5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death

• The safety and efficacy of UTIBRON NEOHALER in patients with asthma have not been established. UTIBRON NEOHALER is not indicated for the treatment of asthma [see Contraindications(4)].
• Use of long-acting beta2-adrenergic agonist (LABA) as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. 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 a 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.
• A 28-week, placebo-controlled U.S. study comparing the safety of another LABA (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 versus 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 LABAs, including indacaterol, one of the ingredients in UTIBRON NEOHALER.
• No study adequate to determine whether the rate of asthma-related death is increased in patients treated with UTIBRON NEOHALER has been conducted.
• Available data do not suggest an increased risk of death with use of LABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes

UTIBRON NEOHALER should not be initiated in patients with acutely deteriorating or potentially life-threatening episodes of COPD. UTIBRON NEOHALER has not been studied in patients with acutely deteriorating COPD. The initiation of UTIBRON NEOHALER in this setting is not appropriate.

UTIBRON NEOHALER should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. UTIBRON 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 beta2-agonist.

When beginning UTIBRON NEOHALER, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing UTIBRON NEOHALER, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled beta2-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 UTIBRON NEOHALER no longer controls the symptoms of bronchoconstriction; the patient's inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more inhalation of short-acting beta2-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 dose of UTIBRON NEOHALER beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of UTIBRON NEOHALER and Use with Other Long-Acting Beta2-Adrenergic Agonists

As with other inhaled drugs containing beta2-adrenergics, UTIBRON NEOHALER should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, 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 UTIBRON NEOHALER should not use another medicine containing a LABA for any reason [see Drug Interactions (7.1)].

5.4 Paradoxical Bronchospasm

As with other inhaled medicines, UTIBRON NEOHALER can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs following dosing with UTIBRON NEOHALER, it should be treated immediately with an inhaled, short-acting bronchodilator; UTIBRON NEOHALER should be discontinued immediately and alternative therapy instituted.

5.5 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrrolate, the components of UTIBRON NEOHALER. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of tongue, lips and face), urticaria, or skin rash, UTIBRON NEOHALER should be discontinued immediately and alternative therapy instituted. UTIBRON NEOHALER should be used with caution in patients with severe hypersensitivity to milk proteins.

5.6 Cardiovascular Effects

Indacaterol, like other beta2-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, UTIBRON 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, UTIBRON NEOHALER should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.7 Coexisting Conditions

UTIBRON NEOHALER, like all medicines containing 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 beta2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.8 Worsening of Narrow-Angle Glaucoma

UTIBRON NEOHALER should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.9 Worsening of Urinary Retention

UTIBRON NEOHALER should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

5.10 Hypokalemia and Hyperglycemia

Beta2-adrenergic agonists may produce significant hypokalemia in some patients, 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 beta2-adrenergic agonists may produce increases in plasma glucose.

In patients with severe COPD, hypokalemia may be potentiated by hypoxia and concomitant treatment [see Drug Interactions (7.2)], which may increase the susceptibility for cardiac arrhythmias.

In 2 clinical trials of 12-weeks duration evaluating UTIBRON NEOHALER in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

6.1 Clinical Trials Experience

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

The UTIBRON NEOHALER safety database included 2654 subjects with COPD in two 12-week lung function trials and one 52-week long-term safety study. A total of 712 subjects received treatment with UTIBRON NEOHALER 27.5 mcg/15.6 mcg twice daily (BID). The safety data described below are based on the two 12-week trials and the one 52-week trial.

6.2 Postmarketing Experience

The following additional adverse reactions of angioedema and dysphonia have been identified during worldwide post-approval use of indacaterol/glycopyrrolate at higher than the recommended dose. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

7.1 Adrenergic Drugs

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the sympathetic effects of indacaterol, a component of UTIBRON NEOHALER, may be potentiated [see Warnings and Precautions (5.3, 5.6, 5.7, 5.10)].

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of beta2-adrenergic agonists such as indacaterol, a component of UTIBRON NEOHALER [see Warnings and Precautions (5.10)].

7.3 Non-Potassium-Sparing Diuretics

The electrocardiographic (ECG) changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as indacaterol, a component of UTIBRON NEOHALER, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical relevance of these effects is not known, caution is advised in the coadministration of UTIBRON NEOHALER with non-potassium-sparing diuretics.

7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc-Prolonging Drugs

Indacaterol, one of the components of UTIBRON NEOHALER, as with other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval because the action of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval may have an increased risk of ventricular arrhythmias.

