2.1 Administration Overview

For oral inhalation only. Do not swallow UTIBRON capsules, as the intended effects on the lungs will not be obtained. UTIBRON capsules should only be used with the NEOHALER device.

2.2 Recommended Dosage for Chronic Obstructive Pulmonary Disease

The recommended dosage is one capsule of UTIBRON (27.5 mcg of indacaterol and 15.6 mcg glycopyrrolate) inhalation powder twice daily by oral inhalation using the NEOHALER device.

UTIBRON NEOHALER should be administered at the same time of the day (1 capsule in the morning and 1 capsule in the evening) every day. More frequent administration or a greater number of inhalations (more than 1 capsule twice daily) of UTIBRON NEOHALER is not recommended.

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 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 Avoid Excessive Use of UTIBRON NEOHALER and Avoid 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 Hypersensitivity Reactions, Including Anaphylaxis

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), anaphylaxis, 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-adrenergic 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 their healthcare provider 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 their healthcare provider 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. The safety data described below are based on the two 12-week trials and the one 52-week trial.

12-Week Trial

The incidence of adverse reactions associated with UTIBRON NEOHALER in Table 1 is based on two 12-week, placebo-controlled trials (Trials 1 and 2; N = 1,001 and N = 1,042, respectively). Of the 2040 subjects, 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. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV1) was 55% (range: 29% to 79%), the mean post-bronchodilator FEV1/forced vital capacity (FVC) ratio was 50% (range: 19% to 71%), and the mean percent reversibility was 23% (range: 0% to 144%).

The most common adverse reaction (incidence greater than or equal to 2% and higher than placebo) was nasopharyngitis and hypertension.

The proportion of patients who discontinued treatment due to adverse reactions was 2.95% for the UTIBRON NEOHALER treated patients and 4.13% for placebo-treated patients.

Subjects received 1 dose twice daily of the following: UTIBRON NEOHALER 27.5 mcg/15.6 mcg, indacaterol 27.5 mcg, glycopyrrolate 15.6 mcg, or placebo.

Other adverse reactions occurring more frequently with UTIBRON NEOHALER than with placebo, but with an incidence of less than 1% include dyspepsia, gastroenteritis, chest pain, fatigue, peripheral edema, rash/pruritus, insomnia, dizziness, bladder obstruction/urinary retention, atrial fibrillation, palpitations, tachycardia.

52-Week Trial

In a long-term safety trial, 614 subjects were treated for up to 52 weeks with indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg twice daily, indacaterol/glycopyrrolate 27.5/31.2 mcg twice daily or indacaterol 75 mcg once daily. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy trials described above. The adverse reactions reported in the long-term safety trial were consistent with those observed in the placebo-controlled trials of 12 weeks. Additional adverse reactions that occurred with a frequency greater than or equal to 2% in the group receiving indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg twice daily that exceeded the frequency of indacaterol 75 mcg once daily in this trial were upper and lower respiratory tract infection, pneumonia, diarrhea, headache, gastroesophageal reflux disease, hyperglycemia, rhinitis.

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 these reactions are 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

Risk Summary

There are no adequate and well-controlled studies with UTIBRON NEOHALER or its individual components, indacaterol and glycopyrrolate, in pregnant women. Women should be advised to contact their healthcare provider if they become pregnant while taking UTIBRON NEOHALER. Animal reproduction studies were conducted with individual components, indacaterol and glycopyrrolate.

Indacaterol: In animal reproduction studies, there was no evidence of fetal harm or structural abnormalities following subcutaneous administration of indacaterol maleate to pregnant Wistar rats and New Zealand White rabbits during the period of organogenesis at exposures approximately 340 and 770 times, respectively, the maximum recommended human dose (MRHD of 55 mcg) on an exposure (AUC) basis (see Data).

Glycopyrrolate: In animal reproduction studies, there was no evidence of fetal harm or structural abnormalities in Wistar rats or New Zealand White rabbits at inhaled doses approximately 1400 and 530 times, respectively, the MRHD (31.2 mcg) on an AUC basis (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Labor or 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.

Data

Animal Data

Indacaterol: In embryo-fetal development studies, pregnant Wistar rats received indacaterol maleate, during the period of organogenesis from Gestation Days 6 to 17, at exposures up to 340 times the MRHD (on an AUC basis with maternal subcutaneous doses up to 1 mg/kg/day) and pregnant New Zealand White rabbits received indacaterol maleate, during the period of organogenesis from Gestation Days 7 to 20, at exposures up to 1900 times the MRHD (on an AUC basis with maternal subcutaneous doses up to 3 mg/kg/day). Indacaterol maleate produced no evidence of structural abnormalities in rats and rabbits at exposures up to 340 and 770 times, respectively, the MRHD. Rabbit fetuses were observed with increased incidences of full supernumerary rib, a structural variation, at an exposure approximately 1900 times the MRHD.

