Current treatment options for COPDShort- and long-acting inhaled therapies by therapeutic class

COPD = chronic obstructive pulmonary disease.

T H I S P R O M O T I O N A L M AT E R I A L WA S D E V E L O P E D B Y S U N O V I O N P H A R M A C E U T I C A L S I N C . PROPERTY OF SUNOVION PHARMACEUTICALS INC. NOT FOR FURTHER DISSEMINATION. ©2019 SUNOVION PHARMACEUTICALS INC. ALL RIGHTS RESERVED.

Please see Important Safety Information throughout and accompanying full Prescribing Information and Patient Information for ARCAPTA NEOHALER, UTIBRON NEOHALER, SEEBRI NEOHALER, BROVANA and LONHALA MAGNAIR.

INDICATION FOR ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR AND UTIBRON NEOHALERARCAPTA® NEOHALER® (indacaterol) Inhalation Powder is a long-acting beta2-adrenergic agonist (LABA), SEEBRI® NEOHALER® (glycopyrrolate) Inhalation Powder and LONHALA® MAGNAIR® (glycopyrrolate) Inhalation Solution are anticholinergics, and UTIBRON® NEOHALER® (indacaterol and glycopyrrolate) Inhalation Powder is a combination of indacaterol and glycopyrrolate; all are indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.Important limitations: ARCAPTA NEOHALER and UTIBRON NEOHALER are not indicated to treat acute deteriorations of COPD and are not indicated to treat asthma.

INDICATION for BROVANABROVANA® (arformoterol tartrate) Inhalation Solution is a long-acting beta2-adrenergic agonist (LABA) indicated for the long-term, twice-daily (morning and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BROVANA is for use by nebulization only.Important limitations: BROVANA is not indicated to treat acute deteriorations of COPD and is not indicated to treat asthma.

Short-acting beta2-agonists (SABA)

Inhalers Nebulizers

Short-acting COPD treatments (rescue)

albuterol sulfateInhalation Aerosol – Proair HFA

– Proventil® HFA– Ventolin® HFA

Inhalation Powder – ProAir® digihaler™

– ProAir® RespiClick

levalbuterol tartrateInhalation Aerosol – Xopenex HFA®

albuterol sulfateInhalation Solution

– AccuNeb®

levalbuterol HClInhalation Solution Concentrate

– Xopenex®

Short-acting muscarinic antagonist (SAMA)

Inhaler

ipratropium bromide HFAInhalation Aerosol – Atrovent® HFA

Short-acting muscarinic antagonist and short-acting beta2-agonist combinations(SAMA+SABA)

Inhaler Nebulizer

ipratropium bromide and albuterolInhalation Spray – Combivent® Respimat®

ipratropium bromide and albuterol sulfateInhalation Solution

– DuoNeb®

This table shows all available long-acting, branded, inhaled therapies by therapeutic class as of August 2019.Use of short-acting bronchodilators for maintenance treatment is generally not recommended.

LABA+ICS combinations LABA+LAMA+ICS combination

Inhalers

Nebulizers

Nebulizers

Long-acting COPD treatments (maintenance)

aclidinium bromideInhalation Powder

– Tudorza® Pressair®

glycopyrrolateInhalation Powder – Seebri® Neohaler®

tiotropium bromideInhalation Powder – Spiriva® HandiHaler®

Inhalation Spray

– Spiriva® Respimat®

umeclidiniumInhalation Powder – Incruse Ellipta

indacaterolInhalation Powder – Arcapta® Neohaler®

olodaterolInhalation Spray

– Striverdi® Respimat®

salmeterol xinafoateInhalation Powder

– Serevent® Diskus®

glycopyrrolateInhalation Solution – Lonhala® Magnair®

revefenacinInhalation Solution – Yupelri®

fluticasone furoate, umeclidinium and vilanterolInhalation Powder – Trelegy Ellipta

arformoterol tartrateInhalation Solution – Brovana®

formoterol fumarateInhalation Solution – Perforomist®

Long-acting muscarinic antagonists (LAMA) Long-acting beta2-agonist and long-acting muscarinic antagonist combinations (LABA+LAMA)

Long-acting beta2-agonists (LABA)

fluticasone propionate and salmeterolInhalation Powder – Advair Diskus®

fluticasone propionate and salmeterolInhalation Powder – Wixela™ Inhub™

budesonide/formoterol fumarate dihydrateInhalation Aerosol

– Symbicort®

fluticasone furoate and vilanterolInhalation Powder – Breo™ Ellipta™

aclidinium bromide/formoterol fumarateInhalation Powder – Duaklir® Pressair®

glycopyrrolate/formoterol fumarateInhalation Aerosol – Bevespi Aerosphere®

indacaterol/glycopyrrolateInhalation Powder

– Utibron® Neohaler®

tiotropium bromide & olodaterolInhalation Spray – Stiolto® Respimat®

umeclidinium and vilanterolInhalation Powder – Anoro® Ellipta®

Inhalers

Inhalers Inhalers Inhaler

This table shows all available short-acting, branded, inhaled therapies by therapeutic class as of August 2019.

The GOLD report recommends a long-acting bronchodilator for maintenance treatment, with a goal to manage symptoms.

GOLD does not endorse any specific treatments.GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroids.

Please see Important Safety Information throughout and accompanying full Prescribing Information and Patient Information for ARCAPTA NEOHALER, UTIBRON NEOHALER, SEEBRI NEOHALER, BROVANA and LONHALA MAGNAIR.

INDICATION FOR ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR AND UTIBRON NEOHALERARCAPTA® NEOHALER® (indacaterol) Inhalation Powder is a long-acting beta2-adrenergic agonist (LABA), SEEBRI® NEOHALER® (glycopyrrolate) Inhalation Powder and LONHALA® MAGNAIR® (glycopyrrolate) Inhalation Solution are anticholinergics, and UTIBRON® NEOHALER® (indacaterol and glycopyrrolate) Inhalation Powder is a combination of indacaterol and glycopyrrolate; all are indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.Important limitations: ARCAPTA NEOHALER and UTIBRON NEOHALER are not indicated to treat acute deteriorations of COPD and are not indicated to treat asthma.

INDICATION for BROVANABROVANA® (arformoterol tartrate) Inhalation Solution is a long-acting beta2-adrenergic agonist (LABA) indicated for the long-term, twice-daily (morning and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BROVANA is for use by nebulization only.Important limitations: BROVANA is not indicated to treat acute deteriorations of COPD and is not indicated to treat asthma.

Short-acting beta2-agonists (SABA)

Inhalers Nebulizers

Short-acting COPD treatments (rescue)

albuterol sulfateInhalation Aerosol – Proair HFA

– Proventil® HFA– Ventolin® HFA

Inhalation Powder – ProAir® digihaler™

– ProAir® RespiClick

levalbuterol tartrateInhalation Aerosol – Xopenex HFA®

albuterol sulfateInhalation Solution

– AccuNeb®

levalbuterol HClInhalation Solution Concentrate

– Xopenex®

Short-acting muscarinic antagonist (SAMA)

Inhaler

ipratropium bromide HFAInhalation Aerosol – Atrovent® HFA

Short-acting muscarinic antagonist and short-acting beta2-agonist combinations(SAMA+SABA)

Inhaler Nebulizer

ipratropium bromide and albuterolInhalation Spray – Combivent® Respimat®

ipratropium bromide and albuterol sulfateInhalation Solution

– DuoNeb®

This table shows all available long-acting, branded, inhaled therapies by therapeutic class as of August 2019.Use of short-acting bronchodilators for maintenance treatment is generally not recommended.

LABA+ICS combinations LABA+LAMA+ICS combination

Inhalers

Nebulizers

Nebulizers

Long-acting COPD treatments (maintenance)

aclidinium bromideInhalation Powder

– Tudorza® Pressair®

glycopyrrolateInhalation Powder – Seebri® Neohaler®

tiotropium bromideInhalation Powder – Spiriva® HandiHaler®

Inhalation Spray

– Spiriva® Respimat®

umeclidiniumInhalation Powder – Incruse Ellipta

indacaterolInhalation Powder – Arcapta® Neohaler®

olodaterolInhalation Spray

– Striverdi® Respimat®

salmeterol xinafoateInhalation Powder

– Serevent® Diskus®

glycopyrrolateInhalation Solution – Lonhala® Magnair®

revefenacinInhalation Solution – Yupelri®

fluticasone furoate, umeclidinium and vilanterolInhalation Powder – Trelegy Ellipta

arformoterol tartrateInhalation Solution – Brovana®

formoterol fumarateInhalation Solution – Perforomist®

Long-acting muscarinic antagonists (LAMA) Long-acting beta2-agonist and long-acting muscarinic antagonist combinations (LABA+LAMA)

Long-acting beta2-agonists (LABA)

fluticasone propionate and salmeterolInhalation Powder – Advair Diskus®

fluticasone propionate and salmeterolInhalation Powder – Wixela™ Inhub™

budesonide/formoterol fumarate dihydrateInhalation Aerosol

– Symbicort®

fluticasone furoate and vilanterolInhalation Powder – Breo™ Ellipta™

aclidinium bromide/formoterol fumarateInhalation Powder – Duaklir® Pressair®

glycopyrrolate/formoterol fumarateInhalation Aerosol – Bevespi Aerosphere®

indacaterol/glycopyrrolateInhalation Powder

– Utibron® Neohaler®

tiotropium bromide & olodaterolInhalation Spray – Stiolto® Respimat®

umeclidinium and vilanterolInhalation Powder – Anoro® Ellipta®

Inhalers

Inhalers Inhalers Inhaler

This table shows all available short-acting, branded, inhaled therapies by therapeutic class as of August 2019.

The GOLD report recommends a long-acting bronchodilator for maintenance treatment, with a goal to manage symptoms.

GOLD does not endorse any specific treatments.GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS = inhaled corticosteroids.

IMPORTANT SAFETY INFORMATION FOR ARCAPTA® NEOHALER®, SEEBRI® NEOHALER®, LONHALA® MAGNAIR®, AND UTIBRON® NEOHALER®

ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients, and UTIBRON NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol, glycopyrrolate, or to any of the ingredients. SEEBRI NEOHALER and LONHALA MAGNAIR are contraindicated in patients with a hypersensitivity to glycopyrrolate or to any of the ingredients.Use of a LABA, including ARCAPTA NEOHALER or UTIBRON NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma. Use of a LABA, including ARCAPTA NEOHALER or UTIBRON NEOHALER, as monotherapy (without inhaled corticosteroids) for asthma, increases the risk of serious asthma-related events, including hospitalization, intubation and death. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with ARCAPTA NEOHALER or UTIBRON NEOHALER has been conducted. Available data do not suggest an increased risk of death with use of LABAs in patients with COPD.ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER should not be initiated in patients with acutely deteriorating or potentially life-threatening episodes of COPD or used as rescue therapy for acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.ARCAPTA NEOHALER or UTIBRON NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medicines containing LABAs as an overdose may result. Patients who have been taking inhaled short-acting beta2-agonists on a regular basis should be instructed to discontinue their regular use and to use them only for symptomatic relief of acute respiratory symptoms. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ARCAPTA NEOHALER or UTIBRON NEOHALER should not use another medicine containing a LABA for any reason.Immediate hypersensitivity reactions have been reported with ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER. If signs occur, discontinue immediately and institute alternative therapy. ARCAPTA NEOHALER, SEEBRI NEOHALER, and UTIBRON NEOHALER should be used with caution in patients with severe hypersensitivity to milk proteins.As with other inhaled medicines, ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs following dosing with ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, or UTIBRON NEOHALER, it should be treated immediately with an inhaled, short-acting bronchodilator; ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, or UTIBRON NEOHALER should be discontinued immediately and alternative therapy instituted.Indacaterol, like other beta2-adrenergic 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. ARCAPTA NEOHALER and UTIBRON NEOHALER should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Beta2-adrenergic agonists may produce significant hypokalemia in some patients.As with other beta2-adrenergic agonists, indacaterol should be administered with extreme caution in patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval because these agents may potentiate the action of adrenergic agonists on the cardiovascular system.As with other beta2-adrenergic agonists, ARCAPTA NEOHALER and UTIBRON NEOHALER should be used with caution in patients treated with additional adrenergic drugs, non-potassium-sparing diuretics, and beta-blockers.ARCAPTA NEOHALER and UTIBRON NEOHALER, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER should be used with caution in patients with narrow-angle glaucoma and in patients with urinary retention. 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) and of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Patients should be instructed to consult a physician immediately should any signs or symptoms develop.In 6 clinical trials, 48% of ARCAPTA NEOHALER patients reported adverse reactions compared with 43% of placebo patients. The most common adverse events reported in ≥2% of patients taking ARCAPTA NEOHALER, and occurring more frequently than in patients taking placebo, were cough (6.5% vs 4.5%), nasopharyngitis (5.3% vs 2.7%), headache (5.1% vs 2.5%), nausea (2.4% vs 0.9%), and oropharyngeal pain (2.2% vs 0.7%). The most common serious adverse reactions of ARCAPTA NEOHALER patients were COPD exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar rates across treatment groups.The most common adverse events reported in ≥1% of patients taking SEEBRI NEOHALER, and occurring more frequently than in patients taking placebo, were upper respiratory tract infection (3.4% vs 2.3%), nasopharyngitis (2.1% vs 1.9%), oropharyngeal pain (1.8% vs 1.2%), urinary tract infection (1.4% vs 1.3%), and sinusitis (1.4% vs 0.7%).

The most common adverse events reported in ≥2% of patients taking LONHALA MAGNAIR, and occurring more frequently than in patients taking placebo, were dyspnea (4.9% vs 3.0%) and urinary tract infection (2.1% vs 1.4%).The most common adverse events reported in ≥1% of patients taking UTIBRON NEOHALER, and occurring more frequently than in patients taking placebo, were nasopharyngitis (4.1% vs 1.8%), hypertension (2.0% vs 1.4%), back pain (1.8% vs 0.6%), and oropharyngeal pain (1.6% vs 1.2%).ARCAPTA capsules, SEEBRI capsules, and UTIBRON capsules must not be swallowed as the intended effects on the lungs will not be obtained. ARCAPTA capsules, SEEBRI capsules, and UTIBRON capsules are only for oral inhalation and should only be used with the NEOHALER device.LONHALA solution is for oral inhalation only and should not be injected or swallowed. LONHALA vials should only be administered with MAGNAIR.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

IMPORTANT SAFETY INFORMATION FOR BROVANA®

BROVANA is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any of the ingredients.Use of a LABA, including BROVANA, without an inhaled corticosteroid is contraindicated in patients with asthma. Use of a LABA, including BROVANA, as monotherapy (without inhaled corticosteroids) for asthma increases the risk of serious asthma-related events, including hospitalization, intubation and death. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with BROVANA Inhalation Solution has been conducted. Available data do not suggest an increased risk of death with use of LABAs in patients with COPD. BROVANA should not be initiated in patients with acutely deteriorating COPD or potentially life-threatening episodes of COPD or used as rescue therapy for acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.BROVANA should not be used more often, at higher doses than recommended, or in conjunction with other medications containing LABAs as an overdose may result. Patients who have been taking inhaled short-acting beta2-agonists on a regular basis should be instructed to discontinue their regular use and to use them only for symptomatic relief for acute respiratory symptoms. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BROVANA should not use another medicine containing a LABA for any reason.Immediate hypersensitivity reactions may occur with BROVANA. If signs occur, discontinue immediately and institute alternative therapy.As with other inhaled beta2-agonists, BROVANA can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, BROVANA should be discontinued immediately and alternative therapy instituted.BROVANA, 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, and/or symptoms. BROVANA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Beta2-adrenergic agonists may produce significant hypokalemia in some patients.As with other beta2-agonists, BROVANA, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because these agents may potentiate the action of adrenergic agonists on the cardiovascular system.As with other beta2-agonists, BROVANA should be used with caution in patients treated with additional adrenergic drugs, non-potassium-sparing diuretics, and beta-blockers.BROVANA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.Overall efficacy of BROVANA was maintained throughout the 12-week trial duration. Some tolerance to the bronchodilator effect of BROVANA was observed after 6 weeks of dosing (at the end of the dosing interval), although the FEV1 improvement remained statistically significant. This was not accompanied by other clinical manifestations of tolerance.The five most common adverse events reported with frequency ≥2% in patients taking BROVANA, and occurring more frequently than in patients taking placebo, were pain (8% vs 5%), chest pain (7% vs 6%), back pain (6% vs 2%), diarrhea (6% vs 4%), and sinusitis (5% vs 4%).BROVANA should not be swallowed as the intended effects on the lungs will not be obtained. BROVANA is only for oral inhalation via a standard jet nebulizer connected to an air compressor.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.

IMPORTANT SAFETY INFORMATION FOR ARCAPTA® NEOHALER®, SEEBRI® NEOHALER®, LONHALA® MAGNAIR®, AND UTIBRON® NEOHALER®

ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients, and UTIBRON NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol, glycopyrrolate, or to any of the ingredients. SEEBRI NEOHALER and LONHALA MAGNAIR are contraindicated in patients with a hypersensitivity to glycopyrrolate or to any of the ingredients.Use of a LABA, including ARCAPTA NEOHALER or UTIBRON NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma. Use of a LABA, including ARCAPTA NEOHALER or UTIBRON NEOHALER, as monotherapy (without inhaled corticosteroids) for asthma, increases the risk of serious asthma-related events, including hospitalization, intubation and death. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with ARCAPTA NEOHALER or UTIBRON NEOHALER has been conducted. Available data do not suggest an increased risk of death with use of LABAs in patients with COPD.ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER should not be initiated in patients with acutely deteriorating or potentially life-threatening episodes of COPD or used as rescue therapy for acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.ARCAPTA NEOHALER or UTIBRON NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medicines containing LABAs as an overdose may result. Patients who have been taking inhaled short-acting beta2-agonists on a regular basis should be instructed to discontinue their regular use and to use them only for symptomatic relief of acute respiratory symptoms. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ARCAPTA NEOHALER or UTIBRON NEOHALER should not use another medicine containing a LABA for any reason.Immediate hypersensitivity reactions have been reported with ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER. If signs occur, discontinue immediately and institute alternative therapy. ARCAPTA NEOHALER, SEEBRI NEOHALER, and UTIBRON NEOHALER should be used with caution in patients with severe hypersensitivity to milk proteins.As with other inhaled medicines, ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs following dosing with ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, or UTIBRON NEOHALER, it should be treated immediately with an inhaled, short-acting bronchodilator; ARCAPTA NEOHALER, SEEBRI NEOHALER, LONHALA MAGNAIR, or UTIBRON NEOHALER should be discontinued immediately and alternative therapy instituted.Indacaterol, like other beta2-adrenergic 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. ARCAPTA NEOHALER and UTIBRON NEOHALER should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Beta2-adrenergic agonists may produce significant hypokalemia in some patients.As with other beta2-adrenergic agonists, indacaterol should be administered with extreme caution in patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval because these agents may potentiate the action of adrenergic agonists on the cardiovascular system.As with other beta2-adrenergic agonists, ARCAPTA NEOHALER and UTIBRON NEOHALER should be used with caution in patients treated with additional adrenergic drugs, non-potassium-sparing diuretics, and beta-blockers.ARCAPTA NEOHALER and UTIBRON NEOHALER, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.SEEBRI NEOHALER, LONHALA MAGNAIR, and UTIBRON NEOHALER should be used with caution in patients with narrow-angle glaucoma and in patients with urinary retention. 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) and of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Patients should be instructed to consult a physician immediately should any signs or symptoms develop.In 6 clinical trials, 48% of ARCAPTA NEOHALER patients reported adverse reactions compared with 43% of placebo patients. The most common adverse events reported in ≥2% of patients taking ARCAPTA NEOHALER, and occurring more frequently than in patients taking placebo, were cough (6.5% vs 4.5%), nasopharyngitis (5.3% vs 2.7%), headache (5.1% vs 2.5%), nausea (2.4% vs 0.9%), and oropharyngeal pain (2.2% vs 0.7%). The most common serious adverse reactions of ARCAPTA NEOHALER patients were COPD exacerbation, pneumonia, angina pectoris, and atrial fibrillation, which occurred at similar rates across treatment groups.The most common adverse events reported in ≥1% of patients taking SEEBRI NEOHALER, and occurring more frequently than in patients taking placebo, were upper respiratory tract infection (3.4% vs 2.3%), nasopharyngitis (2.1% vs 1.9%), oropharyngeal pain (1.8% vs 1.2%), urinary tract infection (1.4% vs 1.3%), and sinusitis (1.4% vs 0.7%).

