) system organ class and sorted in descending order of frequency. Table 1: Number and frequency of adverse drug reactions greater than 2% (and higher than placebo) in COPD patients exposed to ARCAPTA NEOHALER 75 mcg for up to 3 months in multiple dose, controlled trials Indacaterol 75 mcg once daily Placebo n=449 n= 445 n (%) n (%) Respiratory, thoracic and mediastinal disorders - Cough 29 (6.5) 20 (4.5) - Oropharyngeal pain 10 (2.2) 3 (0.7) Infections and infestations - Nasopharyngitis 24 (5.3) 12 (2.7) Nervous system disorders - Headache 23 (5.1) 11 (2.5) Gastrointestinal disorders - Nausea 11 (2.4) 4 (0.9) In these trials the overall frequency of all cardiovascular adverse reactions was 2.5% for ARCAPTA NEOHALER 75 mcg and 1.6% for placebo during a 3 month exposure. There were no frequently occurring specific cardiovascular adverse reactions for ARCAPTA NEOHALER 75 mcg (frequency at least 1% and greater than placebo). Additional adverse drug reactions reported in greater than 2% (and higher than on placebo) in patients dosed with 150, 300 or 600 mcg for up to 12 months were as follows: Musculoskeletal and connective tissue disorders: muscle spasm, musculoskeletal pain General disorders and administration site conditions: edema peripheral Metabolism and nutrition disorder: diabetes mellitus, hyperglycemia Infections and infestations: sinusitis, upper respiratory tract infection C ough experienced p ost - inhalation In the clinical trials, health care providers observed during clinic visits that an average of 24% of patients experienced a cough on at least 20% of visits following inhalation of the recommended 75 mcg dose of ARCAPTA NEOHALER compared to 7% of patients receiving placebo. The cough usually occurred within 15 seconds following inhalation and lasted for no more than 15 seconds. Cough following inhalation in clinical trials was not associated with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy. 6.2 Clinical Trials Experience in Asthma In a 6-month randomized, active controlled asthma safety trial, 805 adult patients with moderate to severe persistent asthma were treated with ARCAPTA NEOHALER 300 mcg (n=268), ARCAPTA NEOHALER 600 mcg (n=268), and salmeterol (n=269), all concomitant with inhaled corticosteroids, which were not co-randomized. Of these patients, there were 2 respiratory-related deaths in the ARCAPTA NEOHALER 300 mcg dose group. There were no deaths in the ARCAPTA NEOHALER 600 mcg dose group or in the salmeterol active control group. Serious adverse reactions related to asthma exacerbation were reported for 2 patients in the indacaterol 300 mcg group, 3 patients in the indacaterol 600 mcg group, and no patients in the salmeterol active control group. In addition, a two-week dose-ranging trial was conducted in 511 adult patients with mild persistent asthma taking inhaled corticosteroids. No deaths, intubations, or serious adverse reactions related to asthma exacerbation were reported in this trial. 6.3 Postmarketing Experience The following adverse reactions have been identified during worldwide post-approval use of indacaterol, the active ingredient in ARCAPTA NEOHALER. 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 adverse reactions are: hypersensitivity reactions, paradoxical bronchospasm, tachycardia/heart rate increase/palpitations, pruritus/rash and dizziness.

<table> <caption>Table 1: Number and frequency of adverse drug reactions greater than 2% (and higher than placebo) in COPD patients exposed to ARCAPTA NEOHALER 75 mcg for up to 3 months in multiple dose, controlled trials</caption> <col width="161"/> <col width="133"/> <col width="123"/> <tbody> <tr> <td styleCode="Toprule Lrule Rrule "/> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">Indacaterol</content> <content styleCode="bold"> 75 mcg once daily</content> </td> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">Placebo</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule "/> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">n=449</content> </td> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">n=</content> <content styleCode="bold">445</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule "/> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">n (%)</content> </td> <td styleCode="Toprule Lrule Rrule " align="center"> <content styleCode="bold">n (%)</content> </td> </tr> <tr> <td styleCode="Toprule Lrule Rrule " colspan="3">Respiratory, thoracic and mediastinal disorders</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">- Cough</td> <td styleCode="Toprule Lrule Rrule " align="center">29 (6.5)</td> <td styleCode="Toprule Lrule Rrule " align="center">20 (4.5)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">- Oropharyngeal pain</td> <td styleCode="Toprule Lrule Rrule " align="center">10 (2.2)</td> <td styleCode="Toprule Lrule Rrule " align="center">3 (0.7)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule " colspan="3">Infections and infestations</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">- Nasopharyngitis</td> <td styleCode="Toprule Lrule Rrule " align="center">24 (5.3)</td> <td styleCode="Toprule Lrule Rrule " align="center">12 (2.7)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule " colspan="3">Nervous system disorders</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">- Headache</td> <td styleCode="Toprule Lrule Rrule " align="center">23 (5.1)</td> <td styleCode="Toprule Lrule Rrule " align="center">11 (2.5)</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule " colspan="3">Gastrointestinal disorders</td> </tr> <tr> <td styleCode="Toprule Lrule Rrule ">- Nausea</td> <td styleCode="Toprule Lrule Rrule " align="center">11 (2.4)</td> <td styleCode="Toprule Lrule Rrule " align="center">4 (0.9)</td> </tr> </tbody> </table>