7.5 Beta-Blockers

Beta-adrenergic receptor antagonists (beta-blockers) and UTIBRON NEOHALER may interfere with the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta-agonists, but may produce severe bronchospasm in COPD patients. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with COPD. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

7.6 Anticholinergics

There is potential for an additive interaction with concomitantly used anticholinergic medicines. Therefore, avoid coadministration of UTIBRON NEOHALER with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [see Warnings and Precautions (5.8, 5.9), Adverse Reactions (6)].

7.7 Inhibitors of Cytochrome P450 3A4 and P-gp Efflux Transporter

Drug interaction studies with indacaterol, a component of UTIBRON NEOHALER, were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil, and ritonavir). The data suggest that systemic clearance of indacaterol is influenced by modulation of both P-gp and CYP3A4 activities and that the 2-fold area under the curve (AUC) increase caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. Indacaterol was evaluated in clinical trials for up to 1 year at doses up to 600 mcg. Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp, has no impact on safety of therapeutic doses of indacaterol. Therefore, no dose adjustment is warranted at the recommended 27.5/15.6 mcg twice-daily dose for UTIBRON NEOHALER when administered concomitantly with inhibitors of CYP3A4 and P-gp [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Labor and Delivery

There are no adequate and well-controlled human trials that have investigated the effects of UTIBRON NEOHALER during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, UTIBRON NEOHALER should be used during labor only if the potential benefit justifies the potential risk.

In human parturients undergoing Caesarean section, 86 minutes after a single intramuscular injection of 0.006 mg/kg glycopyrrolate, umbilical plasma concentrations were low.

8.3 Nursing Mothers

UTIBRON NEOHALER: It is not known whether UTIBRON NEOHALER is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when UTIBRON NEOHALER is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of UTIBRON NEOHALER by nursing mothers, based on the data for the individual components, a decision should be made whether to discontinue nursing or to discontinue UTIBRON NEOHALER, taking into account the importance of UTIBRON NEOHALER to the mother.

Indacaterol: It is not known whether indacaterol is excreted in human breast milk. Indacaterol (including its metabolites) have been detected in the milk of lactating rats.

Glycopyrrolate: It is not known whether glycopyrrolate is excreted in human breast milk. Glycopyrrolate (including its metabolites) have been detected in the milk of lactating rats and reached up to 10-fold higher concentrations in the milk than in the blood of the dam.

8.4 Pediatric Use

UTIBRON NEOHALER is not indicated for use in children. The safety and efficacy of UTIBRON NEOHALER in pediatric patients have not been established.

8.5 Geriatric Use

Based on available data, no adjustment of UTIBRON NEOHALER dosage in geriatric patients is warranted. UTIBRON NEOHALER can be used at the recommended dose in elderly patients 75 years of age and older.

Of the total number of subjects in clinical studies of UTIBRON NEOHALER, 45% were aged 65 and older, while 11% were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment

Based on the pharmacokinetic characteristics of its monotherapy components, UTIBRON NEOHALER can be used at the recommended dose in patients with mild to moderate renal impairment. In patients with severe renal impairment (estimated GFR less than 30 mL/min/1.73 m2) or end-stage renal disease requiring dialysis, UTIBRON NEOHALER should be used if the expected benefit outweighs the potential risk since the systemic exposure to glycopyrrolate may be increased in this population [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Based on the pharmacokinetic characteristics of its monotherapy components, UTIBRON NEOHALER can be used at the recommended dose in patients with mild and moderate hepatic impairment. Studies in subjects with severe hepatic impairment have not been performed [see Clinical Pharmacology (12.3)].

Indacaterol

The potential signs and symptoms associated with overdosage of indacaterol are those of excessive beta-adrenergic stimulation and occurrence or exaggeration of any of the signs and symptoms, e.g., angina, hypertension or hypotension, tachycardia, with rates up to 200 bpm, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps, nausea, vomiting, drowsiness, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosis and insomnia. As with all inhaled sympathomimetic medications, cardiac arrest and even death may be associated with an overdose of indacaterol.

In COPD patients, single doses of indacaterol 3000 mcg were associated with moderate increases in pulse rate, systolic blood pressure and QTc interval.

Glycopyrrolate

An overdose of glycopyrrolate may lead to anticholinergic signs and symptoms such as nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure (causing pain, vision disturbances or reddening of the eye), obstipation or difficulties in voiding.

In COPD patients, repeated orally inhaled administration of glycopyrrolate at total doses of 124.8 mcg and 249.6 mcg once-daily for 28 days were well tolerated.