The most common adverse events reported in ≥2% of patients taking LONHALA MAGNAIR, and occurring more frequently than in patients taking placebo, were dyspnea (4.9% vs 3.0%) and urinary tract infection (2.1% vs 1.4%).The most common adverse events reported in ≥1% of patients taking UTIBRON NEOHALER, and occurring more frequently than in patients taking placebo, were nasopharyngitis (4.1% vs 1.8%), hypertension (2.0% vs 1.4%), back pain (1.8% vs 0.6%), and oropharyngeal pain (1.6% vs 1.2%).ARCAPTA capsules, SEEBRI capsules, and UTIBRON capsules must not be swallowed as the intended effects on the lungs will not be obtained. ARCAPTA capsules, SEEBRI capsules, and UTIBRON capsules are only for oral inhalation and should only be used with the NEOHALER device.LONHALA solution is for oral inhalation only and should not be injected or swallowed. LONHALA vials should only be administered with MAGNAIR.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

IMPORTANT SAFETY INFORMATION FOR BROVANA®

BROVANA is contraindicated in patients with a history of hypersensitivity to arformoterol, racemic formoterol or to any of the ingredients.Use of a LABA, including BROVANA, without an inhaled corticosteroid is contraindicated in patients with asthma. Use of a LABA, including BROVANA, as monotherapy (without inhaled corticosteroids) for asthma increases the risk of serious asthma-related events, including hospitalization, intubation and death. No study adequate to determine whether the rate of asthma-related death is increased in patients treated with BROVANA Inhalation Solution has been conducted. Available data do not suggest an increased risk of death with use of LABAs in patients with COPD. BROVANA should not be initiated in patients with acutely deteriorating COPD or potentially life-threatening episodes of COPD or used as rescue therapy for acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled short-acting beta2-agonist.BROVANA should not be used more often, at higher doses than recommended, or in conjunction with other medications containing LABAs as an overdose may result. Patients who have been taking inhaled short-acting beta2-agonists on a regular basis should be instructed to discontinue their regular use and to use them only for symptomatic relief for acute respiratory symptoms. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BROVANA should not use another medicine containing a LABA for any reason.Immediate hypersensitivity reactions may occur with BROVANA. If signs occur, discontinue immediately and institute alternative therapy.As with other inhaled beta2-agonists, BROVANA can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, BROVANA should be discontinued immediately and alternative therapy instituted.BROVANA, 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, and/or symptoms. BROVANA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Beta2-adrenergic agonists may produce significant hypokalemia in some patients.As with other beta2-agonists, BROVANA, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval because these agents may potentiate the action of adrenergic agonists on the cardiovascular system.As with other beta2-agonists, BROVANA should be used with caution in patients treated with additional adrenergic drugs, non-potassium-sparing diuretics, and beta-blockers.BROVANA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.Overall efficacy of BROVANA was maintained throughout the 12-week trial duration. Some tolerance to the bronchodilator effect of BROVANA was observed after 6 weeks of dosing (at the end of the dosing interval), although the FEV1 improvement remained statistically significant. This was not accompanied by other clinical manifestations of tolerance.The five most common adverse events reported with frequency ≥2% in patients taking BROVANA, and occurring more frequently than in patients taking placebo, were pain (8% vs 5%), chest pain (7% vs 6%), back pain (6% vs 2%), diarrhea (6% vs 4%), and sinusitis (5% vs 4%).BROVANA should not be swallowed as the intended effects on the lungs will not be obtained. BROVANA is only for oral inhalation via a standard jet nebulizer connected to an air compressor.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit http://www.fda.gov/medwatch or call 1-800-FDA-1088.

ARCAPTA, , UTIBRON, , SEEBRI, , and NEOHALER are registered trademarks of Novartis AG, used under license. BROVANA, LONHALA, and are registered trademarks of Sunovion Pharmaceuticals Inc. MAGNAIR is a registered trademark of PARI Pharma GmbH, used under license. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd. SUNOVION and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd. All other trademarks are the property of their respective owners. © 2019 Sunovion Pharmaceuticals Inc. All rights reserved. 9/19 RESP-US-00163-19

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use BROVANA®

safely and effectively. See full prescribing information for BROVANA.

BROVANA® (arformoterol tartrate) Inhalation SolutionInitial U.S. Approval: 2006

RECENT MAJOR CHANGES Box Warning .................................................................................. Removed 05/2019Contraindications, revised (4) ....................................................................... 05/2019Warnings and Precautions, revised ............................................................... 05/2019 Serious Asthma-Related Events – Hospitalizations, Intubations, Death (5.1)

INDICATIONS AND USAGE BROVANA Inhalation Solution is a long-acting beta2-adrenergic agonist (beta2-agonist)indicated for:• Long-term, twice daily (morning and evening) administration in the maintenance

treatment of bronchoconstriction in patients with chronic obstructive pulmonarydisease (COPD), including chronic bronchitis and emphysema. (1.1)

Important limitations of use:• BROVANA Inhalation Solution is not indicated to treat acute deteriorations of

chronic obstructive pulmonary disease. (1.2, 5.2)• BROVANA Inhalation Solution is not indicated to treat asthma. (1.2)

DOSAGE AND ADMINISTRATION For oral inhalation only.• A total daily dose of greater than 30 mcg is not recommended. (2)• One 15 mcg/2 mL vial every 12 hours. (2)• For use with a standard jet nebulizer (with a face mask or mouthpiece) connected

to an air compressor. (2)

DOSAGE FORMS AND STRENGTHS Inhalation Solution (unit-dose vial for nebulization): 15 mcg/2 mL solution (3)

CONTRAINDICATIONS • BROVANA Inhalation Solution is contraindicated in patients with a history of

hypersensitivity to arformoterol, racemic formoterol or to any other componentsof this product. (4)

• Use of a LABA, including BROVANA Inhalation Solution, without an inhaledcorticosteroid is contraindicated in patients with asthma. (4)

WARNINGS AND PRECAUTIONS

• LABA as monotherapy (without an inhaled corticosteroid) for asthma increases therisk of serious asthma-related events. (5.1)

• Do not initiate BROVANA Inhalation Solution in acutely deteriorating patients. (5.2)• Do not use for relief of acute symptoms. Concomitant short-acting beta2-agonists

can be used as needed for acute relief. (5.2)• Do not exceed the recommended dose. Excessive use of BROVANA Inhalation

Solution, or use in conjunction with other medications containing long-actingbeta2-agonists, can result in clinically significant cardiovascular effects, and maybe fatal. (5.3, 5.5)

• Life-threatening paradoxical bronchospasm can occur. Discontinue BROVANAInhalation Solution immediately. (5.4)

• Use with caution in patients with cardiovascular or convulsive disorders,thyrotoxicosis, or with sensitivity to sympathomimetic drugs. (5.6, 5.7)

ADVERSE REACTIONS

Most common adverse reactions (≥2% incidence and more common than placebo)are pain, chest pain, back pain, diarrhea, sinusitis, leg cramps, dyspnea, rash, flu syndrome, peripheral edema and lung disorder. (6.2)

To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc.at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• Other adrenergic drugs may potentiate effect. Use with caution. (5.3, 7.1)• Xanthine derivatives, steroids, diuretics, or non-potassium sparing diuretics

may potentiate hypokalemia or ECG changes. Use with caution. (5.7, 7.2, 7.3)• MAO inhibitors, tricyclic antidepressants and drugs that prolong the QTc interval

may potentiate effect on the cardiovascular system. Use with extreme caution. (7.4)• Beta-blockers may decrease effectiveness. May block bronchodilatory effects

of beta-agonists. Use with caution and only when medically necessary. (7.5)

USE IN SPECIFIC POPULATIONS

• Hepatic ImpairmentUse with caution in patients with hepatic impairment. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and Patient Information.

Revised: 05/2019

5.8 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration ofBROVANA Inhalation Solution as demonstrated by cases of anaphylactic reaction,urticaria, angioedema, rash and bronchospasm.

6 ADVERSE REACTIONS Long-acting beta2-adrenergic agonists, such as BROVANA, as monotherapy(without inhaled corticosteroids) for asthma increase the risk of asthma-relatedevents. BROVANA Inhalation Solution is not indicated for the treatment of asthma[see Warnings and Precautions (5.1)].6.1 Beta2-Agonist Adverse Reaction Profile Adverse reactions to BROVANA Inhalation Solution are expected to be similarin nature to other beta2-adrenergic receptor agonists including: angina, hypertensionor hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth,palpitation, muscle cramps, nausea, dizziness, fatigue, malaise, hypokalemia,hyperglycemia, metabolic acidosis and insomnia. 6.2 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adversereaction rates observed in clinical trials of a drug cannot be directly compared torates in the clinical trials of another drug and may not reflect the rates observed inclinical practice.Adults with COPD in Short-Term Trials (12 weeks) The safety data described below for adults ≥35 years of age are based on2 clinical trials of 12 weeks. In the 2 trials of 12 weeks duration, 1456 patients(860 males and 596 females, ages 34 to 89 years old) with COPD were treated withBROVANA Inhalation Solution 15 mcg twice daily, 25 mcg twice daily, 50 mcg oncedaily, salmeterol 42 mcg twice daily, or placebo. The racial/ethnic distribution inthese two trials included 1383 Caucasians, 49 Blacks, 10 Asians, and 10 Hispanics,and 4 patients classified as Other. Among the 1,456 COPD patients in two 12-week, placebo-controlled trials,288 were treated with BROVANA Inhalation Solution 15 mcg twice daily and 293were treated with placebo. Doses of 25 mcg twice daily and 50 mcg once dailywere also evaluated. Table 1 shows adverse reaction rates among patients from these two trialswhere the frequency was greater than or equal to 2% in the BROVANA InhalationSolution 15 mcg twice daily group and where the rate in the BROVANA InhalationSolution 15 mcg twice daily group exceeded the rate in the placebo group. Thetotal number and percent of patients who reported adverse events were 202 (70%)in the 15 mcg twice daily and 219 (75%) in the placebo groups. Ten adverse eventsdemonstrated a dose relationship: asthenia, fever, bronchitis, COPD, headache,vomiting, hyperkalemia, leukocytosis, nervousness, and tremor.

Table 1: Number of Patients Experiencing Adverse Events from Two 12-Week,Double-Blind, Placebo-Controlled Clinical Trials

* Reported terms coded to “Lung Disorder” were predominantly pulmonary or chestcongestion.

Adverse events occurring in patients treated with BROVANA Inhalation Solution15 mcg twice daily with a frequency of <2%, but greater than placebo, were as follows:Body as a Whole: abscess, allergic reaction, digitalis intoxication, fever, hernia, injection site pain, neck rigidity, neoplasm, pelvic pain, retroperitoneal hemorrhageCardiovascular: arteriosclerosis, atrial flutter, AV block, congestive heart failure,heart block, myocardial infarct, QT interval prolonged, supraventricular tachycardia,inverted T-waveDigestive: constipation, gastritis, melena, oral moniliasis, periodontal abscess,rectal hemorrhageMetabolic and Nutritional Disorders: dehydration, edema, glucose tolerancedecreased, gout, hyperglycemia, hyperlipemia, hypoglycemia, hypokalemiaMusculoskeletal: arthralgia, arthritis, bone disorder, rheumatoid arthritis, tendinouscontractureNervous: agitation, cerebral infarct, circumoral paresthesia, hypokinesia, paralysis,somnolence, tremorRespiratory: carcinoma of the lung, respiratory disorder, voice alterationSkin and Appendages: dry skin, herpes simplex, herpes zoster, skin discoloration,skin hypertrophySpecial Senses: abnormal vision, glaucomaUrogenital: breast neoplasm, calcium crystalluria, cystitis, glycosuria, hematuria,kidney calculus, nocturia, PSA increase, pyuria, urinary tract disorder, urine abnormality.

In these trials, the overall frequency of all cardiovascular adverse events was6.9% in BROVANA Inhalation Solution 15 mcg twice daily and 13.3% in the placebogroup. There were no frequently occurring specific cardiovascular adverse eventsfor BROVANA Inhalation Solution (frequency ≥1% and greater than placebo). Therate of COPD exacerbations was also comparable between the BROVANA InhalationSolution 15 mcg twice daily and placebo groups, 12.2% and 15.1%, respectively.Adults with COPD in Long-Term (52-week) Safety Trial BROVANA Inhalation Solution was evaluated in one 52 week double-blind, randomized, placebo-controlled, safety trial conducted in patients with moderateto severe COPD. The primary endpoint was time to either respiratory death or firstCOPD exacerbation-related hospitalization, whichever occurred first. The eventhad to be a death or hospitalization for which the patient’s respiratory status was predominant and/or inciting contributor, as determined by the clinical investigator.The objective of the trial was to demonstrate that the risk of respiratory death orCOPD exacerbation-related hospitalization for patients treated with BROVANA InhalationSolution was not greater than 40% more than the risk for patient treated with placebo.A total of 841 patients (479 males and 361 females, ages 41 to 94 years old) withCOPD were randomized: 420 to BROVANA Inhalation Solution 15 mcg twice daily and421 to placebo. Of the randomized patients, 255 (61%) in the BROVANA InhalationSolution group and 211 (50%) in the placebo group, completed one year of treatment.The trial objective was met demonstrating that COPD patients treated with BROVANAInhalation Solution are not at an increased risk of respiratory death or COPD exacerbation-related hospitalizations compared to placebo.

7 DRUG INTERACTIONS7.1 Adrenergic Drugs If additional adrenergic drugs are to be administered by any route, theyshould be used with caution because the sympathetic effects of arformoterol maybe potentiated [see Warnings and Precautions (5.3, 5.5, 5.6, 5.7)].7.2 Xanthine Derivatives, Steroids, or Diuretics Concomitant treatment with methylxanthine (aminophylline, theophylline),steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonistsincluding BROVANA Inhalation Solution [see Warnings and Precautions (5.7)]. The concurrent use of intravenously or orally administered methylxanthines(e.g., aminophylline, theophylline) by patients receiving BROVANA InhalationSolution has not been completely evaluated. In two combined 12-week, placebo-controlled trials that included BROVANA Inhalation Solution doses of 15 mcg twicedaily, 25 mcg twice daily, and 50 mcg once daily, 54 of 873 BROVANA InhalationSolution-treated subjects received concomitant theophylline at study entry. In a12-month controlled trial that included a 50 mcg once daily BROVANA InhalationSolution dose, 30 of the 528 BROVANA Inhalation Solution-treated subjects receivedconcomitant theophylline at study entry. In these trials, heart rate and systolic bloodpressure were approximately 2-3 bpm and 6-8 mm Hg higher, respectively, insubjects on concomitant theophylline compared with the overall population.7.3 Non-potassium Sparing Diuretics The ECG changes and/or hypokalemia that may result from the administrationof non-potassium sparing diuretics (such as loop or thiazide diuretics) can beacutely worsened by beta-agonists, especially when the recommended dose of thebeta-agonist is exceeded. Although the clinical significance of these effects is notknown, caution is advised in the co-administration of beta-agonists, includingBROVANA Inhalation Solution, with non-potassium sparing diuretics. 7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs BROVANA Inhalation Solution, as with other beta-agonists, should be administered with extreme caution to patients being treated with monoamineoxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTcinterval because of the effect of adrenergic agonists on the cardiovascular systemmay be potentiated by these agents. Drugs that are known to prolong the QTcinterval have an increased risk of ventricular arrhythmias. 7.5 Beta-Blockers Beta-adrenergic receptor antagonists (beta-blockers) and BROVANAInhalation Solution may inhibit 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 withCOPD should not normally be treated with beta-blockers. However, under certaincircumstances, e.g., as prophylaxis after myocardial infarction, there may be noacceptable alternatives to the use of beta-blockers in patients with COPD. In thissetting, cardioselective beta-blockers could be considered, although they shouldbe administered with caution.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyRisk Summary There are no adequate and well-controlled studies in pregnant women.BROVANA should only be used during pregnancy if the expected benefit to thepatient outweighs the potential risk to the fetus. Women should be advised tocontact their physician if they become pregnant while taking BROVANA. In animalreproduction studies with arformoterol administered by the oral route to rats andrabbits at exposures approximately 370 and 8,400 times the adult exposure at themaximum recommended human daily inhalation dose (MRHDID) of 15 mcg every12 hours, respectively, there were findings of structural abnormalities, embryofetaland infant mortality, and alterations of growth. These adverse effects generallyoccurred at large multiples of the MRHDID when arformoterol was administered bythe oral route to achieve high systemic exposures. No evidence of fetal harm wasobserved in rabbits at an exposure approximately 4,900 times the MRHDID. The estimated background risk of major birth defects and miscarriage forthe indicated population is unknown. In the U.S. general population, the estimatedbackground risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2-4% and 15-20%, respectively.

Clinical ConsiderationsLabor or Delivery: The potential effect of BROVANA on labor and delivery is unknown.Because of the potential for beta-agonists interference with uterine contractility,use of BROVANA Inhalation Solution during labor should be restricted to whom thebenefits clearly outweigh the risk.

DataAnimal Data In an embryofetal development study in which pregnant rats received dosesof 1,000, 5,000 or 10,000 mcg/kg/day from gestation days 6 to 17, arformoterolwas shown to be teratogenic based upon findings of omphalocele (umbilical hernia),

BROVANA Inhalation Solution Placebo 15 mcg twice daily n (%) n (%)Total Patients 288 (100) 293 (100)Pain 23 (8) 16 (5)Chest Pain 19 (7) 19 (6)Back Pain 16 (6) 6 (2)Diarrhea 16 (6) 13 (4)Sinusitis 13 (5) 11 (4)Leg Cramps 12 (4) 6 (2)Dyspnea 11 (4) 7 (2)Rash 11 (4) 5 (2)Flu Syndrome 10 (3) 4 (1)Peripheral Edema 8 (3) 7 (2)Lung Disorder* 7 (2) 2 (1)

a malformation, in rat fetuses at exposures approximately 370 times adult exposureat the MRHDID (on an AUC basis with maternal oral doses of 1,000 mcg/kg/day andhigher. Maternal toxicity was not observed in rats with exposures up to 2,400 timesthe MRHDID (on an AUC basis with maternal oral doses up to 10,000 mcg/kg/day).A no-observed-adverse-effect-level (NOAEL) for rat fetuses was not identified. In an embryofetal development study in which pregnant rabbits receiveddoses of 20,000, 40,000 or 80,000 mcg/kg/day from gestation days 7 to 20,arformoterol was shown to be teratogenic based upon findings of malpositionedright kidney, a malformation, in rabbit fetuses at exposures approximately8400 times and higher than the adult exposure at the MRHDID (on an AUC basiswith maternal oral doses of 20,000 mcg/kg/day and higher). Malformations includingbrachydactyly, bulbous aorta, and liver cysts as well as decreased body weights wereobserved in rabbit fetuses at doses approximately 26,000 times and higher than theMRHDID in adults (on a mcg/m2 basis with maternal oral doses of 40,000 mcg/kg/dayand higher). Malformations including adactyly, lobular dysgenesis of the lung, andinterventricular septal defect as well as embryolethality were observed in rabbitfetuses at a dose approximately 52,000 times the MRHDID in adults (on a mcg/m2

basis with a maternal oral dose of 80,000 mcg/kg/day). Maternal toxicity wasobserved at doses approximately 26,000 times and higher than the MRHDID inadults (on a mcg/m2 basis with maternal oral doses of 40,000 mcg/kg/day andhigher). There was no evidence of fetal harm in rabbits at exposures approximately4,900 times and lower than the adult exposure at the MRHDID (on an AUC basiswith maternal oral doses of 10,000 mcg/kg/day and lower). In a pre- and post-natal development study, female rats received arformoterolat oral doses of 0, 1,000, 5,000, and 10,000 mcg/kg/day from gestation day 6through lactation day 20. Lengths of gestation for female rats receiving doses325 times and higher than the MRHDID (on a mcg/m2 basis with maternal oraldoses of 1,000 mcg/kg/day and higher) were slightly prolonged, which wasattributed to prolonged parturition or dystocia due to the pharmacological actionof β-adrenergic agonists such as arformoterol to relax uterine musculature. Onefemale that had received a dose 3,200 times the MRHDID (on a mcg/m2 basis witha maternal oral dose of 10,000 mcg/kg/day) was euthanized due to complicationsduring parturition. Pup survival and body weights were decreased at doses1,600 times and higher than the MRHDID (on a mcg/m2 basis with maternal oraldoses of 5,000 mcg/kg/day and higher) at birth and during lactation. Umbilicalhernia, a malformation, was observed for 1 pup at a dose 3,200 times the MRHDID(on a mcg/m2 basis with a maternal oral dose of 10,000 mcg/kg/day). Potentialdevelopmental delays of rat pups were observed at a dose 3,200 times the MRHDID(on a mcg/m2 basis with a maternal oral dose of 10,000 mcg/kg/day); however,no developmental delays were evident with doses 1,600 times the MRHDID(on a mcg/m2 basis with a maternal oral dose of 5,000 mcg/kg/day).8.2 LactationRisk Summary There are no data on the presence of arformoterol or its metabolites inhuman milk, the effects on the breastfed infant, or the effects on milk production.However, arformoterol was excreted in the milk of lactating rats. The developmentaland health benefits of breastfeeding should be considered along with the mother’sclinical need for BROVANA and any potential adverse effects on the breastfed infantfrom BROVANA or from the underlying maternal condition.Data Arformoterol and its metabolites were detected in the milk of lactatingrats following oral administration of a 10,000 mcg/kg dose of radiolabeledarformoterol tartrate.8.4 Pediatric Use BROVANA Inhalation Solution is approved for use in the long-term maintenance treatment of bronchoconstriction associated with chronic obstructivepulmonary disease, including chronic bronchitis and emphysema. This disease doesnot occur in children. The safety and efficacy of BROVANA Inhalation Solution inpediatric patients have not been established. 8.5 Geriatric Use Of the 873 patients who received BROVANA Inhalation Solution in twoplacebo-controlled clinical studies in adults with COPD, 391 (45%) were 65 years ofage or older while 96 (11%) were 75 years of age or older. No overall differences insafety or effectiveness were observed between these subjects and younger subjects.Among subjects age 65 years and older, 129 (33%) received BROVANA InhalationSolution at the recommended dose of 15 mcg twice daily, while the remainder receivedhigher doses. ECG alerts for ventricular ectopy in patients 65 to ≤75 years of age werecomparable among patients receiving 15 mcg twice daily, 25 mcg twice daily, andplacebo (3.9%, 5.2%, and 7.1%, respectively). A higher frequency (12.4%) wasobserved when BROVANA Inhalation Solution was dosed at 50 mcg once daily. Theclinical significance of this finding is not known. Other reported clinical experience hasnot identified differences in responses between the elderly and younger patients, butgreater sensitivity of some older individuals cannot be ruled out.8.6 Hepatic Impairment BROVANA Inhalation Solution should be used cautiously in patients withhepatic impairment due to increased systemic exposure in these patients [seeClinical Pharmacology (12.3)].8.7 Renal Impairment The systemic exposure to arformoterol was similar to renally impairedpatients compared with demographically matched healthy control subjects [seeClinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE There were no reported cases of abuse or evidence of drug dependencewith the use of BROVANA Inhalation Solution in the clinical trials.