In a pre- and postnatal development study, pregnant Wistar rats received indacaterol maleate, throughout the periods of organogenesis and lactation from Gestation Day 6 through Lactation Day 20, at doses up to 175 times the MRHD (on a mg/m2 basis with maternal subcutaneous doses up to 1 mg/kg/day). F1 pups received subcutaneous doses of indacaterol maleate up to 1 mg/kg/day from postpartum days 4 through 20. There was no evidence of maternal toxicity with doses up to 175 times the MRHD. There were no effects on the physical or behavioral development of F1 pups with doses up to 55 times the MRHD (on a mg/m2 basis with maternal and F1 pup subcutaneous doses up to 0.3 mg/kg/day). There was a decrease in the number of F1 pregnant animals at a dose approximately 175 times the MRHD (on a mg/m2 basis with maternal and F1 pup subcutaneous doses of 1 mg/kg/day); however, there were no effects on mating or other parameters of reproductive performance.

Glycopyrrolate: In embryo-fetal development studies, pregnant Wistar rats received daily inhalation doses of glycopyrrolate, during the period of organogenesis from Gestation Days 7 to 17, at exposures up to 1400 times the MRHD (on an AUC basis with maternal inhaled doses up to 3.83 mg/kg) and pregnant New Zealand White rabbits received daily inhalation doses of glycopyrrolate, during the period of organogenesis from Gestation Days 7 to 19, at exposures up to 530 times the MRHD (on an AUC basis with maternal inhaled doses up to 4.4 mg/kg). Glycopyrrolate produced no evidence of teratogenicity in Wistar rats or New Zealand White rabbits at exposures up to approximately 1,400 and 530 times, respectively, the MRHD.

In a pre- and postnatal development study in pregnant Wistar rats, glycopyrrolate was administered subcutaneously daily throughout the periods of organogenesis and lactation from Gestation Day 6 through Lactation Day 23 at exposures up to 1100 times the MRHD (on an AUC basis with maternal subcutaneous doses up to 1.88 mg/kg/day). Glycopyrrolate had no effects on physical, neurological, or reproductive development in rats following exposures up to approximately 1100 times the MRHD.

8.2 Lactation

Risk Summary

There is no data on the presence of indacaterol or glycopyrrolate or their metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, in studies of lactating rats, indacaterol and glycopyrrolate were present in the milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UTIBRON NEOHALER and any potential adverse effects on the breastfed child from UTIBRON NEOHALER or from the underlying maternal condition.

Data

Animal Data

Indacaterol: Indacaterol and its metabolites were detected in the milk within 1 hour following a single subcutaneous 650 mcg radiolabeled indacaterol maleate administered to lactating rats postpartum Days 8 and 9.

Glycopyrrolate: Glycopyrrolate and its metabolites were detected in the milk of lactating rats following a single intravenous injection of 4 mg/kg of radiolabeled glycopyrrolate.

8.4 Pediatric Use

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

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 dosage 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, use UTIBRON NEOHALER only 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)].

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 LABA. When inhaled, indacaterol acts locally in the lung as a bronchodilator. 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. This selectivity profile is similar to formoterol. The clinical significance of these findings is unknown. 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 AMP). 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.

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 and acetylcholine -induced bronchoconstrictive 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

Cardiac Electrophysiology

The QTc interval was studied in TQT studies with UTIBRON NEOHALER and with each of the monotherapy components. The TQT studies with indacaterol and glycopyrrolate demonstrated that neither of the compounds had a relevant effect on the corrected QT interval at supratherapeutic and therapeutic doses (for glycopyrrolate only a supratherapeutic dose was tested).

In a randomized, partially-blinded, placebo- and positive-controlled, crossover TQT study in 84 healthy subjects, a supratherapeutic dose of UTIBRON NEOHALER (indacaterol/glycopyrrolate 440/499.2 mcg) was administered. This is a 16/32 dose multiple compared to a single dose of the recommended 27.5/15.6 mcg twice-daily dosage of UTIBRON NEOHALER, which resulted in exposure multiples for mean Cmax of 9.3 for indacaterol and 35.2 for glycopyrrolate compared to steady-state pharmacokinetics of UTIBRON NEOHALER 27.5/15.6 mcg twice daily. The mean maximal change from baseline in QTcI compared to placebo was 8.70 msec (2-sided 90% CI 7.3, 10.1) at 30 minutes after dosing.

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.

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, and 27.5 mcg twice daily). A dose-related increase in FEV1 AUC0-24h compared with placebo was observed. The differences in change from baseline in FEV1 AUC0-24h after 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 ofindacaterol/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, indacaterol 27.5 mcg twice daily, glycopyrrolate 15.6 mcg twice daily, and placebo twice daily. The primary endpoint was the change from baseline in FEV1 AUC0-12h following 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 twice daily, and indacaterol 27.5 mcg twice daily. 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 compared to placebo, indacaterol 27.5 mcg twice daily, and glycopyrrolate 15.6 mcg twice daily (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 odd 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 (27.5 mcg indacaterol and 15.6 mcg glycopyrrolate 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 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [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 [see Contraindications (4), Warnings and Precautions (5.1)].

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 their healthcare provider 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 their healthcare provider 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 their healthcare provider 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 by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

T2021-112