Peak plasma levels and total systemic exposure following intravenous administration of 150 mcg glycopyrrolate (equivalent to 120 mcg active moiety) in healthy volunteers were respectively about 270-fold and 13-fold higher than the peak and total systemic exposure at steady-state achieved with the recommended daily dose of 31.2 mcg of glycopyrrolate (i.e., 15.6 mcg glycopyrrolate twice-daily) and were well tolerated.

12.1 Mechanism of Action

UTIBRON NEOHALER contains both indacaterol and glycopyrrolate. The mechanisms of action described below for the individual components apply to UTIBRON NEOHALER. These drugs represent 2 different classes of medications (a LABA and an anticholinergic) that have different and additive effects on clinical and physiological indices.

Indacaterol: Indacaterol is a long-acting beta2-adrenergic agonist (LABA). When inhaled, indacaterol acts locally in the lung as a bronchodilator. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-adrenergic receptors in the human heart comprising 10% to 50% of the total adrenergic receptors. The precise function of these receptors is not known, but their presence raises the possibility that even highly selective beta2-adrenergic agonists may have cardiac effects.

The pharmacological effects of beta2-adrenoceptor agonist drugs, including indacaterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic monophosphate). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro studies have shown that indacaterol has more than 24-fold greater agonist activity at beta2-receptors compared to beta1-receptors and 20-fold greater agonist activity compared to beta3-receptors. The clinical significance of these findings is unknown.

Glycopyrrolate: Glycopyrrolate is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced broncho-constrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of glycopyrrolate is predominantly a site-specific effect.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.5 Pharmacogenomics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with UTIBRON NEOHALER; however, studies are available for the individual components, indacaterol and glycopyrrolate, as described below.

13.2 Animal Toxicology

Eye findings were seen for glycopyrrolate and were observed in Wistar rats at inhaled doses of 0.67 mg/kg/day and higher (approximately 280 times the MRHD in adults on an AUC basis) based upon findings of anterior capsule opacity, prominent anterior suture line, and anterior cataract. No eye findings in Wistar rats were observed at an inhaled dose of 0.09 mg/kg/day (approximately 60 times the MRHD in adults on an AUC basis). Eye findings were observed in beagle dogs at an inhaled dose of 0.33 mg/kg/day (approximately 150 times the MRHD in adults on an AUC basis) based upon findings of conjunctival hyperemia and corneal opacity. No eye findings in beagle dogs were observed at an inhaled dose of 0.12 mg/kg/day (approximately 100 times the MRHD in adults on an AUC basis).

14.1 Dose-Ranging Trials

Dose selection for UTIBRON NEOHALER for COPD was based on data for the individual components, indacaterol and glycopyrrolate.

Indacaterol: Indacaterol dose selection in UTIBRON NEOHALER is based on the registered dose of 75 mcg once-daily and is also supported by a single-dose, multicenter, randomized, double-blind, placebo-controlled, crossover study in asthma evaluating 5 doses of indacaterol in 91 subjects, (37.5 mcg, 55 mcg, 75 mcg, and 150 mcg once-daily (QD), and 27.5 mcg twice-daily (BID)). A dose-related increase in FEV1 AUC0-24h compared with placebo was observed. The differences in change from baseline in FEV1 AUC0-24h Rafter single dosing for the indacaterol 37.5 mcg, 55 mcg, 75 mcg, and 150 mcg once-daily and the 27.5 mcg twice-daily doses compared to placebo were 0.099 L (95% CI: 0.069, 0.128), 0.132 L (0.103, 0.162), 0.143 L (0.114, 0.171), 0.187 L (0.157, 0.216), and 0.121 L (0.092, 0.151), respectively. These results supported the evaluation of indacaterol 27.5 mcg twice-daily in the confirmatory COPD trials. UTIBRON NEOHALER is not indicated for asthma.

Figure 1. Adjusted mean change from baseline in FEV1(L) over 24 hours on Day 1

Glycopyrrolate: Dose selection for glycopyrrolate in UTIBRON NEOHALER in COPD was supported by a 28-day, randomized, double-blind, placebo-controlled, 2-period, crossover study evaluating 7 doses of glycopyrrolate (15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily) or placebo in 388 subjects with COPD. The differences in trough FEV1 from baseline after 28 days compared to placebo for the 15.6 mcg, 31.2 mcg, 62.4 mcg, and 124.8 mcg once-daily and for 15.6 mcg, 31.2 mcg, and 62.4 mcg twice-daily doses were 0.083 L (95% CI: 0.030, 0.136), 0.098 L (0.048, 0.148), 0.090 L (0.038, 0.142), 0.176 L (0.132, 0.220), 0.139 L (0.089, 0.189), 0.167 L (0.115, 0.219), and 0.177 L (0.132, 0.222), respectively. The dose-ranging results supported the evaluation of glycopyrrolate 15.6 mcg twice-daily in the confirmatory COPD trials.