10 OVERDOSAGE The expected signs and symptoms associated with overdosage of BROVANA(arformoterol tartrate) Inhalation Solution are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptomslisted under ADVERSE REACTIONS. Signs and symptoms may include angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, muscle cramps,nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, metabolic acidosisand insomnia. As with all inhaled sympathomimetic medications, cardiac arrest andeven death may be associated with an overdose of BROVANA Inhalation Solution. Treatment of overdosage consists of discontinuation of BROVANA InhalationSolution together with institution of appropriate symptomatic and/or supportive therapy.The judicious use of a cardioselective beta-receptor blocker may be considered, bearingin mind that such medication can produce bronchospasm. There is insufficient evidenceto determine if dialysis is beneficial for overdosage of BROVANA Inhalation Solution.Cardiac monitoring is recommended in cases of overdosage.11 DESCRIPTION BROVANA (arformoterol tartrate) Inhalation Solution is a sterile, clear, colorless, aqueous solution of the tartrate salt of arformoterol, the (R,R)-enantiomerof formoterol. Arformoterol is a selective beta2-adrenergic bronchodilator. The chemical name for arformoterol tartrate is formamide, N-[2-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]phenyl]-,(2R,3R)-2,3-dihydroxybutanedioate (1:1 salt), and its established structuralformula is as follows:

The molecular weight of arformoterol tartrate is 494.5 g/mol, and its empiricalformula is C19H24N2O4•C4H6O6 (1:1 salt). It is a white to off-white solid that is slightlysoluble in water. Arformoterol tartrate is the United States Adopted Name (USAN) for(R,R)-formoterol L-tartrate. BROVANA (arformoterol tartrate) Inhalation Solution is supplied as 2 mLof arformoterol tartrate solution packaged in 2.1 mL unit-dose, low-density polyethylene (LDPE) unit-dose vials. Each unit-dose vial contains 15 mcg of arformoterol (equivalent to 22 mcg of arformoterol tartrate) in a sterile, isotonicsaline solution, pH-adjusted to 5.0 with citric acid and sodium citrate. BROVANA Inhalation Solution requires no dilution before administration bynebulization. Like all other nebulized treatments, the amount delivered to the lungswill depend upon patient factors, the nebulizer used, and compressor performance.Using the PARI LC® Plus nebulizer (with mouthpiece) connected to a PARI DURANEBTM 3000 compressor under in vitro conditions, the mean delivered dose fromthe mouthpiece (% nominal) was approximately 4.1 mcg (27.6%) at a mean flowrate of 3.3 L/min. The mean nebulization time was 6 minutes or less. BROVANAInhalation Solution should be administered from a standard jet nebulizer atadequate flow rates via face mask or mouthpiece. Patients should be carefully instructed on the correct use of this drugproduct (please refer to the accompanying Patient Information).

12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action Arformoterol, the (R,R)-enantiomer of formoterol, is a selective long-actingbeta2-adrenergic receptor agonist (beta2-agonist) that has two-fold greater potencythan racemic formoterol (which contains both the (S,S) and (R,R)-enantiomers).The (S,S)-enantiomer is about 1,000-fold less potent as a beta2-agonist than the(R,R)-enantiomer. While it is recognized that beta2-receptors are the predominantadrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, data indicate that there are also beta2-receptorsin the human heart comprising 10% to 50% of the total beta-adrenergic receptors.The precise function of these receptors has not been established, but they raise thepossibility that even highly selective beta2-agonists may have cardiac effects. The pharmacologic effects of beta2-adrenoceptor agonist drugs, includingarformoterol, are at least in part attributable to stimulation of intracellular adenylcyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP)to cyclic-3′,5′-adenosine monophosphate (cyclic AMP). Increased intracellular cyclicAMP levels cause relaxation of bronchial smooth muscle and inhibition of releaseof mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that arformoterol is an inhibitor of the release of mastcell mediators, such as histamine and leukotrienes, from the human lung.Arformoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogswith airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.12.2 PharmacodynamicsSystemic Safety and Pharmacokinetic/Pharmacodynamic Relationships The predominant adverse effects of inhaled beta2-agonists occur as a resultof excessive activation of systemic beta-adrenergic receptors. The most commonadverse effects may include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in plasma potassium, and increases in plasma glucose.Effects on Serum Potassium and Serum Glucose Levels Changes in serum potassium and serum glucose were evaluated in a dose-ranging study of twice daily (5 mcg, 15 mcg, or 25 mcg; 215 patients with COPD) andonce daily (15 mcg, 25 mcg, or 50 mcg; 191 patients with COPD) BROVANA InhalationSolution in COPD patients. At 2 and 6 hours post dose at week 0 (after the first dose),mean changes in serum potassium ranging from 0 to -0.3 mEq/L were observed inthe BROVANA Inhalation Solution groups with similar changes observed after 2 weeksof treatment. Changes in mean serum glucose levels, ranging from a decrease of1.2 mg/dL to an increase of 32.8 mg/dL were observed for BROVANA InhalationSolution dose groups at both 2 and 6 hours post dose, both after the first dose and14 days of daily treatment.Electrophysiology The effect of BROVANA Inhalation Solution on QT interval was evaluated in adose-ranging study following multiple doses of BROVANA Inhalation Solution 5 mcg,15 mcg, or 25 mcg twice daily or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeksin patients with COPD. ECG assessments were performed at baseline, time of peakplasma concentration and throughout the dosing interval. Different methods ofcorrecting for heart rate were employed, including a subject-specific method and theFridericia method.

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 1.1 Maintenance Treatment of COPD 1.2 Important Limitations of Use 2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Serious Asthma-Related Events -

Hospitalizations, Intubations Deaths 5.2 Deterioration of Disease and Acute Episodes 5.3 Excessive Use of BROVANA Inhalation

Solution and Use with Other Long-ActingBeta2-Agonists

5.4 Paradoxical Bronchospasm 5.5 Cardiovascular Effects 5.6 Coexisting Conditions 5.7 Hypokalemia and Hyperglycemia 5.8 Immediate Hypersensitivity Reactions

6 ADVERSE REACTIONS 6.1 Beta2-Agonist Adverse Reaction Profile 6.2 Clinical Trials Experience7 DRUG INTERACTIONS 7.1 Adrenergic Drugs 7.2 Xanthine Derivatives, Steroids or Diuretics 7.3 Non-potassium Sparing Diuretics 7.4 MAO Inhibitors, Tricyclic Antidepressants,

QTc Prolonging Drugs 7.5 Beta-Blockers8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment9 DRUG ABUSE AND DEPENDENCE10 OVERDOSAGE

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE1.1 Maintenance Treatment of COPD BROVANA (arformoterol tartrate) Inhalation Solution is indicated for thelong-term, twice daily (morning and evening) maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD),including chronic bronchitis and emphysema. BROVANA Inhalation Solution is for useby nebulization only.1.2 Important Limitations of Use BROVANA Inhalation Solution is not indicated to treat acute deteriorations ofchronic obstructive pulmonary disease [see Warnings and Precautions (5.2)]. BROVANA Inhalation Solution is not indicated to treat asthma. The safety andeffectiveness of BROVANA Inhalation Solution in asthma have not been established.

2 DOSAGE AND ADMINISTRATION The recommended dose of BROVANA (arformoterol tartrate) InhalationSolution is one 15 mcg unit-dose vial administered twice daily (morning andevening) by nebulization. A total daily dose of greater than 30 mcg (15 mcg twicedaily) is not recommended. BROVANA Inhalation Solution should be administered by the orally inhaledroute via a standard jet nebulizer connected to an air compressor (see the accompanying Patient Information). BROVANA Inhalation Solution should not be swallowed. BROVANA Inhalation Solution should be stored refrigerated in foil pouches.After opening the pouch, unused unit-dose vials should be returned to, and stored in,the pouch. An opened unit-dose vial should be used right away. If the recommended maintenance treatment regimen fails to provide theusual response, medical advice should be sought immediately, as this is often asign of destabilization of COPD. Under these circumstances, the therapeutic regimenshould be reevaluated and additional therapeutic options should be considered. No dose adjustment is required for patients with renal or hepaticimpairment. However, since the clearance of BROVANA Inhalation Solution isprolonged in patients with hepatic impairment, they should be monitored closely. The drug compatibility (physical and chemical), efficacy, and safety ofBROVANA Inhalation Solution when mixed with other drugs in a nebulizer have notbeen established. The safety and efficacy of BROVANA Inhalation Solution have been established in clinical trials when administered using the PARI LC® Plus nebulizer(with a face mask or mouthpiece) and the PARI DURA NEBTM 3000 compressor.The safety and efficacy of BROVANA Inhalation Solution delivered from non-compressor based nebulizer systems have not been established.

3 DOSAGE FORMS AND STRENGTHS BROVANA (arformoterol tartrate) Inhalation Solution is supplied as a sterilesolution for nebulization in low-density polyethylene unit-dose vials. Each 2 mLvial contains 15 mcg of arformoterol equivalent to 22 mcg of arformoterol tartrate.

4 CONTRAINDICATIONS BROVANA Inhalation Solution is contraindicated in patients with a historyof hypersensitivity to arformoterol, racemic formoterol or to any other componentsof this product. Use of a LABA, including BROVANA Inhalation Solution, without an inhaledcorticosteroid is contraindicated in patients with asthma [see Warnings andPrecautions (5)]. BROVANA Inhalation Solution is not indicated for the treatmentof asthma.

5 WARNINGS AND PRECAUTIONS5.1 Serious Asthma-Related Events - Hospitalizations, Intubations, Deaths • The safety and efficacy of BROVANA Inhalation Solution in patients with

asthma have not been established. BROVANA Inhalation Solution is notindicated for the treatment of asthma [see Contraindications (4)].

• Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy[without inhaled corticosteroids (ICS)] for asthma is associated with anincreased risk of asthma-related death. Available data from controlledclinical trials also suggest that use of LABA as monotherapy increasesthe risk of asthma-related hospitalization in pediatric and adolescentpatients. These findings are considered a class effect of LABA monotherapy.When LABA are used in fixed-dose combination with ICS, data from largeclinical trials do not show a significant increase in the risk of seriousasthma-related events (hospitalizations, intubations, and death)compared with ICS alone.

• A 28-week, placebo-controlled US study comparing the safety of anotherLABA (salmeterol) with placebo, each added to usual asthma therapy,showed an increase in asthma-related deaths in patients receivingsalmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). Theincreased risk of asthma-related death is considered a class effect ofthe LABA, including BROVANA Inhalation Solution.

• No study adequate to determine whether the rate of asthma-related deathis increased in patients treated with BROVANA Inhalation Solution hasbeen conducted. Clinical studies with racemic formoterol suggested a

higher incidence of serious asthma exacerbations in patients whoreceived racemic formoterol than in those who received placebo.The sizes of these studies were not adequate to precisely quantifythe differences in serious asthma exacerbation rates betweentreatment groups.

• Available data do not suggest an increased risk of death with use ofLABA in patients with COPD.

5.2 Deterioration of Disease and Acute Episodes BROVANA Inhalation Solution should not be initiated in patients withacutely deteriorating COPD, which may be a life-threatening condition. The use ofBROVANA Inhalation Solution in this setting is inappropriate. BROVANA Inhalation Solution is not indicated for the treatment of acuteepisodes of bronchospasm, i.e., as rescue therapy and extra doses should not beused for that purpose. Acute symptoms should be treated with an inhaled short-acting beta2-agonist. When beginning BROVANA Inhalation Solution, patients who have beentaking inhaled short-acting beta2-agonists on a regular basis (e.g., four times a day)should be instructed to discontinue the regular use of these drugs and use themonly for symptomatic relief of acute respiratory symptoms. When prescribingBROVANA Inhalation Solution, the healthcare provider should also prescribe aninhaled, short-acting beta2-agonist and instruct the patient how it should be used.Increasing inhaled beta2-agonist use is a signal of deteriorating disease for whichprompt medical attention is indicated. COPD may deteriorate acutely over a periodof hours or chronically over several days or longer. If BROVANA Inhalation Solutionno longer controls the symptoms of bronchoconstriction, or 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 reevaluation of the patient and the COPDtreatment regimen should be undertaken at once. Increasing the daily dosage ofBROVANA Inhalation Solution beyond the recommended 15 mcg twice daily doseis not appropriate in this situation. 5.3 Excessive Use of BROVANA Inhalation Solution and Use with Other Long-

Acting Beta2-Agonists Fatalities have been reported in association with excessive use of inhaledsympathomimetic drugs. As with other inhaled beta2-adrenergic drugs, BROVANAInhalation Solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-actingbeta2-agonists. 5.4 Paradoxical Bronchospasm As with other inhaled beta2-agonists, BROVANA Inhalation Solution canproduce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, BROVANA Inhalation Solution should be discontinued immediately and alternative therapy instituted. 5.5 Cardiovascular Effects BROVANA Inhalation Solution, like other beta2-agonists, can produce a clinicallysignificant cardiovascular effect in some patients as measured by increases in pulserate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur,the drug may need to be discontinued. In addition, beta-agonists have been reportedto produce ECG changes, such as flattening of the T-wave, prolongation of the QTcinterval, and ST segment depression. The clinical significance of these findings isunknown. BROVANA Inhalation Solution, as with other sympathomimetic amines,should be used with caution in patients with cardiovascular disorders, especiallycoronary insufficiency, cardiac arrhythmias, and hypertension. 5.6 Coexisting Conditions BROVANA Inhalation Solution, like other sympathomimetic amines, shouldbe used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. In two pooled, 12-week, placebo-controlled trials investigating BROVANA Inhalation Solution doses of 15 μg BID, 25 μg BID, and50 μg QD, changes in mean predose and 2-hour post dose systolic and/or diastolicblood pressure were seen as a general fall of 2-4 mm/Hg; for pulse rate the mean ofmaximal increases were 8.8-12.0 beats/min. Over the course of a one-year studymeasuring serial electrocardiograms while receiving a dose of 50 mcg daily ofBROVANA Inhalation Solution resulted in an approximately 3.0 ms increase in QTC-F

compared to the active comparator, salmeterol. Doses of the related beta2-agonistalbuterol, when administered intravenously, have been reported to aggravatepreexisting diabetes mellitus and ketoacidosis. 5.7 Hypokalemia and Hyperglycemia Beta-agonist medications may produce significant hypokalemia in somepatients, possibly through intracellular shunting, which has the potential to produceadverse cardiovascular effects [see Clinical Pharmacology (12.2)]. The decrease inserum potassium is usually transient, not requiring supplementation. Beta-agonistmedications may produce transient hyperglycemia in some patients. Clinically significant and dose-related changes in serum potassium andblood glucose were infrequent during clinical trials with long-term administrationof BROVANA Inhalation Solution at the recommended dose.

11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis,

Impairment of Fertility 13.2 Animal Toxicology and/or

Pharmacology14 CLINICAL STUDIES 14.1 Adult COPD Trials16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the fullprescribing information are not listed.

®

15 mcg*/2 mL*potency expressed as arformoterol

Relative to placebo, the mean change in subject-specific QTc averaged overthe dosing interval ranged from -1.8 to 2.7 msec, indicating little effect of BROVANAInhalation Solution on cardiac repolarization after 2 weeks of treatment. The maximummean change in subject-specific QTc for the BROVANA Inhalation Solution 15 mcgtwice daily dose was 17.3 msec, compared with 15.4 msec in the placebo group. Noapparent correlation of QTc with arformoterol plasma concentration was observed.Electrocardiographic Monitoring in Patients with COPD The effect of different doses of BROVANA Inhalation Solution on cardiacrhythm was assessed using 24-hour Holter monitoring in two 12-week, double-blind, placebo-controlled studies of 1,456 patients with COPD (873 receivedBROVANA Inhalation Solution at 15 or 25 mcg twice daily or 50 mcg once dailydoses; 293 received placebo; 290 received salmeterol). The 24-hour Holter monitoring occurred once at baseline, and up to 3 times during the 12-week treatment period. The rates of new-onset cardiac arrhythmias not present atbaseline over the double-blind 12-week treatment period were similar (approximately33-34%) for patients who received BROVANA Inhalation Solution 15 mcg twicedaily to those who received placebo. There was a dose-related increase in new, treatment-emergent arrhythmias seen in patients who received BROVANA InhalationSolution 25 mcg twice daily and 50 mcg once daily, 37.6% and 40.1%, respectively.The frequencies of new treatment-emergent events of non-sustained (3-10 beatrun) and sustained (>10 beat run) ventricular tachycardia were 7.4% and 1.1% inBROVANA Inhalation Solution 15 mcg twice daily and 6.9% and 1.0% in placebo.In patients who received BROVANA Inhalation Solution 25 mcg twice daily and50 mcg once daily, the frequencies of non-sustained (6.2% and 8.2%, respectively)and sustained ventricular tachycardia (1.0% and 1.0%, respectively) were similar.Five cases of ventricular tachycardia were reported as adverse events (1 inBROVANA Inhalation Solution 15 mcg twice daily and 4 in placebo), with two ofthese events leading to discontinuation of treatment (2 in placebo). There were no baseline occurrences of atrial fibrillation/flutter observed on24-hour Holter monitoring in patients treated with BROVANA Inhalation Solution15 mcg twice daily or placebo. New, treatment-emergent atrial fibrillation/flutteroccurred in 0.4% of patients who received BROVANA Inhalation Solution 15 mcgtwice daily and 0.3% of patients who received placebo. There was a dose-relatedincrease in the frequency of atrial fibrillation/flutter reported in the BROVANAInhalation Solution 25 mcg twice daily and 50 mcg once daily dose groups of0.7% and 1.4%, respectively. Two cases of atrial fibrillation/flutter were reportedas adverse events (1 in BROVANA Inhalation Solution 15 mcg twice daily and 1 inplacebo). Dose-related increases in mean maximum change in heart rate in the12 hours after dosing were also observed following 12 weeks of dosing withBROVANA Inhalation Solution 15 mcg twice daily (8.8 bpm), 25 mcg twice daily(9.9 bpm) and 50 mcg once daily (12 bpm) versus placebo (8.5 bpm).Tachyphylaxis/Tolerance Tolerance to the effects of inhaled beta-agonists can occur with regularly-scheduled, chronic use. In two placebo-controlled clinical trials in patients with COPD involvingapproximately 725 patients in each, the overall efficacy of BROVANA InhalationSolution was maintained throughout the 12-week trial duration. However, toleranceto the bronchodilator effect of BROVANA Inhalation Solution was observed after6 weeks of dosing, as measured by a decrease in trough FEV1. FEV1 improvementat the end of the 12-hour dosing interval decreased by approximately one-third(22.1% mean improvement after the first dose compared to 14.6% at week 12).Tolerance to the trough FEV1 bronchodilator effect of BROVANA Inhalation Solutionwas not accompanied by other clinical manifestations of tolerance in these trials.12.3 Pharmacokinetics The pharmacokinetics (PK) of arformoterol have been investigated inhealthy subjects, elderly subjects, renally and hepatically impaired subjects, andCOPD patients following the nebulization of the recommended therapeutic dose anddoses up to 96 mcg.Absorption In COPD patients administered 15 mcg arformoterol every 12 hours for14 days, the mean steady-state peak (R,R)-formoterol plasma concentration (Cmax)and systemic exposure (AUC0-12h) were 4.3 pg/mL and 34.5 pg•hr/mL, respectively.The median steady-state peak (R,R)-formoterol plasma concentration time (tmax)was observed approximately one-half hour after drug administration. Systemic exposure to (R,R)-formoterol increased linearly with dose in COPDpatients following arformoterol doses of 5 mcg, 15 mcg, or 25 mcg twice daily for2 weeks or 15 mcg, 25 mcg, or 50 mcg once daily for 2 weeks. In a crossover study in patients with COPD, when arformoterol 15 mcg inhalation solution and 12 and 24 mcg formoterol fumarate inhalation powder(Foradil® Aerolizer®) was administered twice daily for 2 weeks, the accumulationindex was approximately 2.5 based on the plasma (R,R)-formoterol concentrationsin all three treatments. At steady- state, geometric means of systemic exposure(AUC0-12h) to (R,R)-formoterol following 15 mcg of arformoterol inhalation solutionand 12 mcg of formoterol fumarate inhalation powder were 39.33 pg•hr/mL and33.93 pg•hr/mL, respectively (ratio 1.16; 90% CI 1.00, 1.35), while the geometricmeans of the Cmax were 4.30 pg/mL and 4.75 pg/mL, respectively (ratio 0.91;90% CI 0.76, 1.09). In a study in patients with asthma, treatment with arformoterol 50 mcgwith pre- and post-treatment with activated charcoal resulted in a geometric meandecrease in (R,R)-formoterol AUC0-6h by 27% and Cmax by 23% as compared to treatment with arformoterol 50 mcg alone. This suggests that a substantial portionof systemic drug exposure is due to pulmonary absorption.Distribution The binding of arformoterol to human plasma proteins in vitro was 52-65%at concentrations of 0.25, 0.5 and 1.0 ng/mL of radiolabeled arformoterol. Theconcentrations of arformoterol used to assess the plasma protein binding werehigher than those achieved in plasma following inhalation of multiple doses of50 mcg arformoterol.Metabolism In vitro profiling studies in hepatocytes and liver microsomes have shownthat arformoterol is primarily metabolized by direct conjugation (glucuronidation)and secondarily by O-demethylation. At least five human uridine diphosphoglucuro -nosyltransferase (UGT) isozymes catalyze arformoterol glucuronidation in vitro.Two cytochrome P450 isozymes (CYP2D6 and secondarily CYP2C19) catalyze theO-demethylation of arformoterol. Arformoterol was almost entirely metabolized following oral administrationof 35 mcg of radiolabeled arformoterol in eight healthy subjects. Direct conjugationof arformoterol with glucuronic acid was the major metabolic pathway. Most of the drug-related material in plasma and urine was in the form of glucuronide or sulfate conjugates of arformoterol. O-Desmethylation and conjugates of the O-desmethylmetabolite were relatively minor metabolites accounting for less than 17% of thedose recovered in urine and feces.Elimination After administration of a single oral dose of radiolabeled arformoterol toeight healthy male subjects, 63% of the total radioactive dose was recovered inurine and 11% in feces within 48 hours. A total of 89% of the total radioactive dosewas recovered within 14 days, with 67% in urine and 22% in feces. Approximately1% of the dose was recovered as unchanged arformoterol in urine over 14 days.Renal clearance was 8.9 L/hr for unchanged arformoterol in these subjects. In COPD patients given 15 mcg inhaled arformoterol twice a day for 14 days,the mean terminal half-life of arformoterol was 26 hours.Special Populations:Gender A population PK analysis indicated that there was no effect of gender uponthe pharmacokinetics of arformoterol.Race The influence of race on arformoterol pharmacokinetics was assessed usinga population PK analysis and data from healthy subjects. There was no clinicallysignificant impact of race upon the pharmacokinetic profile of arformoterol.Geriatric The pharmacokinetic profile of arformoterol in 24 elderly subjects (aged65 years or older) was compared to a younger cohort of 24 subjects (18-45 years)that were matched for body weight and gender. No significant differences in systemicexposure (AUC and Cmax) were observed when the two groups were compared.Pediatric The pharmacokinetics of arformoterol have not been studied in pediatricsubjects.Hepatic Impairment The pharmacokinetic profile of arformoterol was assessed in 24 subjectswith mild, moderate, and severe hepatic impairment. The systemic exposure(Cmax and AUC) to arformoterol increased 1.3 to 2.4-fold in subjects with hepatic impairment compared to 16 demographically matched healthy control subjects.No clear relationship between drug exposure and the severity of hepatic impairmentwas observed. BROVANA Inhalation Solution should be used cautiously in patientswith hepatic impairment.Renal Impairment The impact of renal disease upon the pharmacokinetics of arformoterol wasstudied in 24 subjects with mild, moderate, or severe renal impairment. Systemicexposure (AUC and Cmax) to arformoterol was similar in renally impaired patientscompared with demographically matched healthy control subjects.Drug-Drug Interaction When paroxetine, a potent inhibitor of CYP2D6, was co-administered withBROVANA Inhalation Solution at steady-state, exposure to either drug was notaltered. Dosage adjustments of BROVANA Inhalation Solution are not necessarywhen the drug is given concomitantly with potent CYP2D6 inhibitors. Arformoterol did not inhibit CYP1A2, CYP2A6, CYP2C9/10, CYP2C19,CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11 enzymes at >1,000-fold higher concentrations than the expected peak plasma concentrations following a therapeutic dose.12.5 Pharmacogenomics Arformoterol is eliminated through the action of multiple drug metabolizingenzymes. Direct glucuronidation of arformoterol is mediated by several UGTenzymes and is the primary elimination route. O-Desmethylation is a secondaryroute catalyzed by the CYP enzymes CYP2D6 and CYP2C19. In otherwise healthysubjects with reduced CYP2D6 and/or UGT1A1 enzyme activity, there was no impacton systemic exposure to arformoterol compared to subjects with normal CYP2D6and/or UGT1A1 enzyme activities.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies were conducted in mice using oral administration andrats using inhalation administration to evaluate the carcinogenic potential ofarformoterol.In a 24-month carcinogenicity study in CD-1 mice, arformoterol caused a dose-related increase in the incidence of uterine and cervical endometrial stromal polypsand stromal cell sarcoma in female mice at oral doses of 1,000 mcg/kg and above(AUC exposure approximately 70 times adult exposure at the MRHDID). In a 24-month carcinogenicity study in Sprague-Dawley rats, arformoterolcaused a statistically significant increase in the incidence of thyroid gland c-celladenoma and carcinoma in female rats at an inhalation dose of 200 mcg/kg (AUCexposure approximately 130 times adult exposure at the MRHDID). There were notumor findings with an inhalation dose of 40 mcg/kg (AUC exposure approximately55 times adult exposure at the MRHDID). Arformoterol was not mutagenic or clastogenic in the following tests:mutagenicity tests in bacteria, chromosome aberration analyses in mammalian cells,and micronucleus test in mice. Arformoterol had no effects on fertility and reproductive performance in ratsat oral doses up to 10,000 mcg/kg (approximately 3,200 times the MRHDID inadults on a mcg/m2 basis).

13.2 Animal Toxicology and/or PharmacologyAnimal Pharmacology In animal studies investigating its cardiovascular effects, arformoterolinduced dose-dependent increases in heart rate and decreases in blood pressureconsistent with its pharmacology as a beta-adrenergic agonist. In dogs, at systemicexposures higher than anticipated clinically, arformoterol also induced exaggerated pharmacologic effects of a beta-adrenergic agonist on cardiac function as measuredby electrocardiogram (sinus tachycardia, atrial premature beats, ventricular escapebeats, PVCs). Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of arrhythmias and sudden death (with histologicevidence of myocardial necrosis) when beta-agonists and methyl xanthines are administered concurrently. The clinical significance of these findings is unknown.

14 CLINICAL STUDIES14.1 Adult COPD Trials BROVANA (arformoterol tartrate) Inhalation Solution was studied in two identical, 12-week, double-blind, placebo- and active-controlled, randomized, multi-center, parallel group trials conducted in the United States (Clinical Trial Aand Clinical Trial B). A total of 1,456 adult patients (age range: 34 to 89 years;mean age: 63 years; gender: 860 males and 596 females) with COPD who had amean FEV1 of 1.3 L (42% of predicted) were enrolled in the two clinical trials. Theracial/ethnic distribution in these two trials included 1383 Caucasians, 49 Blacks,10 Asians, and 10 Hispanics, and 4 patients classified as Other. The diagnosis ofCOPD was based on a prior clinical diagnosis of COPD, a smoking history (greaterthan 15 pack-years), age (at least 35 years), spirometry results (baseline FEV1

≤65% of predicted value and >0.70 L, and a FEV1/forced vital capacity (FVC) ratio≤70%). About 80% of patients in these studies had bronchodilator reversibility,defined as a 10% or greater increase in FEV1 after inhalation of 2 actuations(180 mcg racemic albuterol from a metered dose inhaler). Both trials comparedBROVANA Inhalation Solution 15 mcg twice daily (288 patients), 25 mcg twice daily(292 patients), 50 mcg once daily (293 patients) with placebo (293 subjects).Both trials included salmeterol inhalation aerosol, 42 mcg twice daily as an activecomparator (290 patients). In both 12-week trials, BROVANA Inhalation Solution 15 mcg twice dailyresulted in a statistically significant change of approximately 11% in mean FEV1

(as measured by percent change from study baseline FEV1 at the end of the dosinginterval over the 12 weeks of treatment, the primary efficacy endpoint) compared toplacebo. Compared to BROVANA Inhalation Solution 15 mcg twice daily, BROVANAInhalation Solution 25 mcg twice daily and 50 mcg once daily did not provide sufficient additional benefit on a variety of endpoints, including FEV1, to support theuse of higher doses. Plots of the mean change in FEV1 values obtained over the12 hours after dosing for the BROVANA Inhalation Solution 15 mcg twice daily dosegroup and for the placebo group are provided in Figures 1 and 2 for Clinical Trial A,below. The plots include mean FEV1 change observed after the first dose and after12 weeks of treatment. The results from Clinical Trial B were similar.

Figure 1 Mean Change in FEV1 Over Time for Clinical Trial A at Week 0 (Day 1)

Figure 2 Mean Change in FEV1 Over Time for Clinical Trial A at Week 12

BROVANA Inhalation Solution 15 mcg twice daily significantly improved bronchodilation compared to placebo over the 12 hours after dosing (FEV1 AUC0-12h).This improvement was maintained over the 12-week study period. Following the first dose of BROVANA Inhalation Solution 15 mcg, themedian time to onset of bronchodilation, defined by an FEV1 increase of 15%,occurred at 6.7 min. When defined as an increase in FEV1 of 12% and 200 mL, thetime to onset of bronchodilation was 20 min after dosing. Peak bronchodilatoreffect was generally seen within 1-3 hours of dosing. In both clinical trials, compared to placebo, patients treated with BROVANAInhalation Solution demonstrated improvements in peak expiratory flow rates, supplemental ipratropium and rescue albuterol use.16 HOW SUPPLIED/STORAGE AND HANDLING BROVANA (arformoterol tartrate) Inhalation Solution is supplied in a singlestrength (15 mcg of arformoterol, equivalent to 22 mcg of arformoterol tartrate)as 2 mL of a sterile solution in low-density polyethylene (LDPE) unit-dose vials overwrapped in foil. BROVANA Inhalation Solution is available in a shelf-cartoncontaining 30 or 60 unit-dose vials.NDC 63402-911-30: carton of 30 individually pouched unit-dose vials.NDC 63402-911-64: carton of 60 unit-dose vials (15×4 unit-dose vial pouches).Storage and Handling Store BROVANA Inhalation Solution in the protective foil pouch under refrigeration at 36°-46°F (2°-8°C). Protect from light and excessive heat. Afteropening the pouch, unused unit-dose vials should be returned to, and stored in,the pouch. An opened unit-dose vial should be used right away. Discard any unit-dose vial if the solution is not colorless. Unopened foil pouches of BROVANAInhalation Solution can also be stored at room temperature 68°-77°F (20°-25°C)for up to 6 weeks. If stored at room temperature, discard if not used after 6 weeksor if past the expiration date, whichever is sooner.17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (PatientInformation and Instructions for Use) with each new prescription and refill. The complete text of the Patient Information is reprinted at the end of thisdocument. Patients should be given the following information:

Serious Asthma-Related Events, Acute Exacerbations or Deteriorations Patients should be informed that long-acting beta2-adrenergic agonists,such as BROVANA Inhalation Solution, when used as monotherapy [without aninhaled corticosteroid], increase risk of serious asthma-related events, includingasthma-related death. BROVANA Inhalation Solution is not indicated for thetreatment of asthma. BROVANA Inhalation Solution is not indicated to relieve acute respiratorysymptoms and extra doses should not be used for that purpose. Acute symptomsshould be treated with an inhaled, short-acting beta2-agonist (the healthcareprovider should prescribe the patient with such medication and instruct the patientin how it should be used). Patients should be instructed to seek medical attentionif their symptoms worsen despite recommended doses of BROVANA InhalationSolution, if BROVANA Inhalation Solution treatment becomes less effective, orif they need more inhalations of a short-acting beta2-agonist than usual.Appropriate Dosing Patients should not stop using BROVANA Inhalation Solution unless told todo so by a healthcare provider because symptoms may get worse. Patients shouldnot inhale more than one dose at any one time. The daily dosage of BROVANAInhalation Solution should not exceed one unit-dose vial (15 mcg) by inhalationtwice daily (30 mcg total daily dose). Excessive use of sympathomimetics maycause significant cardiovascular effects, and may be fatal. Concomitant Therapy Patients who have been taking inhaled, short-acting beta2-agonists (e.g., levalbuterol) on a regular basis should be instructed to discontinue the regular useof these products and use them only for the symptomatic relief of acute symptoms. BROVANA Inhalation Solution should not be used in conjunction with otherinhaled medications containing long-acting beta2-agonists. Patients should bewarned not to stop or change the dose of other concomitant COPD therapy withoutmedical advice, even if symptoms improve after initiating treatment with BROVANAInhalation Solution. Common Adverse Reactions with Beta2 -agonists Patients should be informed that treatment with beta2-agonists may lead toadverse reactions that include palpitations, chest pain, rapid heart rate, increasedor decreased blood pressure, headache, tremor, nervousness, dry mouth, musclecramps, nausea, dizziness, fatigue, malaise, low blood potassium, high blood sugar,high blood acid, or trouble sleeping [see Adverse Reactions (6.1)].Instructions for Administration It is important that patients understand how to use BROVANA InhalationSolution with a nebulizer appropriately and how it should be used in relation toother medications to treat COPD they are taking [see the accompanying PatientInformation]. Patients should be instructed not to mix other medications withBROVANA Inhalation Solution and not to inject or swallow BROVANA InhalationSolution. Patients should throw the plastic dispensing vials away immediately afteruse. Due to their small size, the vials pose a danger of choking to young children. Women should be advised to contact their physician if they becomepregnant or if they are nursing.FDA-Approved Patient Information

See the accompanying Patient Information.

Manufactured for:Sunovion Pharmaceuticals Inc.Marlborough, MA 01752 USA

© 2019 Sunovion Pharmaceuticals Inc. All rights reserved.

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

10043-02-MKT1

Figure 2

Figure 3 Figure 4

Figure 5 Figure 6

Figure 1

PATIENT INFORMATION

BROVANA® [Bro va´-nah](arformoterol tartrate)

Inhalation Solution

What is BROVANA?• BROVANA is for long-term use and should be taken 2 times

each day (morning and evening), to help control the symptomsof chronic obstructive pulmonary disease (COPD) for betterbreathing.

• COPD is a chronic lung disease that includes chronicbronchitis, emphysema, or both.

• BROVANA is only for use with a nebulizer.• Long acting beta2 adrenergic agonist (LABA) medicines, such

as BROVANA, help the muscles around the airways in yourlungs stay relaxed to prevent symptoms, such as wheezing,cough, chest tightness, and shortness of breath.

• BROVANA is not used to treat sudden symptoms of COPD.Always have a short-acting beta2-agonist medicine (rescueinhaler) with you to treat sudden symptoms of COPD. If youdo not have a rescue inhaler, contact your healthcare providerto have one prescribed for you.

• BROVANA is not for the treatment of asthma. It is not knownif BROVANA is safe and effective in people with asthma.

• BROVANA should not be used in children. It is not knownif BROVANA is safe and effective in children

Do not use BROVANA if you: • are allergic to arformoterol, racemic formoterol, or any of the

ingredients in BROVANA. Ask your healthcare provider if youare not sure. See the end of this leaflet for a complete list ofingredients in BROVANA.

• have asthma.

Before you use BROVANA, tell your healthcare provider aboutall of your medical conditions, including if you:• have heart problems• have high blood pressure• have seizures• have thyroid problems• have diabetes• have liver problems• are pregnant or plan to become pregnant. It is not known if

BROVANA can harm your unborn baby.• are breastfeeding or plan to breastfeed. It is not known if the

arformoterol or any other ingredients in BROVANA passesinto your milk and if it can harm your baby. You and yourhealthcare provider should decide if you will take BROVANAor breastfeed.

Tell your healthcare provider about all the medicines youtake including prescription and over-the-counter medicines,vitamins and herbal supplements. BROVANA and certain othermedicines may interact with each other. This may cause seriousside effects.Know the medicines you take. Keep a list of them to show yourhealthcare provider and pharmacist each time you get a newmedicine.

How should I use BROVANA?Read the step-by-step Instructions for Use for BROVANA atthe end of this Patient Information leaflet.• Use BROVANA exactly as prescribed. Do not use BROVANA

more often than prescribed.• One unit dose vial of BROVANA is 1 dose. The usual dose

of BROVANA is 1 unit dose vial, 2 times a day (morning andevening) breathed in through your nebulizer machine. The2 doses should be taken about 12 hours apart. Do not usemore than 2 unit dose vials of BROVANA a day.

• Do not swallow or inject BROVANA.• BROVANA is for use with a standard jet nebulizer machine

connected to an air compressor. Read the completeinstructions for use at the end of this Patient Informationleaflet before starting BROVANA.

• Do not mix other medicines with BROVANA in your nebulizermachine.

• While you are using BROVANA 2 times each day: ○ Do not use other medicines that contain a long-acting

beta2-agonist (LABA) for any reason. ○ Do not use your short-acting beta2-agonist medicine on a

regular basis (four times a day).• BROVANA does not relieve sudden symptoms of COPD.

Always have a rescue inhaler medicine with you to treatsudden symptoms. If you do not have a rescue inhalermedicine, call your healthcare provider to have oneprescribed for you.

• Do not stop using BROVANA or other medicines to control ortreat your COPD unless told to do so by your healthcareprovider because your symptoms might get worse. Yourhealthcare provider will change your medicines as needed.

Call your healthcare provider or get emergency medical careright away if your breathing problems worsen with BROVANA,you need to use your rescue medicine more often than usual, oryour rescue inhaler medicine does not work as well for you atrelieving symptoms.

What are the possible side effects of BROVANA?BROVANA can cause serious side effects, including:• people with asthma who take long-acting beta2-

adrenergic agonist (LABA) medicines, such asarformoterol (the medicine in BROVANA), without alsousing a medicine called an inhaled corticosteroid have anincreased risk of serious problems from asthma,including being hospitalized, needing a tube placed intheir airway to help them breathe, or death.

○ Call your healthcare provider if breathing problemsworsen over time while using BROVANA. You may needa different treatment.

○ Get emergency medical care if: • your breathing problems worsen quickly. • you use a rescue inhaler medicine, but it does not

relieve your breathing problems.• COPD symptoms that get worse over time. If your COPD

symptoms worsen over time, do not increase your dose ofBROVANA, instead call your healthcare provider.

• using too much of a LABA medicine may cause: ○ chest pain ○ increased blood pressure ○ fast and irregular heartbeat ○ headache ○ tremor ○ nervousness• sudden shortness of breath immediately after use of

BROVANA. Sudden shortness of breath may be life threating.If you have sudden breathing problems immediately afterinhaling your medicine, stop taking BROVANA and call yourhealthcare provider or go to the nearest hospital emergencyroom right away.

• effects on the heart which may include: ○ increased blood pressure ○ chest pain ○ a fast or irregular heartbeat, awareness of a heartbeat• serious allergic reactions including rash, hives, swelling

of the face, mouth, and tongue, and breathing problems.Call your healthcare provider or get emergency medical careif you get any symptoms of a serious allergic reaction.

• Changes in laboratory levels, including high levels ofblood sugar (hyperglycemia) and low levels of potassium(hypokalemia).

Instructions for Using BROVANA (arformoterol tartrate)Inhalation Solution

BROVANA is used only in a standard jet nebulizer machineconnected to an air compressor. Make sure you know how to useyour nebulizer machine before you use it to breathe in BROVANAor other medicines.

Do not mix BROVANA with other medicines in your nebulizermachine.

BROVANA comes sealed in a foil pouch. Do not open a sealed pouchuntil you are ready to use a dose of BROVANA. After opening the pouch,unused unit dose vials should be returned to, and stored in, the pouch.An opened unit dose vial should be used right away.

1. Open the foil pouch by tearing on the rough edge along the seamof the pouch. Remove a unit dose vial of BROVANA.

2. Carefully twist open thetop of the unit dosevial and use it rightaway (Figure 1).

3. Squeeze all of themedicine from theunit dose vialinto the nebulizermedicine cup(reservoir) (Figure 2).

4. Connect the nebulizerreservoir to themouth- piece (Figure 3)or face mask (Figure 4).

5. Connect thenebulizer to thecompressor (Figure 5).

6. Sit in a comfortable,upright position.Place the mouth piecein your mouth(Figure 6) (or put onthe face mask) and turnon the compressor.

7. Breathe as calmly,deeply, and evenly aspossible until no moremist is formed in thenebulizer reservoir.It takes about 5 to10 minutes for eachtreatment.

8. Clean the nebulizer (see manufacturer’s instructions).

Rx Only

This Instructions for Use has been approved by the Food andDrug Administration.

Manufactured for:Sunovion Pharmaceuticals Inc.Marlborough, MA 01752 USA

© 2019 Sunovion Pharmaceuticals Inc.All rights reserved.

05/2019

10043-02-MKT1

Common side effects of BROVANA include: • pain• sinus congestion• rash• chest congestion or bronchitis• chest or back pain • leg cramps • flu-like symptoms• diarrhea• trouble breathing• swelling in your legsTell your healthcare provider if you get any side effect thatbothers you or that does not go away.These are not all the possible side effects of BROVANA. Call yourdoctor for medical advice about side effects. You may reportside effects to FDA at 1-800-FDA-1088.