Figure 2. Adjusted mean change from baseline in FEV1(L) over 24 hours on Days 1 and 28

Based on the findings from dose-ranging studies of the individual components, a twice-daily dose of

indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg was evaluated in the confirmatory COPD trials.

14.2 Confirmatory Trials

The clinical development program for UTIBRON NEOHALER included two (Trial 1 and Trial 2) 12-week, randomized, double-blinded, placebo- and active-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy and safety of UTIBRON NEOHALER; and one 12-month, randomized, double-blind, active-controlled trial (Trial 3) that evaluated bronchodilation and effects on long-term safety.

The 12-week trials evaluated the efficacy of 2038 subjects that had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a post-albuterol FEV1 greater than or equal to 30% and less than 80% of predicted normal values, had a ratio of FEV1/FVC of less than 0.7, and were symptomatic as determined by a Modified Medical Research Council (mMRC) score greater than or equal to 2. Of the 2038 subjects included in the efficacy analysis, 63% were male and 91% were Caucasian. They had a mean age of 63 years and an average smoking history of 47 pack-years, with 52% identified as current smokers, and 46% used concomitant inhaled corticosteroids. At screening, the mean post-bronchodilator percent predicted FEV1 was 55% (range: 29% to 79%), the mean post-bronchodilator FEV1/FVC ratio was 50% (range: 19% to 71%), and the mean percent reversibility was 23% (range: 0% to 144%).

Trial 1 and Trial 2 evaluated UTIBRON NEOHALER (indacaterol/glycopyrrolate) 27.5 mcg/15.6 mcg twice-daily (BID), indacaterol 27.5 mcg BID, glycopyrrolate 15.6 mcg BID, and placebo BID. The primary endpoint was the change from baseline in FEV1 AUC0-12h Rfollowing the morning dose at Day 85 (defined as the mean FEV1 change from baseline over 0 to 12 hours divided by 12 hours) compared with placebo, glycopyrrolate 15.6 mcg BID, and indacaterol 27.5 mcg BID. The comparison of UTIBRON NEOHALER with indacaterol 27.5 mcg and glycopyrrolate 15.6 mcg was assessed to evaluate the contribution of the individual comparators to UTIBRON NEOHALER. In both trials, UTIBRON NEOHALER demonstrated a larger increase in mean change from baseline in FEV1 AUC0-12h Rcompared to placebo, indacaterol 27.5 mcg BID, and glycopyrrolate 15.6 mcg BID (see Table 2).

In Trial 1 and Trial 2, serial spirometric evaluations throughout the 12-hour dosing interval were performed in all subjects at Days 1 and 85. The spirometric curves from Trial 1 at Days 1 and 85 are displayed in Figure 3. In Trial 2, the results for UTIBRON NEOHALER in FEV1 AUC0-12h were similar to those observed in Trial 1.

Figure 3. Adjusted mean change from baseline in FEV1(L) over 12 hours on Days 1 and 85 in Trial 1 (All patient Population)

The peak FEV1 was defined as the maximum FEV1 recorded within 4 hours after the morning dose on Days 1 and 85. The mean peak FEV1 improvement from baseline for UTIBRON NEOHALER compared with placebo at Day 1 and at Day 85 was 0.185 L and 0.290 L (Trial 1) and 0.151 L and 0.260 L (Trial 2), respectively. The median time to onset on Day 1, defined as a 100 mL increase from baseline in FEV1, was 12 minutes and 16 minutes in Trials 1 and 2, respectively, in subjects receiving UTIBRON NEOHALER.

In Trials 1 and 2, patients treated with UTIBRON NEOHALER used less daily rescue albuterol compared to patients treated with placebo.