How should I store BROVANA?• Store BROVANA in a refrigerator between 36° to 46°F

(2° to 8°C) in the protective foil pouch. Protect from light andexcessive heat. Do not open a sealed pouch until you areready to use a dose of BROVANA. After opening the pouch,unused unit dose vials should be returned to, and storedin, the pouch. An opened unit dose vial should be usedright away.

• BROVANA may also be stored at room temperature between68° to 77°F (20° to 25°C) for up to 6 weeks (42 days). Ifstored at room temperature, discard BROVANA if it is notused after 6 weeks or if past the expiration date, whicheveris sooner. Space is provided on the packaging to recordroom temperature storage times.

• Do not use BROVANA after the expiration date providedon the foil pouch and unit dose vial.

• BROVANA should be colorless. Throw away (discard)BROVANA if it is not colorless.

• Keep BROVANA and all medicines out of the reach ofchildren.

General information about the safe and effective use ofBROVANA.Medicines are sometimes prescribed for purposes not mentionedin this Patient Information leaflet. Do not use BROVANA for acondition for which it was not prescribed. Do not give BROVANAto other people, even if they have the same symptoms that youmay have. It may harm them. You can ask your pharmacist or healthcare provider for informationabout BROVANA that was written for health professionals.

What are the ingredients in BROVANA?Active ingredient: arformoterolInactive ingredients: citric acid and sodium citrate

Manufactured for: Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USA

© 2019 Sunovion Pharmaceuticals Inc.All rights reserved.

For more information go to www.BROVANA.comor call 1-888-394-7377.

This Patient Information has been approved by theFood and Drug Administration.

Revised: 05/2019

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Maintenance Treatment of COPD

ARCAPTA NEOHALER is a long-acting beta2-agonist indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

1.2 Important Limitations of Use

ARCAPTA NEOHALER is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [see Warnings and Precautions (5.2)].

ARCAPTA NEOHALER is not indicated to treat asthma. The safety and effectiveness of ARCAPTA NEOHALER in asthma have not been established.

2 DOSAGE AND ADMINISTRATION

DO NOT SWALLOW ARCAPTA CAPSULES

FOR USE WITH NEOHALER DEVICE ONLY

FOR ORAL INHALATION ONLY

ARCAPTA capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of ARCAPTA capsules are only for oral inhalation and should only be used with the NEOHALER device.

The recommended dosage of ARCAPTA NEOHALER is the once-daily inhalation of the contents of one 75 mcg ARCAPTA capsule using the NEOHALER inhaler.

ARCAPTA NEOHALER should be administered once daily every day at the same time of the day by the orally inhaled route only. If a dose is missed, the next dose should be taken as soon as it is remembered. Do not use ARCAPTA NEOHALER more than one time every 24 hours.

ARCAPTA capsules must always be stored in the blister, and only removed IMMEDIATELY BEFORE USE.

No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or renally impaired patients. No data are available for subjects with severe hepatic impairment [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder:

75 mcg: hard gelatin capsule with black product code “IDL 75” above a bar printed on one side of the capsule and the logo “ ” printed on the other side.

4 CONTRAINDICATIONS

Use of a LABA, including ARCAPTA NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5.1)]. ARCAPTA NEOHALER is not indicated for the treatment of asthma.

ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

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

• 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)].

Use of long-acting beta2-adreneric agonists (LABA), such as indacaterol, the active ingredient in ARCAPTA NEOHALER, 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 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 US 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 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 LABAs, 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. 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)].

• 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

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 beta2-agonist.

When beginning ARCAPTA NEOHALER, patients who have been taking inhaled, short-acting beta2-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 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 ARCAPTA NEOHALER no longer controls the symptoms of bronchoconstriction, or 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 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 Beta2-Agonists

As with other inhaled beta2-adrenergic drugs, ARCAPTA NEOHALER should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-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 beta2-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 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, 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 beta2-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

5.8 Hypokalemia and Hyperglycemia

Beta2-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 beta2-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

Long-acting beta2-adrenergic agonists, such as ARCAPTA NEOHALER, as monotherapy (without inhaled corticosteroids) for asthma increase the risk of asthma-related events. ARCAPTA NEOHALER is not indicated for the treatment of asthma [see Warnings and Precautions (5.1)].

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 (FEV1) 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

n=449 n (%)

Placebo

n=445n (%)

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

Cough experienced post-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.

7 DRUG INTERACTIONS

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 ARCAPTA NEOHALER may be potentiated [see Warnings and Precautions (5.3, 5.6, 5.7, 5.8)].

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of ARCAPTA NEOHALER [see Warnings and Precautions (5.8)].

7.3 Non-Potassium Sparing Diuretics

The ECG changes 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, 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 co-administration of ARCAPTA NEOHALER with non-potassium-sparing diuretics.

7.4 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

Indacaterol, 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 ARCAPTA 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 Inhibitors of Cytochrome P450 3A4 and P-gp Efflux Transporter

Drug interaction studies 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 is influenced by modulation of both P-gp and CYP3A4 activities and that the 1.9-fold AUC0-24  increase caused by the strong dual inhibitor ketoconazole reflects the impact of maximal combined inhibition. ARCAPTA NEOHALER was evaluated in clinical trials for up to one year at doses up to 600 mcg. No dose adjustment is warranted at the 75 mcg dose. [See Drug-drug Interaction (12.3)]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C.

There are no adequate and well-controlled studies with ARCAPTA NEOHALER in pregnant women. ARCAPTA NEOHALER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Indacaterol was not teratogenic following subcutaneous administration to rats and rabbits at doses up to 1 mg/kg, approximately 130 and 260 times, respectively, the 75 mcg dose on a mg/m2 basis.

8.2 Labor and Delivery

There are no adequate and well-controlled human studies that have investigated effects of ARCAPTA NEOHALER on preterm labor or labor at term. Because of the potential for beta-agonist interference with uterine contractility, use of ARCAPTA NEOHALER during labor should be restricted to those patients in whom the benefits clearly outweigh the risks.

8.3 Nursing Mothers

It is not known that the active component of ARCAPTA NEOHALER, indacaterol, is excreted in human milk. Because many drugs are excreted in human milk and because indacaterol has been detected in the milk of lactating rats, caution should be exercised when ARCAPTA NEOHALER is administered to nursing women.

8.4 Pediatric Use

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

8.5 Geriatric Use

Based on available data, no adjustment of ARCAPTA NEOHALER dosage in geriatric patients is warranted. Of the total number of patients who received ARCAPTA NEOHALER at the recommended dose of 75 mcg once daily in the clinical studies from the pooled 3-month database, 239 were <65 years, 153 were 65-74 years and 57 were ≥75 years of age.

No overall differences in effectiveness were observed, and in the 3-month pooled data, the adverse drug reaction profile was similar in the older population compared to the patient population overall. When treated at higher doses (300 mcg and 600 mcg) over the course of a year, the adverse drug reaction profiles for patients >65 years was similar to that of the general patient population.

8.6 Hepatic Impairment

Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.

8.7 Renal Impairment

Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.

10 OVERDOSAGE

10.1 Human Experience

In COPD patients single doses of 40 times the 75 mcg dose were associated with moderate increases in pulse rate, systolic blood pressure and QTc interval.

The expected signs and symptoms associated with overdosage of ARCAPTA NEOHALER 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, 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 ARCAPTA NEOHALER.

Treatment of overdosage consists of discontinuation of ARCAPTA NEOHALER together with institution of appropriate symptomatic and supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of ARCAPTA NEOHALER. Cardiac monitoring is recommended in cases of overdosage.

11 DESCRIPTION

ARCAPTA NEOHALER consists of a dry powder formulation of indacaterol maleate for oral inhalation only with the NEOHALER inhaler. The inhalation powder is packaged in clear gelatin capsules.

Each clear, hard gelatin capsule contains a dry powder blend of 75 mcg of indacaterol (equivalent to 97 mcg of indacaterol maleate) with approximately 25 mg of lactose monohydrate (which contains trace levels of milk protein) as the carrier.

The active component of ARCAPTA NEOHALER is indacaterol maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic agonist. Its chemical name is (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one maleate; its structural formula is

Indacaterol maleate has a molecular weight of 508.56, and its empirical formula is C24H28N2O3 • C4H4O4. Indacaterol maleate is a white to very slightly grayish or very slightly yellowish powder. Indacaterol maleate is freely soluble in N-methylpyrrolidone and dimethylformamide, slightly soluble in methanol, ethanol, propylene glycol and polyethylene glycol 400, very slightly soluble in water, isopropyl alcohol and practically insoluble in 0.9% sodium chloride in water, ethyl acetate and n-octanol.

The NEOHALER inhaler is a plastic device used for inhaling ARCAPTA. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 60 L/min for 2 seconds, the NEOHALER inhaler delivered 57 mcg for the 75 mcg dose strength ( equivalent to 73.9 mcg of indacaterol maleate) from the mouthpiece. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER inhaler were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52-133 L/min) for adult patients. Approximately ninety-five percent of the population studied generated a PIFR through the device exceeding 60 L/min.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ARCAPTA NEOHALER safely and effectively. See full prescribing information for ARCAPTA NEOHALER.

ARCAPTA® NEOHALER® (indacaterol) inhalation powderInitial U.S. Approval: 2011

RECENT MAJOR CHANGES Box Warning, Removed 05/2019Contraindications, revised (4) 05/2019Warnings and Precautions, revised Serious Asthma-Related Events – Hospitalizations, Intubations, Death (5.1) 05/2019

INDICATIONS AND USAGE

ARCAPTA NEOHALER is a long-acting beta2-adrenergic agonist indicated for: The long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in

patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. (1.1)

Important limitations:• ARCAPTA NEOHALER is NOT indicated to treat acute deteriorations of chronic obstructive

pulmonary disease. (1.2)• ARCAPTA NEOHALER is NOT indicated for asthma. (1.2)

DOSAGE AND ADMINISTRATION

For oral inhalation only. DO NOT swallow ARCAPTA capsule. ARCAPTA capsules should always be used with the NEOHALER inhaler only. 75 mcg inhaled every day (once-daily). (2)

DOSAGE FORMS AND STRENGTHS

Inhalation powder hard capsules: 75 mcg. (3)

CONTRAINDICATIONS

• Use of a LABA, including ARCAPTA NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma. (4)

• ARCAPTA NEOHALER is contraindicated in patients with a history of hypersensitivity to indacaterol or to any of the ingredients. (4)

WARNINGS AND PRECAUTIONS

• LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. (5.1)

• Do not initiate in acutely deteriorating COPD patients. (5.2)• Do not use for relief of acute symptoms. Concomitant short-acting beta2-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)

ADVERSE REACTIONS

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 Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• Other adrenergic drugs may potentiate effect: Use with caution. (5.3, 7.1)• Xanthine derivatives, steroids, diuretics or non-potassium sparing diuretics may potentiate

hypokalemia or ECG changes. Use with caution. (7.2, 7.3)• MAO inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate

effect on cardiovascular system. Use with extreme caution. (7.4)• Beta-blockers may decrease effectiveness: Use with caution and only when medically

necessary. (7.5)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 05/2019

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE 1.1 Maintenance Treatment of COPD 1.2 Important Limitations of Use2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Serious Asthma-Related Events –

Hospitalizations, Intubations, Death 5.2 Deterioration of Disease and Acute Episodes 5.3 Excessive Use of ARCAPTA NEOHALER and

Use with Other Long-Acting Beta2-Agonists 5.4 Immediate Hypersensitivity Reactions 5.5 Paradoxical Bronchospasm 5.6 Cardiovascular Effects 5.7 Coexisting Conditions 5.8 Hypokalemia and Hyperglycemia

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience in Chronic

Obstructive Pulmonary Disease 6.2 Clinical Trials Experience in Asthma 6.3 Postmarketing Experience7 DRUG INTERACTIONS 7.1 Adrenergic Drugs 7.2 Xanthine Derivatives, Steroids,

or Diuretics 7.3 Non-Potassium Sparing Diuretics 7.4 Monoamine Oxidase Inhibitors,

Tricyclic Antidepressants, QTc Prolonging Drugs

7.5 Beta-Blockers 7.6 Inhibitors of Cytochrome P450 3A4

and P-gp Efflux Transporter

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment10 OVERDOSAGE 10.1 Human Experience11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Pharmacogenomics

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis,

Impairment of Fertility14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling17 PATIENT COUNSELING INFORMATION 17.1 Serious Asthma-Related Events 17.2 Instructions for Administering

ARCAPTA NEOHALER 17.3 Not for Acute Symptoms 17.4 Do Not Use Additional Long-Acting

Beta2-Agonists 17.5 Risks Associated With Beta-

Agonist Therapy

* Sections or subsections omitted from the full prescribing information are not listed.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Indacaterol is a long-acting beta2-adrenergic agonist.

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%-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. 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.

12.2 Pharmacodynamics

Systemic Safety

The major adverse effects of inhaled beta2-adrenergic agonists occur as a result of excessive activation of systemic beta-adrenergic receptors. The most common adverse effects in adults include skeletal muscle tremor and cramps, insomnia, tachycardia, decreases in serum potassium and increases in plasma glucose.

Changes in serum potassium and plasma glucose were evaluated in COPD patients in double-blind Phase III studies. In pooled data, at the recommended 75 mcg dose, at 1 hour post-dose at week 12, there was no change compared to placebo in serum potassium, and change in mean plasma glucose was 0.07 mmol/L.

Electrophysiology

The effect of ARCAPTA NEOHALER on the QT interval was evaluated in a double-blind, placebo- and active (moxifloxacin)-controlled study following multiple doses of indacaterol 150 mcg, 300 mcg or 600 mcg once-daily for 2 weeks in 404 healthy volunteers. Fridericia’s method for heart rate correction was employed to derive the corrected QT interval (QTcF). Maximum mean prolongation of QTcF intervals were <5 ms, and the upper limit of the 90% confidence interval was below 10 ms for all time-matched comparisons versus placebo. During these studies, there were no clinically meaningful QT-interval prolongations. There was no evidence of a clinically relevant concentration-delta QTc relationship in the range of doses evaluated.

The effect of 150 mcg and 300 mcg once daily of ARCAPTA NEOHALER on heart rate and rhythm was assessed using continuous 24-hour ECG recording (Holter monitoring) in a subset of 605 patients with COPD from a 26-week, double-blind, placebo-controlled Phase III study. Holter monitoring occurred once at baseline and up to 3 times during the 26-week treatment period (at weeks 2, 12 and 26). A comparison of the mean heart rate over 24 hours showed no increase from baseline. The hourly heart rate analysis was similar compared to placebo. The pattern of diurnal variation over 24 hours was maintained and was similar to placebo. No difference from placebo was seen in the rates of atrial fibrillation, time spent in atrial fibrillation and also the maximum ventricular rate of atrial fibrillation. No clear patterns in the rates of single ectopic beats, couplets or runs were seen across visits. Because the summary data on rates of ventricular ectopic beats can be difficult to interpret, specific pro-arrhythmic criteria were analyzed. In this analysis, baseline occurrence of ventricular ectopic beats was compared to change from baseline, setting certain parameters for the change to describe the pro-arrhythmic response. The number of patients with a documented pro-arrhythmic response was very similar compared to placebo. Overall, there was no clinically relevant difference in the development of arrhythmic events in patients receiving indacaterol treatment over those patients who received placebo.

Tachyphylaxis/Tolerance

Tolerance to the effects of inhaled beta-agonists can occur with regularly scheduled, chronic use. In two 12-week clinical efficacy trials in 323 and 318 adult patients with COPD, ARCAPTA NEOHALER improvement in lung function (as measured by the forced expiratory volume in one second, FEV1) observed at Week 4 with ARCAPTA NEOHALER was consistently maintained over the 12-week treatment period in both trials.

12.3 Pharmacokinetics

Absorption

The median time to reach peak serum concentrations of indacaterol was approximately 15 minutes after single or repeated inhaled doses. Systemic exposure to indacaterol increased with increasing dose (150 mcg to 600 mcg) in a dose proportional manner, and was about dose-proportional in the dose range of 75 mcg to 150 mcg. Absolute bioavailability of indacaterol after an inhaled dose was on average 43-45%. Systemic exposure results from a composite of pulmonary and intestinal absorption.

Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-hour dosing interval on day 14 or day 15 compared to day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg and 600 mcg.

Distribution

After intravenous infusion the volume of distribution (Vz) of indacaterol was 2,361 L to 2,557 L indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1-95.3% and 95.1-96.2%, respectively.

Metabolism

After oral administration of radiolabeled indacaterol in the human ADME (absorption, distribution, metabolism, excretion) study unchanged indacaterol was the main component in serum, accounting for about one third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.

In vitro investigations indicated that UGT1A1 was the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol.

In vitro investigations indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.

In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo, indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.

Elimination

In clinical studies which included urine collection the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 and 1.2 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2 to 6% of systemic clearance) in the elimination of systemically available indacaterol.

In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with ≥90% of the dose recovered in the excreta.

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing with once daily doses between 75 mcg and 600 mcg ranged from 40 to 56 hours which is consistent with the observed time-to-steady state of approximately 12-15 days.

Special Populations

A population pharmacokinetic analysis was performed for indacaterol utilizing data from 3 controlled clinical trials that included 1,844 patients with COPD aged 40 to 88 years who received treatment with ARCAPTA NEOHALER.

The population analysis showed that no dose adjustment is warranted based on the effect of age, gender and weight on systemic exposure in COPD patients after inhalation of ARCAPTA NEOHALER. The population pharmacokinetic analysis did not suggest any difference between ethnic subgroups in this population.

Hepatic Impairment

Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatically impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed.

Renal Impairment

Due to the very low contribution of the urinary pathway to total body elimination, a study in renally impaired subjects was not performed.

Drug-drug Interaction

Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir).

Verapamil: Co-administration of indacaterol 300 mcg (single dose) with verapamil (80 mg t.i.d. for 4 days) showed 2-fold increase in indacaterol AUC0-24, and 1.5-fold increase in indacaterol Cmax.

Erythromycin: Co-administration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg q.i.d for 7 days) showed a 1.4-fold increase in indacaterol AUC0-24, and 1.2-fold increase in indacaterol Cmax.

Ketoconazole: Co-administration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg b.i.d for 7 days) caused a 1.9-fold increase in indacaterol AUC0-24, and 1.3-fold increase in indacaterol Cmax.

Ritonavir: Co-administration of indacaterol 300 mcg (single dose) with ritonavir (300 mg b.i.d for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC0-24  whereas indacaterol Cmax was unaffected. [See Drug Interactions (7.6)].

12.4 Pharmacogenomics

The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and Cmax of indacaterol were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies were conducted in transgenic mice using oral administration and in rats using inhalation administration to evaluate the carcinogenic potential of indacaterol maleate. Indacaterol did not show a statistically significant increase in tumor formation in mice or rats.

Lifetime treatment of rats resulted in increased incidences of benign ovarian leiomyoma and focal hyperplasia of ovarian smooth muscle in females at doses approximately 270-times the dose of 75 mcg once-daily for humans (on a mg/m2 basis).

A 26-week oral (gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol did not show any evidence of tumorigenicity at doses approximately 39,000-times the dose of 75 mcg once-daily for humans (on a mg/m2 basis).

Increases in leiomyomas of the female rat genital tract have been similarly demonstrated with other beta2-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Indacaterol was not mutagenic or clastogenic in Ames test, chromosome aberration test in V79 Chinese hamster cells, and bone marrow micronucleus test in rats.

Indacaterol did not impair fertility of rats in reproduction studies.

14 CLINICAL STUDIES

The ARCAPTA NEOHALER COPD clinical development program included three dose-ranging trials and six confirmatory trials (Trial 3, a 26-week seamless adaptive design trial that included an initial 2 week dose ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week trial; and Trial 8, a 52-week trial).

Dose-ranging trials:

Dose selection for ARCAPTA NEOHALER for COPD was based on three dose-ranging trials (Trial 1, a 2-week dose-ranging trial in an asthma population; Trial 2, a 2-week dose-ranging trial in a COPD population; and Trial 3, a 26-week adaptive seamless design trial that included an initial 2-week dose ranging phase). Although ARCAPTA NEOHALER is not indicated for asthma, dose selection was primarily based upon the results from the dose-ranging trial in asthma patients (Trial 1) as an asthma population is the most responsive to beta-agonist bronchodilation and is most likely to demonstrate a dose response. Dose-ranging in COPD patients (Trials 2 and 3) provided supportive information.

Dose-ranging in asthma

ARCAPTA NEOHALER is not indicated for asthma.

Trial 1 was a 2-week, randomized, double-blinded, placebo-controlled design that enrolled 511 patients with persistent asthma 18 years of age and older. All enrolled patients were required to be taking inhaled corticosteroids, had a forced expiratory volume in one second (FEV1) of ≥ 50% and ≤ 90% predicted, and FEV1 reversibility after albuterol of at least 12% and at least 200 mL. Trial 1 included ARCAPTA NEOHALER doses of 18.75, 37.5, 75, and 150 mcg once daily, a salmeterol active control group, and placebo. The trial showed that the effect on FEV1 in patients treated with ARCAPTA NEOHALER 18.75 and 37.5 mcg doses was lower compared to patients treated with other ARCAPTA NEOHALER doses, particularly after the first dose. The effect did not clearly differ between the 75 and 150 mcg doses.

Results of the ARCAPTA NEOHALER and placebo treatment arms are as follows. After the first dose (Day 1), the peak (4 hour) FEV1 was 2.58L in the placebo group, with a treatment difference of 0.04L (95% CI -0.01, 0.09) in the 18.75 mcg ARCAPTA NEOHALER group, 0.04L (-0.01, 0.09) in the 37.5 mcg group, 0.12L (0.07, 0.17) in the 75 mcg group, and 0.15L (0.10, 0.20) in the 150 mcg group. The Day 2 trough FEV1 was 2.45L in the placebo group, with a treatment difference of 0.02L (95% CI -0.05, 0.08), 0.08L (0.01, 0.15), 0.09L (0.03, 0.16) and 0.16L (0.09, 0.22) in the ARCAPTA NEOHALER groups, respectively. At Day 14, the peak (4 hour) FEV1 was 2.55L in the placebo group, with a treatment difference of 0.12L (95% CI 0.05, 0.20) in the 18.75 mcg ARCAPTA NEOHALER group, 0.14L (0.06, 0.21) in the 37.5 mcg group, 0.23L (0.15, 0.30) in the 75 mcg group, and 0.20L (0.13, 0.27) in the 150 mcg group. The Day 15 FEV1 (primary endpoint) was 2.42L in the placebo group, with a treatment difference of 0.09L (95% CI 0.00, 0.17), 0.11L (0.02, 0.19), 0.17L (0.08, 0.26), and 0.12L (0.04, 0.21) in the ARCAPTA NEOHALER groups, respectively.

Dose-ranging in COPD

Trial 2 was a 2-week, randomized, double-blinded, placebo-controlled design that enrolled 552 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 10 pack years, had a post-bronchodilator FEV1 less than 80% and at least 30% of the predicated normal value and a post-bronchodilator ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 70%. Trial 2 included ARCAPTA NEOHALER doses of 18.75, 37.5, 75 and 150 mcg once daily, a salmeterol active control group, and placebo. Results of the ARCAPTA NEOHALER and placebo arms are shown in Figure 1. The trial showed that the effect on FEV1 in patients treated with ARCAPTA NEOHALER 18.75 mcg dose was lower compared to patients treated with other ARCAPTA NEOHALER doses. Although a dose-response relationship was observed at Day 1, the effect did not clearly differ among the 37.5, 75 and 150 mcg doses by Day 15.

Figure 1: LS Mean FEV1 time profile curve over 24 hours after ARCAPTA NEOHALER Day 1 and Week 2 in Trial 2 (COPD dose ranging)

The 2-week dose ranging phase of Trial 3 included ARCAPTA NEOHALER doses of 75, 150, 300, and 600 mcg once daily, placebo, and two active comparators. Although a dose-response relationship was observed at week 2, the effect did not clearly differ among the ARCAPTA NEOHALER doses.

Confirmatory Trials:

The ARCAPTA NEOHALER COPD development program included six confirmatory trials that were randomized, double-blinded placebo and active-controlled in design (Trial 3, a 26-week seamless adaptive design trial that included an initial 2 week dose-ranging phase; Trials 4, 5, and 6, 12-week trials; Trial 7, a 26-week trial; and Trial 8, a 52-week trial). After the initial 2-week dose-ranging portion of the design, Trial 3 was conducted with ARCAPTA NEOHALER doses of 150 mcg and 300 mcg once daily, placebo, and an active comparator. Trials 4 and 5 were conducted with ARCAPTA NEOHALER dose of 75 mcg once daily, and placebo. Trial 6 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily and placebo. Trial 7 was conducted with ARCAPTA NEOHALER dose of 150 mcg once daily, an active comparator, and placebo. Trial 8 was conducted with ARCAPTA NEOHALER doses of 300 mcg and 600 mcg once daily, an active comparator, and placebo.

As Trials 3, 6, 7, and 8 were conducted with doses of ARCAPTA NEOHALER higher than 75 mcg, the results of Trials 4 and 5, which included ARCAPTA NEOHALER 75 mcg, are the focus of this section.

These six trials enrolled 5474 patients with a clinical diagnosis of COPD, who were 40 years or older, had a smoking history of at least 10 pack years, had a post-bronchodilator FEV1 less than 80% and at least 30% of the predicted normal value and a post-bronchodilator ratio of FEV1 over FVC of less than 70%.

Assessment of efficacy in these six COPD trials was based on FEV1. The primary efficacy endpoint was 24-hour post-dose trough FEV1 (defined as the average of two FEV1 measurements taken after 23 hours 10 minutes and 23 hours and 45 minutes after the previous dose) after 12 weeks of treatment in all 6 trials. Other efficacy variables included other FEV1 and FVC time points, rescue medication use, symptoms, and health-related quality of life measured using the St. George’s Respiratory Questionnaire (SGRQ).

In all six confirmatory COPD trials, all doses of ARCAPTA NEOHALER tested (75 mcg, 150 mcg, 300 mcg, and 600 mcg) showed significantly greater 24-hour post-dose trough FEV1 compared to placebo at 12 weeks. Results of Trials 4 and 5, which compared ARCAPTA NEOHALER at the dose of 75 mcg once daily to placebo are shown in Table 2.

Table 2: LS Mean for trough FEV1 at 12 weeks

Treatment Trough FEV1 at Week 12 (liters)

Treatment Difference

LS Mean (95% CI)

Trial 4 (N=323)

Indacaterol 75 mcg 1.38 0.12 (0.08, 0.15)

Placebo 1.26

Trial 5 (N=318)

Indacaterol 75 mcg 1.49 0.14 (0.10, 0.18)

Placebo 1.35

In addition, serial FEV1 measurements in patients treated with ARCAPTA NEOHALER demonstrated a bronchodilatory treatment effect after the first dose compared to placebo at 5 minutes post dose of 0.09 L (Trial 4) and 0.10 L (Trial 5). The mean peak improvement relative to baseline within the first 4 hours after the first dose (Day 1) was 0.19 L (Trial 4) and 0.22 L (Trial 5) and was 0.24 L (Trial 4) and 0.27 L (Trial 5) after 12 weeks. Improvement in lung function observed at week 4 was consistently maintained over the 12-week treatment period in both trials. In Trial 5, 24-hour spirometry was assessed in a subset of 239 patients. See Figure 2.

Figure 2: LS Mean FEV1 time profile curve over 24 hours at Week 12 in Trial 5

In both COPD clinical trials including the 75 mcg dose (Trials 4 and 5), patients treated with ARCAPTA NEOHALER used less daily rescue albuterol during the trial compared to patients treated with placebo.

Health-related quality of life was measured using the St. George’s Respiratory Questionnaire (SGRQ) in all six confirmatory COPD clinical trials. SGRQ is a disease-specific patient reported instrument which measures symptoms, activities, and its impact on daily life. At week 12, pooled data from these trials demonstrated an improvement over placebo in SGRQ total score of -3.8 with a 95% CI of (-5.3, -2.3) for the ARCAPTA NEOHALER 75 mcg dose, -4.6 with a 95% CI of (-5.5, -3.6) for 150 mcg, and -3.8 with a 95% CI of (-4.9, -2.8) for 300 mcg. The confidence intervals for this change are widely overlapping with no dose ordering. Results from individual studies were variable, but are generally consistent with the pooled data results.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

75 mcg ARCAPTA NEOHALER contains ARCAPTA (indacaterol) inhalation powder capsules packaged in aluminum blister cards, one NEOHALER inhaler, and an FDA-approved Patient Information.

Unit Dose (blister pack), Box of 30 (5 blister cards with 6 capsules each) NDC 63402-675-30.

The NEOHALER inhaler consists of a white protective cap and a base with mouthpiece, capsule chamber and two translucent red push buttons.

• ARCAPTA NEOHALER does not relieve sudden symptoms of COPD. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler medicine, call your healthcare provider to have one prescribed for you.

• Do not stop using ARCAPTA NEOHALER or other medicines to control or treat your COPD unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.

• Call your healthcare provider or get emergency medical care right away if your breathing problems worsen with ARCAPTA NEOHALER, you need to use your rescue medicine more often than usual, or your rescue inhaler medicine does not work as well for you at relieving your symptoms.

What are the possible side effects with ARCAPTA NEOHALER?

ARCAPTA NEOHALER can cause serious side effects, including:

• People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines, such as ARCAPTA NEOHALER, without also using medicine called an inhaled corticosteroid, have an increased risk of serious problems from asthma, including being hospitalized, needing a tube placed in their airway to help them breathe, or death.

○ Call your healthcare provider if breathing problems worsen over time while using ARCAPTA NEOHALER. You may need a different treatment.

○ Get emergency medical care if:

• breathing problems worsen quickly.

• you use your rescue inhaler medicine, but it does not relieve your breathing problems.

• COPD symptoms that get worse over time. If your COPD symptoms worsen over time, do not increase your dose of ARCAPTA NEOHALER, instead call your healthcare provider.

• Using too much of a LABA medicine may cause:

○ chest pain ○ increased blood pressure

○ fast and irregular heartbeat ○ headache

○ tremor ○ nervousness

• Serious allergic reactions including rash, hives, swelling of the tongue, lips and face, difficulties in breathing or swallowing. Call your healthcare provider or get emergency medical care if you get any symptoms of a serious allergic reaction.

• Sudden shortness of breath can happen immediately after using ARCAPTA NEOHALER. Sudden shortness of breath may be life-threatening. If you have sudden breathing problems immediately after inhaling your medicine, call your healthcare provider or go to the nearest hospital emergency room right away.

• Effects on your heart:

○ fast or irregular heartbeat, awareness of a heartbeat

○ chest pain

○ increased blood pressure

• Changes in laboratory blood levels, including high levels of blood sugar (hyperglycemia) and low levels of potassium (hypokalemia), which may cause symptoms of muscle spasm, muscle weakness or abnormal heart rhythm.

Common side effects of ARCAPTA NEOHALER include: runny nose, cough, sore throat, headache and nausea.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of ARCAPTA NEOHALER. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store ARCAPTA NEOHALER?

• Store ARCAPTA NEOHALER (inhaler and blister-packaged capsules) at room temperature between 59°F to 86°F (15°C to 30°C).

• Store ARCAPTA NEOHALER in a dry place.

• Protect ARCAPTA capsules from light and moisture.

• Do not remove ARCAPTA capsules from their foil package until just before use.

• Do not store ARCAPTA capsules in the NEOHALER inhaler.

• Keep ARCAPTA NEOHALER and all medicines out of the reach of children.

General Information about the safe and effective use of ARCAPTA NEOHALER.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ARCAPTA NEOHALER for a condition for which it was not prescribed. Do not give ARCAPTA NEOHALER to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about ARCAPTA NEOHALER that is written for health professionals.

Active ingredient: indacaterol

Inactive ingredients: lactose monohydrate (contains trace levels of milk protein)

Manufactured for Sunovion Pharmaceuticals Inc. Marlborough MA 01752 USA

Made in Switzerland ARCAPTA, , and NEOHALER are registered trademarks of Novartis AG, used under license

© 2019 Sunovion Pharmaceuticals Inc. For more information, go to www.arcapta.com or call 1-888-669-6682.

This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 05/2019

16.2 Storage and Handling

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

75 mcg: Protect capsule from light and moisture.

• ARCAPTA capsules should be used with the NEOHALER inhaler only. The NEOHALER inhaler should not be used with any other capsules.

• Capsules should always be stored in the blister and only removed from the blister immediately before use.

• Always use the new NEOHALER inhaler provided with each new prescription.

Keep out of the reach of children.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information)

17.1 Serious Asthma-Related Events

Patients should be informed that LABA, such as ARCAPTA NEOHALER, when used as monotherapy [without an inhaled corticosteroid], increase the risk of serious asthma-related events, including asthma-related death. ARCAPTA NEOHALER is not indicated for the treatment of asthma.

17.2 Instructions for Administering ARCAPTA NEOHALER

It is important for patients to understand how to correctly administer ARCAPTA capsules using the NEOHALER device [see Instructions for Use at the end of the Patient Information]. Patients should be instructed that ARCAPTA capsules should only be administered via the NEOHALER device and the NEOHALER device should not be used for administering other medications. The contents of ARCAPTA capsules are for oral inhalation only and must not be swallowed.

ARCAPTA capsules should always be stored in sealed blisters. Only one ARCAPTA capsule should be removed immediately before use, or its effectiveness may be reduced. Additional ARCAPTA capsules that are exposed to air (i.e., not intended for immediate use) should be discarded.

17.3 Not for Acute Symptoms

ARCAPTA NEOHALER is not meant to relieve acute symptoms or exacerbations of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist such as albuterol. (The healthcare provider should provide the patient with such medication and instruct the patient in how it should be used.)

Patients should be instructed to notify their physician immediately if they experience any of the following: • Worsening of symptoms • Decreasing effectiveness of inhaled, short-acting beta2-agonists • Need for more inhalations than usual of inhaled, short-acting beta2-agonists • Significant decrease in lung function as outlined by the physician.

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

17.4 Do Not Use Additional Long-Acting Beta2-Agonists

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

When patients are prescribed ARCAPTA NEOHALER, other inhaled medications containing long-acting beta2-agonists should not be used. Patients should not use more than the recommended once daily dose of ARCAPTA NEOHALER. Excessive use of sympathomimetics may cause significant cardiovascular effects, and may be fatal.

17.5 Risks Associated With Beta-Agonist Therapy

Patients should be informed of adverse effects associated with beta2- agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Manufactured forSunovion 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

Instructions for Use ARCAPTA® (ar-CAP-ta) NEOHALER®

(indacaterol) inhalation powder

Do not swallow ARCAPTA capsules.

Follow the instructions below for using ARCAPTA NEOHALER. You will breathe-in (inhale) the medicine in the ARCAPTA capsules from the NEOHALER inhaler. If you have any questions, ask your healthcare provider or pharmacist.

ARCAPTA NEOHALER

ARCAPTA NEOHALER consists of both the inhaler and the blister-packaged capsules. Each package contains ARCAPTA capsules and a NEOHALER inhaler. ○ ARCAPTA capsules come in blister cards (see figure above). ○ NEOHALER inhaler consists of a cap and a base (see figure above).Your inhaler is made to give you the medicine contained in the capsules.Do not use ARCAPTA capsules with any other capsule inhaler, and do not use NEOHALER inhaler to take any other capsule medicine.

How to use your inhaler

Figure A

Step 1. Pull off cap. See Figure A1

Figure B

Step 2. Open inhaler: See Figure B

Hold the base of the inhaler firmly and tilt the mouthpiece to open the inhaler.

2

Figure C

Step 3. Prepare capsule: See Figure C

Separate one of the blisters from the blister card by tearing along the perforation.

Take one blister and peel away the protective backing to expose the foil.

3

Figure D

Step 4. Remove an ARCAPTA capsule: See Figure D

Capsules should always be stored in the blister and only removed immediately before use.

With dry hands, remove one capsule from the blister by pushing the ARCAPTA capsule through the foil.

4

Do not swallow ARCAPTA capsule.

Figure E

Step 5. Insert capsule: See Figure E

Place the capsule into the capsule chamber.

Do not place a capsule directly into the mouthpiece.

5

Figure F

Step 6. Close the inhaler: See Figure F

Close the inhaler fully. You should hear a ‘click’ as it fully closes.

6

Figure G

Step 7. Pierce the capsule: See Figure G

Hold the inhaler upright.

Press both buttons fully one time. You should hear a ‘click’ as the capsule is being pierced.

7

Do not press the piercing buttons more than one time.

Figure H

Step 8. Release the buttons fully. See Figure H8

Figure I

Step 9. Breathe out: See Figure I

Before placing the mouthpiece in your mouth, breathe out fully.

Never blow into the mouthpiece.

9

Figure J

Step 10. Inhale the medicine: See Figure J

Before breathing in, place the mouthpiece in your mouth and close your lips around the mouthpiece. Hold the inhaler with the buttons to the left and right (not up and down).

10

Breathe in rapidly and steadily, as deeply as you can. Do not press the piercing buttons.

Figure K

Note: See Figure K

As you breathe in through the inhaler, the capsule spins around in the chamber and you should hear a whirring noise.

11

If you do not hear a whirring noise, the capsule may be stuck in the capsule cavity. If this occurs, open the inhaler and carefully loosen the capsule by tapping the base of the device. Do not press the piercing buttons to loosen the capsule. (Repeat steps 9 and 10 if needed.)

Figure L

Step 11. Hold breath: See Figure L

Continue to hold your breath as long as comfortably possible while removing the inhaler from your mouth. Then breathe out.

12

Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule, close the inhaler and repeat steps 9 to 12. Most people are able to empty the capsule in one or two inhalations.

Some people may cough soon after inhaling the medicine. If you do, don’t worry, as long as the capsule is empty, you have received the full dose.

Figure M

Step 12. Remove capsule: See Figure M13 After you have finished taking your daily dose of the

ARCAPTA NEOHALER, open the mouthpiece again, remove the empty capsule by tipping it out, and discard it. Close the inhaler and replace the cap.

Do not store the capsules in the NEOHALER device.

Additional InformationOccasionally, very small pieces of the capsule can get past the screen and enter your mouth. If this happens, you may be able to feel these pieces on your tongue. It is not harmful if these pieces are swallowed or inhaled. The chances of the capsule shattering will be increased if the capsule is pierced more than once (Step 7). Therefore it is recommended that you follow the storage directions, remove the capsule from the blister immediately before use and pierce each capsule only once.

How to clean your inhalerCleaning the device is not necessary, however, if desired, a clean, dry lint-free cloth, or a clean, dry soft brush may be used to wipe the inhaler between uses.

Remember:• ARCAPTA capsules should be stored in the blister, and only removed immediately

before use.

• Do not breathe into the NEOHALER inhaler.

• Do not place the ARCAPTA capsule directly into the mouthpiece of the NEOHALER inhaler.

• Do not store the ARCAPTA capsule in the NEOHALER inhaler chamber.

• Always release the push buttons prior to inhalation.

• Do not wash the NEOHALER inhaler. Keep it dry.• Always keep the NEOHALER inhaler and ARCAPTA capsules in a dry place.

• Always use the new NEOHALER inhaler that comes with your refill.

• Do not use ARCAPTA capsules with inhalers from other medicines.

• Keep this and all drugs out of the reach of children.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured for Sunovion Pharmaceuticals Inc. Marlborough MA 01752 USA

Made in Switzerland

© 2019 Sunovion Pharmaceuticals Inc.

Revised: 05/2019

10034-02-MKT1

Cap

Base

Blisters

Capsule chamber

Mouthpiece

Screen

Button

Inhaler Blister card Inhaler base

PATIENT INFORMATION ARCAPTA® (ar-CAP-ta) NEOHALER®

(indacaterol) inhalation powder

Important: Do not swallow ARCAPTA capsules. ARCAPTA capsules are used only with the NEOHALER inhaler that comes with ARCAPTA NEOHALER. Do not place a capsule in the mouthpiece of the NEOHALER inhaler.

What is ARCAPTA NEOHALER?

• ARCAPTA NEOHALER is a long-acting beta2-adrenergic agonist (LABA) used to control the symptoms of COPD in adults with COPD. COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both. LABA medicines such as ARCAPTA NEOHALER help the muscles around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness and shortness of breath.

• ARCAPTA NEOHALER is for long-term use and should be taken 1 time each day, to improve the symptoms of COPD for better breathing.

• ARCAPTA NEOHALER is not used to treat sudden symptoms of COPD. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden symptoms of COPD. If you do not have a rescue inhaler, contact your healthcare provider to have one prescribed for you.

• ARCAPTA NEOHALER is not for the treatment of asthma. It is not known if ARCAPTA NEOHALER is safe and effective in people with asthma.

• ARCAPTA NEOHALER should not be used in children. It is not known if ARCAPTA NEOHALER is safe and effective in children.

Do not use ARCAPTA NEOHALER if you:

• have asthma.

• are allergic to indacaterol or any of the ingredients in ARCAPTA NEOHALER. Ask your healthcare provider if you are not sure. See the end of this Patient Information leaflet for a complete list of ingredients in ARCAPTA NEOHALER.

Before using ARCAPTA NEOHALER, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems.

• have high blood pressure.

• have seizures.

• have thyroid problems.

• have diabetes.

• are pregnant or plan to become pregnant. It is not known if ARCAPTA NEOHALER can harm your unborn baby.

• are breastfeeding or plan to breastfeed. It is not known if the medicine indacaterol in ARCAPTA NEOHALER passes into your breast milk and if it can harm your baby. You and your healthcare provider should decide if you will take ARCAPTA or breastfeed.

• are allergic to any of the ingredients in ARCAPTA NEOHALER, any other medicines, or food products. ARCAPTA NEOHALER contains lactose (milk sugar) and a small amount of milk proteins. It is possible that allergic reactions may happen in patients who have a severe milk protein allergy.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ARCAPTA NEOHALER and certain other medicines may interact with each other. This may cause serious side effects.

Know the medicines you take. Keep a list of your medicines with you to show your healthcare provider and pharmacist each time you get a new medicine.

How should I use ARCAPTA NEOHALER?

Read the step-by-step instructions for using ARCAPTA NEOHALER at the end of this Patient Information leaflet.

• Do not use ARCAPTA NEOHALER unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. Ask your healthcare provider or pharmacist if you have any questions.

• Use ARCAPTA NEOHALER exactly as prescribed. Do not use ARCAPTA NEOHALER more often than prescribed.

• Use 1 ARCAPTA capsule inhaled through the NEOHALER inhaler 1 time each day, at the same time of the day.

• If you miss a dose of ARCAPTA NEOHALER, take it as soon as you remember. Do not take more than 1 dose in 24 hours.