The St. George's Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 2, the SGRQ responder rate

(defined as an improvement in score of 4 or more as threshold) was 57%, 46%, 48%, and 39%, for UTIBRON NEOHALER, glycopyrrolate, indacaterol, and placebo, respectively, with odds ratios of 1.6 (95% CI 1.1, 2.3), 1.5 (95% CI 1.1, 2.2), and 2.2 (95% CI 1.5, 3.2), for UTIBRON NEOHALER vs. glycopyrrolate, UTIBRON NEOHALER vs. indacaterol, and UTIBRON NEOHALER vs. placebo, respectively. In Trial 1, the trends were similar, with odds ratios of 1.4 (95% CI 1.0, 2.0), 1.1 (95% CI 0.8, 1.7), and 2.9 (95% CI 1.9, 4.2), for UTIBRON NEOHALER vs. glycopyrrolate, UTIBRON NEOHALER vs. indacaterol, and UTIBRON NEOHALER vs placebo, respectively.

How Supplied

UTIBRON NEOHALER contains UTIBRON (indacaterol/glycopyrrolate, (27.5 mcg, 15.6 mcg) inhalation powder) in hypromellose (HPMC) capsule with yellow transparent cap and uncolored transparent body, with capsules packaged in aluminum blister cards, one NEOHALER device, and an FDA-approved Patient Information.

Unit Dose (blister pack), Box of 60 (10 blister cards with 6 yellow transparent capsules each) NDC 63402-681-60

Unit Dose (blister pack), Box of 6 (1 blister card with 6 yellow transparent capsules each) NDC 63402-681-06

The NEOHALER device consists of a white protective cap and a base with mouthpiece, capsule chamber and 2 yellow push buttons.

Storage and Handling

Store in a dry place at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

• UTIBRON capsules should be used with the NEOHALER device only. Do not use the NEOHALER device with any other capsules.
• Store UTIBRON capsules in the blister protected from light and moisture. Remove the UTIBRON capsules from the blister immediately before use.
• Always use the new NEOHALER inhaler provided with each new prescription.

Keep out of the reach of children.

Serious Asthma-Related Events

Inform patients that LABAs, such as indacaterol, one of the active ingredients in UTIBRON NEOHALER, when used as monotherapy [without an inhaled corticosteroid] increase the risk of serious asthma-related events, including asthma-related death. UTIBRON NEOHALER is not indicated for the treatment of asthma.

Not for Acute Symptoms

Inform patients that UTIBRON NEOHALER is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise them to treat acute symptoms with a rescue inhaler such as albuterol. Provide patients with such medicine and instruct them on how it should be used [see Warnings and Precautions (5.2)].

Instruct patients to seek medical attention immediately if they experience any of the following:

• Symptoms get worse
• Need for more inhalations than usual of their rescue inhaler

Patients should not stop therapy with UTIBRON NEOHALER without physician/healthcare provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists

Instruct patients to not use other medicines containing a LABA. Patients should not use more than the recommended twice-daily dose of UTIBRON NEOHALER [see Warnings and Precautions (5.3)].

Instruct patients who have been taking inhaled, short-acting beta2-agonists on a regular basis to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

Paradoxical Bronchospasm

Inform patients that UTIBRON NEOHALER can produce paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue UTIBRON NEOHALER.

Risks Associated with Beta2-Agonist Therapy

Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness. Instruct patients to consult a physician immediately should any of these signs or symptoms develop [see Warnings and Precautions (5.6)].

Worsening of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop [see Warnings and Precautions (5.8)].

Worsening of Urinary Retention

Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop [see Warnings and Precautions (5.9)].

Instructions for Administering UTIBRON NEOHALER

It is important for patients to understand how to correctly administer UTIBRON capsules using the NEOHALER device [see Instructions for Use]. Instruct patients that UTIBRON capsules should only be administered via the NEOHALER device and the NEOHALER device should not be used for administering other medications. Remind patients that the contents of UTIBRON capsules are for oral inhalation only and must not be swallowed.

Instruct patients always to store UTIBRON capsules in sealed blisters and to only remove 1 UTIBRON capsule immediately before use or it may not be as effective. Instruct patients to discard unused additional UTIBRON capsules that are exposed to air (i.e., not intended for immediate use).

Inform patients to use 1 inhalation of UTIBRON NEOHALER orally twice-daily (1 capsule in the morning and 1 capsule in the evening) at the same time every day.

Inform patients that if they miss a dose of UTIBRON NEOHALER, they should use their next capsule at the usual time. Instruct patients to not use 2 capsules at one time and to not use more than 2 capsules in a day.

Manufactured for
Sunovion Pharmaceuticals Inc.
Marlborough, MA 01752 USA
Made in Switzerland

© 2019 Sunovion Pharmaceuticals Inc.

For customer service, call 1-888-394-7377
For medical information, call 1-800-739-0565
To report suspected adverse events, call 1-877-737-7226

Revised: 05/2019
10184-02