• Do not swallow ARCAPTA capsules. ARCAPTA capsules are for oral inhalation use only.

• Only use ARCAPTA capsules with the NEOHALER inhaler.

• ARCAPTA capsules should always be stored in the sealed blisters and removed immediately before use. Throw away (discard) any ARCAPTA capsules that are removed from the blister and not used immediately.

• Always use the new NEOHALER inhaler that is provided with each new prescription.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

UTIBRON® NEOHALER® is a combination of indacaterol and glycopyrrolate indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations of Use: UTIBRON NEOHALER is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma [see Warnings and Precautions (5.1, 5.2)]. The safety and effectiveness of UTIBRON in asthma have not been established.

2 DOSAGE AND ADMINISTRATION

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 [see Overdosage (10)].

The recommended dosage of UTIBRON NEOHALER is the inhalation of the contents of one UTIBRON capsule twice-daily 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.

Store UTIBRON capsules in the blister, and only remove IMMEDIATELY BEFORE USE with the NEOHALER device.

No dosage adjustment is required for geriatric patients, patients with mild and moderate hepatic impairment, or patients with mild to moderate renal impairment.

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder: UTIBRON NEOHALER consists of UTIBRON capsules containing indacaterol/glycopyrrolate powder for oral inhalation and the NEOHALER device. UTIBRON capsules contain 27.5 mcg/15.6 mcg of indacaterol/glycopyrrolate in a hypromellose capsule with yellow transparent cap and uncolored transparent body with black “ ” logo on the cap and black product code “IGP27.5_15.6” under the black bar on the body.

4 CONTRAINDICATIONS

Use of a LABA, including UTIBRON NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5.1)]. UTIBRON NEOHALER is not indicated for the treatment of asthma.

UTIBRON NEOHALER is contraindicated in patients who have demonstrated hypersensitivity to indacaterol, glycopyrrolate, or to any of the ingredients [see Warnings and Precautions (5.5)].

5 WARNINGS AND PRECAUTIONS

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 ADVERSE REACTIONS

LABAs, such as indacaterol, one of the active ingredients in UTIBRON NEOHALER, as monotherapy (without inhaled corticosteroids) for asthma increase the risk of asthma-related events. UTIBRON NEOHALER is not indicated for the treatment of asthma [see Warnings and Precautions (5.1)].The following adverse reactions are described in greater detail in other sections:• Paradoxical bronchospasm [see Warnings and Precautions (5.4)].• Immediate hypersensitivity reactions [see Warnings and Precautions (5.5)].• Cardiovascular effects [see Warnings and Precautions (5.6)].• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.8)].• Worsening of urinary retention [see Warnings and Precautions (5.9)].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.

12-Week Trials

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.

Table 1. Adverse reactions with UTIBRON NEOHALER (greater than or equal to 1% incidence and higher than placebo) in COPD patients

Adverse Reaction

UTIBRON NEOHALER27.5/15.6 mcg BID

(N=508)n (%)

Indacaterol27.5 mcg BID

(N=511)n (%)

Glycopyrrolate15.6 mcg BID

(N=513)n (%)

Placebo

(N=508)n (%)

Nasopharyngitis 21 (4.1) 13 (2.5) 12 (2.3) 9 (1.8)

Hypertension 10 (2.0) 5 (1.0) 3 (0.6) 7 (1.4)

Back pain 9 (1.8) 7 (1.4) 2 (0.4) 3 (0.6)

Oropharyngeal pain 8 (1.6) 4 (0.8) 8 (1.6) 6 (1.2)

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 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 DRUG INTERACTIONS

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies with UTIBRON NEOHALER or its individual components, indacaterol and glycopyrrolate, in pregnant women. Animal reproduction studies were conducted with individual components, indacaterol and glycopyrrolate. Because animal reproduction studies are not always predictive of human response, UTIBRON NEOHALER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their physician if they become pregnant while taking UTIBRON NEOHALER.

Indacaterol: Indacaterol was not teratogenic in Wistar rats and New Zealand rabbits at approximately 340 and 770 times, respectively, the MRHD in adults (on an AUC basis at maternal subcutaneous doses up to 1 mg/kg/day in rats and rabbits).

Glycopyrrolate: Glycopyrrolate was not teratogenic in Wistar rats or New Zealand White rabbits at approximately 1400 and 530 times, respectively, the MRHD in adults (on an AUC basis at maternal inhaled doses up to 3.83 mg/kg/day in rats and up to 4.4 mg/kg/day in rabbits).

Non-teratogenic Effects:

Indacaterol: There were no effects on perinatal and postnatal developments in rats at approximately 110 times the MRHD in adults (on an AUC basis at maternal subcutaneous doses up to 0.3 mg/kg/day).

Glycopyrrolate: There were no effects on perinatal and postnatal developments in rats at approximately 1100 times the MRHD in adults (on an AUC basis at maternal subcutaneous doses up to 1.88 mg/kg/day).

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)].

10 OVERDOSAGE

In COPD patients, doses of up to 600/124.8 mcg UTIBRON NEOHALER were inhaled over 2 weeks and there were no relevant effects on heart rate, QTc interval, blood glucose or serum potassium. There was an increase in ventricular ectopies after 14 days of dosing with 300/124.8 mcg and 600/124.8 mcg UTIBRON NEOHALER, but low prevalence and small patient numbers (N=49 and N=51 for 600/124.8 mcg and 300/124.8 mcg UTIBRON NEOHALER, respectively) precluded accurate analysis. In a total of four patients, non-sustained ventricular tachycardia was recorded, with the longest episode recorded being 9 beats (4 seconds).

In healthy volunteers, single dose administration of UTIBRON NEOHALER at up to a dose of 440/499.2 mcg indacaterol/glycopyrrolate was well-tolerated without clinically significant effects on the ECG, serum potassium or blood glucose.

UTIBRON NEOHALER contains both indacaterol and glycopyrrolate; therefore, the risks associated with overdosage for the individual components described below apply to UTIBRON NEOHALER. Treatment of overdosage consists of discontinuation of UTIBRON NEOHALER together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

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.

11 DESCRIPTION

UTIBRON NEOHALER consists of a dry powder formulation for delivery of a combination of indacaterol and glycopyrrolate to patients by oral inhalation only with the NEOHALER device. The inhalation powder is packaged in hypromellose (HPMC) capsules with yellow transparent cap and uncolored transparent body.

Each capsule contains a dry powder blend of 27.5 mcg/15.6 mcg of indacaterol/glycopyrrolate with approximately 24.9 mg of lactose monohydrate (which contains trace levels of milk protein) and 0.03 mg of magnesium stearate.

One active component of UTIBRON NEOHALER is indacaterol maleate, a (R) enantiomer. Indacaterol maleate is a selective beta2-adrenergic agonist. Its chemical name is (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8- hydroxy-1H-quinolin-2-one maleate; its structural formula is:

Indacaterol maleate has a molecular weight of 508.56, and its empirical formula is C24H28N2O3 • C4H4O4. Indacaterol maleate is a white to very slightly grayish or very slightly yellowish powder. Indacaterol maleate is slightly soluble in ethanol and very slightly soluble in water.

The other active component of UTIBRON NEOHALER is glycopyrrolate, which is chemically described as (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-phenylacetyl) oxy]-1,1-dimethylpyrrolidinium bromide. This synthetic quaternary ammonium compound acts as a competitive antagonist at muscarinic acetylcholine receptors, also referred to as anticholinergic. Glycopyrrolate, C19H28BrNO3, is a white powder that is freely soluble in water and sparingly soluble in absolute ethanol. It has a molecular mass of 398.33. The structural formula is:

The NEOHALER device is a plastic inhalation device used to inhale the dry powder within the UTIBRON capsule. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time.

Under standardized in vitro testing at a fixed flow rate of 90 L/min for 1.3 seconds, the NEOHALER inhaler delivered 20.8 mcg of indacaterol and 12.8 mcg glycopyrrolate for the 27.5 mcg/15.6 mcg dose strength (equivalent to 27.5 mcg/12.5 mcg of indacaterol/glycopyrronium) from the mouthpiece. This in vitro testing revealed that the NEOHALER device had a specific resistance of 0.059 cm H2O1/2/L/min. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER device were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52 to 133 L/min) for adult patients. Twenty-five of 26 patients (96%) in this study generated a PIFR through the device exceeding 60 L/min.

12 CLINICAL PHARMACOLOGY

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

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. Although a marginal QT effect of UTIBRON NEOHALER was observed at the supratherapeutic dose, it is unlikely there will be a clinically relevant effect at the therapeutic exposure.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use UTIBRON NEOHALER safely and effectively. See full prescribing information for UTIBRON NEOHALER.

UTIBRON® NEOHALER® (indacaterol and glycopyrrolate) inhalation powder, for oral inhalation useInitial U.S. Approval: 2015

RECENT MAJOR CHANGES

Box Warning, Removed 05/2019Contraindications, revised (4) 05/2019Warnings and Precautions, revised Serious Asthma-Related Events – Hospitalizations, Intubations, Death (5.1) 05/2019

INDICATIONS AND USAGE

UTIBRON NEOHALER is a combination of indacaterol, a long-acting beta2-adrenergic agonist (LABA), and glycopyrrolate, an anticholinergic, indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). (1)

Limitations of Use: Not indicated for the relief of acute bronchospasm or for the treatment of asthma. (1, 5.1, 5.2)

DOSAGE AND ADMINISTRATION

• For oral inhalation only. Do not swallow UTIBRON capsules. Only use UTIBRON capsules with the NEOHALER device. (2)

• Maintenance treatment of COPD: The inhalation of the powder contents of one UTIBRON capsule twice-daily. (2)

DOSAGE FORMS AND STRENGTHS

• Inhalation powder: UTIBRON capsules contain 27.5 mcg of indacaterol and 15.6 mcg glycopyrrolate inhalation powder for use with the NEOHALER device. (3)

CONTRAINDICATIONS

• Use of a LABA, including UTIBRON NEOHALER, without an inhaled corticosteroid is contraindicated in patients with asthma. (4)

• History of known hypersensitivity to indacaterol, glycopyrrolate, or to any of the ingredients. (4, 5.5)

WARNINGS AND PRECAUTIONS

• LABA as monotherapy (without an inhaled corticosteroid) for asthma increases the risk of serious asthma-related events (5.1)

• Do not initiate in acutely deteriorating COPD or to treat acute symptoms. (5.2)• Do not use in combination with an additional medicine containing LABA because of risk of overdose. (5.3, 7.1)• If paradoxical bronchospasm occurs, discontinue UTIBRON NEOHALER immediately and institute alternative

therapy. (5.4)• Use with caution in patients with cardiovascular or convulsive disorders, thyrotoxicosis, sensitivity to

sympathomimetic drugs, diabetes mellitus, and ketoacidosis. (5.6, 5.7, 7.1)• Worsening of narrow-angle glaucoma or urinary retention may occur. Use with caution in patients with

narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction and instruct patients to contact a physician immediately if symptoms occur. (5.8, 5.9)

• Be alert to hypokalemia and hyperglycemia. (5.10)

ADVERSE REACTIONS

Most common adverse reactions (incidence greater than or equal to 2% and higher than placebo) are nasopharyngitis and hypertension. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• Other adrenergic drugs may potentiate effect: Use with caution. (5.3, 7.1)• Xanthine derivatives, steroids, diuretics or non-potassium-sparing diuretics may potentiate hypokalemia or

ECG changes. Use with caution. (7.2, 7.3)• Monoamine Oxidase inhibitors, tricyclic antidepressants, and drugs that prolong QTc interval may potentiate

effect on cardiovascular system. Use with extreme caution. (7.4)• Beta-blockers may decrease effectiveness: Use with caution and only when medically necessary. (7.5)• Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid

administration of UTIBRON NEOHALER with other anticholinergic-containing drugs. (7.6)

USE IN SPECIFIC POPULATIONS

• Use in patients with severe renal impairment should be considered if the potential benefit of the treatment outweighs the risk. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 05/2019

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Serious Asthma-Related Events –

Hospitalizations, Intubations, Death 5.2 Deterioration of Disease and Acute Episodes 5.3 Excessive Use of UTIBRON NEOHALER

and Use with Other Long-Acting Beta2-Adrenergic Agonists

5.4 Paradoxical Bronchospasm 5.5 Immediate Hypersensitivity Reactions 5.6 Cardiovascular Effects

5.7 Coexisting Conditions 5.8 Worsening of Narrow-Angle Glaucoma 5.9 Worsening of Urinary Retention 5.10 Hypokalemia and Hyperglycemia6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience7 DRUG INTERACTIONS 7.1 Adrenergic Drugs 7.2 Xanthine Derivatives, Steroids,

or Diuretics 7.3 Non-Potassium-Sparing Diuretics 7.4 Monoamine Oxidase Inhibitors, Tricyclic

Antidepressants, QTc-Prolonging Drugs 7.5 Beta-Blockers

7.6 Anticholinergics 7.7 Inhibitors of Cytochrome P450 3A4

and P-gp Efflux Transporter8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action

12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.5 Pharmacogenomics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis,

Impairment of Fertility14 CLINICAL STUDIES 14.1 Dose-Ranging Trials 14.2 Confirmatory Trials16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

12.3 Pharmacokinetics

Absorption

Following inhalation of UTIBRON NEOHALER, the median time to reach peak plasma concentrations of indacaterol and glycopyrrolate was achieved rapidly at approximately 15 minutes and 5 minutes, respectively.

The steady-state systemic exposure (AUC0-12h,ss; Cmax,ss) to indacaterol and glycopyrrolate is similar after the twice-daily inhalation of 2 (times 2) capsules of UTIBRON NEOHALER 27.5 mcg/15.6 mcg as compared to the twice-daily inhalation of the monotherapy products indacaterol 27.5 mcg (times 2) alone or glycopyrrolate 15.6 mcg (times 2) alone, respectively.

Indacaterol: Absolute bioavailability of indacaterol after an inhalation dose was on average 43% to 45%. Systemic exposure results from a composite of pulmonary and intestine absorption. Indacaterol serum concentrations increased with repeated once-daily administration. Steady-state was achieved within 12 to 15 days. The mean accumulation ratio of indacaterol, i.e., AUC over the 24-hour dosing interval on Day 14 or Day 15 compared to Day 1, was in the range of 2.9 to 3.8 for once-daily inhaled doses between 75 mcg and 600 mcg.

Glycopyrrolate: Following repeated once-daily inhalation in patients with COPD, pharmacokinetic steady-state of glycopyrrolate was reached within 1 week of treatment. There was no indication that the glycopyrrolate pharmacokinetics changes over time. With once-daily doses of 124.8 mcg and 249.6 mcg, steady-state exposure to glycopyrrolate (AUC over the dosing interval) was about 1.4- to 1.7-fold higher than after the first dose.

Distribution

Indacaterol: After intravenous infusion, the volume of distribution (Vz) of indacaterol was 2,361 to 2,557 L, indicating an extensive distribution. The in vitro human serum and plasma protein binding was 94.1% to 95.3% and 95.1% to 96.2%, respectively.

Glycopyrrolate: After intravenous administration, the steady-state volume of distribution (Vss) of glycopyrrolate was 83 L and the volume of distribution in the terminal phase (Vz) was 376 L. The in vitro human plasma protein binding of glycopyrrolate was 38% to 41% at concentrations of 1 to 10 ng/mL.

Metabolism

Indacaterol: In vitro investigations indicated that UGT1A1 is the only UGT isoform that metabolized indacaterol to the phenolic O-glucuronide. The oxidative metabolites were found in incubations with recombinant CYP1A1, CYP2D6, and CYP3A4. CYP3A4 is concluded to be the predominant isoenzyme responsible for hydroxylation of indacaterol. In vitro investigations further indicated that indacaterol is a low affinity substrate for the efflux pump P-gp.

After oral administration of radiolabelled indacaterol in a human ADME (absorption, distribution, metabolism, excretion) study, unchanged indacaterol was the main component in serum, accounting for about one-third of total drug-related AUC over 24 hours. A hydroxylated derivative was the most prominent metabolite in serum. Phenolic O-glucuronides of indacaterol and hydroxylated indacaterol were further prominent metabolites. A diastereomer of the hydroxylated derivative, a N-glucuronide of indacaterol, and C- and N-dealkylated products were further metabolites identified.

Glycopyrrolate: In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9). Further in vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrrolate and the hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family pre-systemically and/or via first pass metabolism from the swallowed dose fraction of orally inhaled glycopyrrolate. Glucuronide and/or sulfate conjugates of glycopyrrolate were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.

Elimination

Indacaterol: In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. Renal clearance of indacaterol was, on average, between 0.46 L/h and 1.20 L/h. When compared with the serum clearance of indacaterol of 18.8 L/h to 23.3 L/h, it is evident that renal clearance plays a minor role (about 2% to 6% of systemic clearance) in the elimination of systemically available indacaterol.

In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). Mass balance was complete with greater than or equal to 90% of the dose recovered in the excreta.

Indacaterol serum concentrations declined in a multi-phasic manner with an average terminal half-life ranging from 45.5 to 126 hours. The effective half-life, calculated from the accumulation of indacaterol after repeated dosing, ranged from 40 to 56 hours, which is consistent with the observed time to steady-state of approximately 12 to 15 days.

Glycopyrrolate:Renal elimination of parent drug accounts for about 60% to 70% of total clearance of systemically available glycopyrrolate whereas non-renal clearance processes account for about 30% to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.

Following inhalation of single and repeated once-daily doses between 62.4 mcg and 249.6 mcg glycopyrrolate by healthy volunteers and patients with COPD, mean renal clearance of glycopyrrolate was in the range of 17.4 L/h and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrrolate.

Glycopyrrolate plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life of glycopyrrolate was much longer after inhalation (33 to 53 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration.

Drug Interactions

There is no pharmacokinetic drug-drug interaction resulting from the concomitant administration of inhaled glycopyrrolate and inhaled indacaterol based on steady-state exposure data.

No specific drug-drug interaction studies were conducted with UTIBRON NEOHALER. Information on the potential for interactions for UTIBRON NEOHALER is based on the potential for each of its 2 monotherapy components.

Effect of co-administered drugs on indacaterol and glycopyrrolate exposureIndacaterol:Inhibitors of Cytochrome P450 3A4 and P-gp Efflux Transporter: Drug interaction studies were carried out using potent and specific inhibitors of CYP3A4 and P-gp (i.e., ketoconazole, erythromycin, verapamil and ritonavir). Coadministration of indacaterol 300 mcg (single dose) with verapamil (80 mg 3 times a day for 4 days) showed 2-fold increase in indacaterol AUC0-24h, and 1.5-fold increase in indacaterol Cmax. Coadministration of indacaterol inhalation powder 300 mcg (single dose) with erythromycin (400 mg 4 times a day for 7 days) showed a 1.4-fold increase in indacaterol AUC0-24h, and 1.2-fold increase in indacaterol Cmax. Coadministration of indacaterol inhalation powder 300 mcg (single dose) with ketoconazole (200 mg twice-daily for 7 days) caused a 1.9-fold increase in indacaterol AUC0-24h, and 1.3-fold increase in indacaterol Cmax. Coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg twice-daily for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC0-24h whereas indacaterol Cmax was unaffected [see Drug Interactions (7.7)].Glycopyrrolate:Cimetidine or Other Inhibitors of Organic Cationic Transport: In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport that is thought to contribute to the renal excretion of glycopyrrolate, increased total exposure (AUC) to glycopyrrolate by 22% and decreased renal clearance by 23%.

Effect of UTIBRON on co-administered drugs exposureIn vitro studies show that UTIBRON NEOHALER is not likely to inhibit or induce the metabolism of other drugs, nor processes involving drug transporters.

Indacaterol: In vitro investigations indicated that indacaterol has negligible potential to cause metabolic interactions with medications (by inhibition or induction of cytochrome P450 enzymes, or induction of UGT1A1) at the systemic exposure levels achieved in clinical practice. In vitro investigation furthermore indicated that, in vivo, indacaterol is unlikely to significantly inhibit transporter proteins such as P-gp, MRP2, BCRP, the cationic substrate transporters hOCT1 and hOCT2, and the human multidrug and toxin extrusion transporters hMATE1 and hMATE2K, and that indacaterol has negligible potential to induce P-gp or MRP2.

Glycopyrrolate: In vitro inhibition studies demonstrated that glycopyrrolate has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrrolate for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically significant effect of age (40 to 85 years), body weight (45 to 120 kg), gender, smoking status, and baseline FEV1 on systemic exposure of either indacaterol or glycopyrrolate following inhalation of UTIBRON NEOHALER.

Similarly no relevant covariate effect (of age, body weight, gender, smoking status, and baseline FEV1) was observed following the inhalation of the 2 components indacaterol and glycopyrrolate separately.

Patients with Renal ImpairmentIndacaterol: Due to the very low contribution of the urinary pathway to total body elimination of indacaterol, a study in renally impaired subjects was not performed.

Glycopyrrolate: Renal impairment has an impact on the systemic exposure to glycopyrrolate. A moderate mean increase in total systemic exposure (AUC last) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment [estimated GFR greater than or equal to 30 mL/min/1.73m2] and up to 2.2-fold in subjects with severe renal impairment and end stage renal disease [estimated GFR less than 30 mL/min/1.73m2] [see Use in Specific Populations (8.6)].Patients with Hepatic ImpairmentBased on the clinical pharmacokinetic characteristics of its monotherapy components, UTIBRON NEOHALER can be used at the recommended dose in patients with mild and moderate hepatic impairment. UTIBRON NEOHALER has not been evaluated in subjects with severe hepatic impairment.

Indacaterol: Patients with mild and moderate hepatic impairment showed no relevant changes in Cmax or AUC of indacaterol, nor did protein binding differ between mild and moderate hepatic impaired subjects and their healthy controls. Studies in subjects with severe hepatic impairment were not performed [see Use in Specific Populations (8.7)].Glycopyrrolate: Clinical studies in patients with hepatic impairment have not been conducted. Glycopyrrolate is cleared predominantly from the systemic circulation by renal excretion.

EthnicityThere was no evidence of a clinically significant ethnic/race effect (across Caucasian, Chinese, and Japanese subjects) on the systemic exposure to indacaterol and glycopyrrolate following inhalation of UTIBRON NEOHALER.

Similarly, no relevant ethnic effect was observed following the inhalation of the 2 components indacaterol and glycopyrrolate separately.

12.5 Pharmacogenomics

Indacaterol: The pharmacokinetics of indacaterol were prospectively investigated in subjects with the UGT1A1 (TA)7/(TA)7 genotype (low UGT1A1 expression; also referred to as *28) and the (TA)6, (TA)6 genotype. Steady-state AUC and Cmax of indacaterol were 1.2-fold higher in the [(TA)7, (TA)7] genotype, suggesting no relevant effect of UGT1A1 genotype of indacaterol exposure.

Glycopyrrolate: The effects of pharmacogenomic variants on the pharmacokinetics of glycopyrrolate have not been investigated.

13 NONCLINICAL TOXICOLOGY

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.

Indacaterol: Indacaterol produced no treatment-related increases in the incidence of tumors in a 2-year inhalation study in Wistar rats at inhaled doses up to 2.09 mg/kg/day (approximately 110 times the MRHD in adults on an AUC basis, respectively). A 26-week oral (gavage) study in CB6F1/TgrasH2 hemizygous mice with indacaterol at doses up to 600 mg/kg/day did not show any evidence of tumorigenicity.

Indacaterol tested negative in the following genotoxicity assays: the in vitro Ames test, in vitro chromosome aberration test in V79 Chinese hamster cells, and in vivo rat bone marrow micronucleus test.

Indacaterol had no effects on fertility and reproductive performance in male and female rats at subcutaneous doses up to 2 mg/kg/day (approximately 890 and 670 times in males and females, respectively, the MRHD in adults on an AUC basis).

Glycopyrrolate: Glycopyrrolate produced no treatment-related increases in the incidence of tumors in a 2-year inhalation study in Wistar rats at inhaled doses up to 0.56 mg/kg/day (approximately 170 times the MRHD in adults on an AUC basis). A 26-week oral (gavage) study in male and female TgrasH2 mice that received glycopyrrolate at doses up to 93.8 and 125.1 mg/kg/day, respectively, did not show any evidence of tumorigenicity.

Glycopyrrolate tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro human lymphocyte chromosomal aberration assay, and in vivo rat bone marrow micronucleus assay.

Impairment of fertility was observed in male and female rats at a subcutaneous dose of 1.88 mg/kg/day (approximately 1900 and 1100 times the MRHD in adults on an AUC basis, respectively) based upon findings of decreased corpora lutea, implantation sites and live fetuses. No effects on fertility and reproductive performance in male and female rats were observed at a subcutaneous dose of 0.63 mg/kg/day (approximately 350 times the MRHD in adults on an AUC basis).

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 CLINICAL STUDIESThe safety and efficacy of UTIBRON NEOHALER were evaluated in a clinical development program that included 3 dose-ranging trials, 2 lung function trials of 12 weeks duration (placebo-controlled and active-controlled) and a 12-month long-term safety trial. The efficacy of UTIBRON NEOHALER is based primarily on the dose-ranging trials in 562 subjects with COPD or asthma and the 2 placebo- and active-controlled confirmatory trials in 2043 subjects with additional support from one active-controlled 12-month trial in 615 subjects with COPD.

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 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 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 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 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 compared to placebo, indacaterol 27.5 mcg BID, and glycopyrrolate 15.6 mcg BID (see Table 2).

Table 2. Least squares (LS) mean change from baseline in FEV1 (L) AUC(0-12h) at Day 85 in Trials 1 and 2 (Intent-to-Treat Population)

Treatment N

FEV1 (L) AUC0-12h at Week 12

Difference from

Placebo

LS Mean(95% CI)

Indacaterol27.5 mcg BID*

LS Mean(95% CI)

Glycopyrrolate15.6 mcg BID*

LS Mean(95% CI)

Trial 1 (N=996)

UTIBRON NEOHALER27.5 mcg/15.6 mcg BID

249 N=246

0.262 L (0.224, 0.300)

N=251

0.112 L (0.075, 0.149)

N=250

0.079 L (0.042, 0.116)

Trial 2 (N=1039)

UTIBRON NEOHALER27.5 mcg/15.6 mcg BID

258 N=260

0.231 L (0.192, 0.271)

N=260

0.094 L (0.055, 0.133)

N=261

0.098 L (0.059, 0.137)

N = Number in intent-to-treat population* The indacaterol and glycopyrrolate comparators used the same inhaler and excipients as UTIBRON NEOHALER

With the limited data available, there was no suggestion of a difference in FEV1 AUC0-12h with respect to age, sex, degree of airflow limitation, GOLD stage, smoking status, or inhaled corticosteroid use.

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.

52-week Effects on Lung Function: At week 52 (Trial 3), UTIBRON NEOHALER demonstrated a significant treatment effect with an increase of 0.080 L in pre-dose trough FEV1 compared to indacaterol 75 mcg once-daily.

PATIENT INFORMATION UTIBRON® (yoo-TEE-bron) NEOHALER®

(indacaterol and glycopyrrolate)inhalation powder, for oral inhalation use

Important: Do not swallow UTIBRON capsules. UTIBRON capsules are used only with the NEOHALER inhaler that comes with UTIBRON NEOHALER. Do not place a capsule in the mouthpiece of the NEOHALER inhaler.

What is UTIBRON NEOHALER? UTIBRON NEOHALER combines a long-acting beta2 adrenergic agonist (LABA) medicine (indacaterol) and an anticholinergic medicine (glycopyrrolate).• LABA and anticholinergic medicines help the muscles around the airways in your

lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath. This makes it hard to breathe.

• UTIBRON NEOHALER is used to treat (COPD). COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both.

• UTIBRON NEOHALER is for long-term use and should be taken, 2 times each day, to improve symptoms of COPD for better breathing.

• UTIBRON NEOHALER is not used to treat sudden symptoms of COPD. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden symptoms of COPD. If you do not have a rescue inhaler, contact your healthcare provider to have one prescribed for you.

• UTIBRON NEOHALER is not for the treatment of asthma. It is not known if UTIBRON NEOHALER is safe and effective in people with asthma.

• UTIBRON NEOHALER should not be used in children. It is not known if UTIBRON NEOHALER is safe and effective in children.

Do not use UTIBRON NEOHALER if you:• have asthma.• are allergic to indacaterol, glycopyrrolate, or any of the ingredients in UTIBRON

NEOHALER. Ask your healthcare provider if you are not sure. See “What are the ingredients in UTIBRON NEOHALER?” at the end of this Patient Information leaflet for a complete list of ingredients in UTIBRON NEOHALER.

Before using UTIBRON NEOHALER, tell your healthcare provider about all of your medical conditions, including if you:• have heart problems• have high blood pressure• have seizures• have thyroid problems• have diabetes• have liver problems• have kidney problems• have eye problems such as glaucoma. UTIBRON NEOHALER may make your

glaucoma worse.• have prostate or bladder problems, or problems passing urine. UTIBRON NEOHALER

may make these problems worse.• have any other medical conditions.• are pregnant or plan to become pregnant. It is not known if UTIBRON NEOHALER

can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if the medicines in UTIBRON

NEOHALER pass into your breast milk and if it can harm your baby. You and your healthcare provider should decide if you will take UTIBRON NEOHALER or breastfeed.

• are allergic to UTIBRON NEOHALER or any of its ingredients, any other medicines, or food products.

UTIBRON NEOHALER contains lactose (milk sugar) and a small amount of milk proteins. It is possible that allergic reactions may happen in people who have a severe milk protein allergy.Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. UTIBRON NEOHALER may affect the way other medicines work, and other medicines can affect how UTIBRON NEOHALER works. Using UTIBRON NEOHALER with other medicines may cause serious side effects. Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use UTIBRON NEOHALER?Read the step-by-step instructions for using UTIBRON NEOHALER at the end of this Patient Information leaflet.• Do not use UTIBRON NEOHALER unless your healthcare provider has taught you

how to use the inhaler and you understand how to use it correctly.• Use UTIBRON NEOHALER exactly as your healthcare provider tells you to use it.

Do not use UTIBRON NEOHALER more often than prescribed for you.• Do not swallow UTIBRON capsules. Only use UTIBRON capsules with the

UTIBRON NEOHALER inhaler.• Use 1 UTIBRON capsule inhaled through the NEOHALER inhaler 2 times each

day (1 capsule in the morning and 1 capsule in the evening).• To make sure that the full dose has been taken, you should open the inhaler to

check that there is no powder left in the capsule. As long as the capsule is empty, you have received 1 full dose.

• If you miss a dose of UTIBRON NEOHALER, take it as soon as you remember. Take your next dose at your usual time.

○ Do not use 2 capsules at one time.

○ Do not use more than 2 capsules in a day.

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Time (h)

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glycopyrrolate 15.6 mcg QDglycopyrrolate 62.4 mcg QD

glycopyrrolate 31.2 mcg QD

glycopyrrolate 62.4 mcg BID

glycopyrrolate 15.6 mcg BIDglycopyrrolate 31.2 mcg BID glycopyrrolate 124.8 mcg QDplacebo

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glycopyrrolate 15.6 mcg QDglycopyrrolate 62.4 mcg QD

glycopyrrolate 31.2 mcg QD

glycopyrrolate 62.4 mcg BID

glycopyrrolate 15.6 mcg BIDglycopyrrolate 31.2 mcg BID glycopyrrolate 124.8 mcg QDplacebo

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Indacaterol 150 mcg QDIndacaterol 37.5 mcg QD

Indacaterol 75 mcg QDIndacaterol 27.5 mcg BID

Indacaterol 55 mcg QDplacebo

16 HOW SUPPLIED/STORAGE AND HANDLING

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 63402-681-60Unit 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.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

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 USAMade in Switzerland

© 2019 Sunovion Pharmaceuticals Inc.

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

Revised: 05/201910184-02-MKT1

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glycopyrrolate 15.6 mcg BIDUTIBRON NEOHALER 27.5/ 15.6 mcg BID

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Instructions for Use UTIBRON® (yoo-TEE-bron) NEOHALER®

(indacaterol and glycopyrrolate) inhalation powder, for oral inhalation use

For Oral Inhalation Only

Do not swallow UTIBRON capsules.

Follow the instructions below for using UTIBRON NEOHALER. You will breathe-in (inhale) the medicine in the UTIBRON capsules from the NEOHALER inhaler. If you have any questions, ask your healthcare provider or pharmacist.

Your UTIBRON NEOHALER

UTIBRON NEOHALER consists of both the inhaler and the blister-packaged capsules. Each package contains UTIBRON capsules and a NEOHALER inhaler.• (1) NEOHALER inhaler, which consists of a cap and a base (see figure below)• UTIBRON capsules come in blister cards to be used only in the NEOHALER inhaler

(see figure below)

Your inhaler is made to give you the medicine contained in the capsules.

Only use the NEOHALER inhaler contained in this pack. Do not use UTIBRON NEOHALER capsules with any other inhaler, do not use NEOHALER inhaler to take any other capsule medicine.

How to use your inhaler:

Step 1. Pull off cap.

Cap

Base

Blisters

Capsule chamber

Mouthpiece

Screen

Piercing button

Inhaler Blister card Inhaler base

Step 2. Open inhaler:

Hold the base of the inhaler firmly and tilt the mouthpiece to open the inhaler.

Step 3. Prepare capsule:

Separate 1 of the blisters from the blister card by tearing along the perforation.

Take 1 blister and peel away the protective backing to expose the capsule.

Do not push the capsule through the foil to remove it from the blister.

Step 4. Remove a UTIBRON capsule:

Capsules should always be stored in the blister and only removed immediately before use.

With dry hands, remove 1 capsule from the blister.

Do not swallow the UTIBRON capsule.

Step 5. Insert capsule:

Place the capsule into the capsule chamber.

Do not place a capsule directly into the mouthpiece.

Step 6. Close the inhaler:

Close the inhaler fully. You should hear a ‘click’ as it fully closes.

Step 7. Pierce the capsule:

Hold the inhaler upright with the mouthpiece pointing up.

Press both piercing buttons together firmly at the same time. You should hear a ‘click’ as the capsule is being pierced.

Do not press the piercing buttons more than 1 time.

Step 8. Release the piercing buttons fully.

Step 9. Breathe out:

Before placing the mouthpiece in your mouth, breathe out fully.

Do not blow into the mouthpiece.

Step 10. Inhale the medicine:

Before breathing in: • Hold the inhaler as shown in the figure for Step 10.

Make sure that the piercing buttons are to the left and right of the inhaler (not up and down).

• Place the mouthpiece in your mouth and close your lips firmly around the mouthpiece.

• Breathe in rapidly but steadily, as deeply as you can. Do not press the piercing buttons.

Step 11. Note:

As you breathe in through the inhaler, the capsule spins around in the chamber and you should hear a whirring noise. You may experience a sweet flavor as you inhale the medicine.

If you do not hear a whirring noise, the capsule may be stuck in the capsule chamber. If this occurs, open the inhaler and carefully loosen the capsule by tapping the base of the inhaler. Do not press the piercing buttons to loosen the capsule. (Repeat steps 9 and 10 if necessary.)

Step 12. Hold breath:

Continue to hold your breath for at least 5 to 10 seconds or as long as comfortably possible while removing the inhaler from your mouth. Then breathe out.

Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule, close the inhaler and repeat steps 9 to 12. Most people are able to empty the capsule with 1 or 2 inhalations.

Some people may cough soon after inhaling the medicine. If you do, don’t worry, as long as the capsule is empty, you have received 1 full dose.

Step 13. Remove capsule:

After you have finished taking your dose of UTIBRON NEOHALER, open the mouthpiece again, remove the empty capsule by tipping it out of the capsule chamber, and throwing it away. Close the inhaler and replace the cap.

Do not leave the used capsules in the NEOHALER inhaler.

Additional Information:

Occasionally, very small pieces of the capsule can get past the screen and enter your mouth. If this happens, you may be able to feel these pieces on your tongue. It is not harmful if these pieces are swallowed or inhaled. The chances of the capsule shattering will be increased if the capsule is pierced more than once (see Step 7). Therefore, it is recommended that you follow the storage directions, remove the capsule from the blister immediately before use and pierce each capsule only once.

How to clean your inhaler:

Cleaning the inhaler device is not necessary; however, if you want to clean your inhaler, wipe the mouthpiece inside and outside with a clean, dry, lint-free cloth, or a clean, dry, soft brush may be used to wipe the inhaler between uses to remove any powder residue. Keep the inhaler dry.

REMEMBER:

• Do not swallow UTIBRON capsules.• Only use the NEOHALER inhaler contained in this pack.• Do not place a UTIBRON capsule directly into the mouthpiece of the NEOHALER inhaler.• Do not blow into the mouthpiece of the NEOHALER inhaler.• Always release the piercing buttons before inhalation.• Do not press the piercing buttons more than once.• Do not take the NEOHALER inhaler apart.• Always use the new NEOHALER inhaler that comes with your new UTIBRON NEOHALER

medication pack.• Do not use UTIBRON capsules with inhalers from other medicines.

How should I store UTIBRON NEOHALER?

• Store UTIBRON NEOHALER (inhaler and blister-packaged capsules) at room temperature between 68°F and 77°F (20°C and 25°C).

• Do not remove UTIBRON capsules from the blister card until you are ready to use a dose of UTIBRON NEOHALER.

• Do not store UTIBRON capsules in the NEOHALER inhaler.

• Keep UTIBRON NEOHALER in a dry place away from light and moisture.

Keep UTIBRON NEOHALER and all medicines out of the reach of children.

UTIBRON, , and NEOHALER are registered trademarks of Novartis AG used under license.

Manufactured for Sunovion Pharmaceuticals Inc. Marlborough, MA 01752 USA

© 2019 Sunovion Pharmaceuticals Inc.

10184-02-MKT1

This Instructions for Use has been approved by the U.S. Food and Drug Administration. 05/2019

• UTIBRON capsules should always be stored in the blister strip and only removed immediately before use. Peel the backing foil away from the blister to open it, do not push the capsule through the foil.

• Always use the new NEOHALER inhaler that is provided with each new prescription.• UTIBRON NEOHALER does not relieve sudden symptoms of COPD. Always have

a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler medicine, call your healthcare provider to have a rescue inhaler prescribed for you.

• Do not stop using UTIBRON NEOHALER or other medicines to control or treat your COPD unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.

• Call your healthcare provider or get emergency medical care right away if your breathing problems worsen with UTIBRON NEOHALER, you need to use your rescue medicine more often than usual, or your rescue inhaler medicine does not work as well for you at relieving your symptoms.

What are the possible side effects of UTIBRON NEOHALER?UTIBRON NEOHALER can cause serious side effects, including:• people with asthma who take long-acting beta2-adrenergic agonist (LABA)

medicines, such as indacaterol (one of the medicines in UTIBRON NEOHALER), without also using a medicine called an inhaled corticosteroid, have an increased risk of serious problems from asthma, including being hospitalized, needing a tube placed in their airway to help them breathe, or death.

○ Call your healthcare provider if breathing problems worsen over time while using UTIBRON NEOHALER. You may need a different treatment.

○ Get emergency medical care if: • your breathing problems worsen quickly • you use your rescue inhaler medicine, but it does not relieve your

breathing problems• COPD symptoms that get worse over time. If your COPD symptoms worsen

over time, do not increase your dose of UTIBRON NEOHALER, instead call your healthcare provider.

• using too much of a LABA medicine may cause: ○ chest pain ○ increased blood pressure

○ fast and irregular heartbeat ○ headache

○ tremor ○ nervousness• sudden shortness of breath immediately after use of UTIBRON NEOHALER.

Sudden shortness of breath may be life-threatening. If you have sudden breathing problems immediately after inhaling your medicine, stop taking UTIBRON NEOHALER and call your healthcare provider or go to the nearest hospital emergency room right away.

• serious allergic reactions. Stop using UTIBRON NEOHALER and call your healthcare provider or get emergency medical care right away if you get any of the following symptoms of a serious allergic reaction:

○ rash ○ hives

○ swelling of the tongue, ○ difficulty breathing or swallowing lips, and face

• effects on your heart ○ fast or irregular heartbeat, ○ increased blood pressure

awareness of a heartbeat

○ chest pain • new or worsened eye problems including acute narrow-angle glaucoma.

Acute narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include:

○ eye pain or discomfort ○ nausea or vomiting

○ blurred vision ○ seeing halos or bright colors around lights

○ red eyes If you have these symptoms, stop taking UTIBRON NEOHALER and call your healthcare provider right away before taking another dose.• new or worsened urinary retention. People who use UTIBRON NEOHALER may

develop new or worse urinary retention. Urinary retention can be caused by a blockage in your bladder. Urinary retention can also happen in men who have a larger than normal prostate. Symptoms of urinary retention may include:

○ difficulty urinating ○ painful urination

○ urinating frequently ○ urination in a weak stream or dripsIf you have these symptoms, stop taking UTIBRON NEOHALER and call your healthcare provider right away before using another dose.• changes in laboratory blood levels, including high levels of blood sugar

(hyperglycemia) and low levels of potassium (hypokalemia) which may cause symptoms of muscle spasm, muscle weakness or abnormal heart rhythm.

Common side effects of UTIBRON NEOHALER include sore throat and runny nose, high blood pressure, and back pain.Tell your healthcare provider about any side effect that bothers you or that does not go away.These are not all of the possible side effects of UTIBRON NEOHALER. For more information, ask your healthcare provider or pharmacist. Call your doctor or pharmacist for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store UTIBRON NEOHALER?• Store UTIBRON NEOHALER (inhaler and blister-packaged capsules) at room

temperature between 68°F and 77°F (20°C and 25°C). • Do not remove UTIBRON capsules from the blister card it comes in until you are

ready to use a dose of UTIBRON NEOHALER.• Do not store UTIBRON capsules in the NEOHALER inhaler.• Keep UTIBRON NEOHALER in a dry place away from light and moisture. Keep UTIBRON NEOHALER and all medicines out of the reach of children.

General information about the safe and effective use of UTIBRON NEOHALER.Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use UTIBRON NEOHALER for a condition for which it was not prescribed. Do not give UTIBRON NEOHALER to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information that is written for healthcare professionals.For more information about UTIBRON NEOHALER or to report side effects, go to www.Utibron.com or call 1-888-394-7377.

What are the ingredients in UTIBRON NEOHALER?Active ingredients: indacaterol maleate, glycopyrrolate Inactive ingredients: lactose monohydrate (contains milk proteins) and magnesium stearate.

Revised: 05/2019

This Patient Information has been approved by the U.S. Food and Drug Administration. 05/2019

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

SEEBRI™ NEOHALER® is indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

2 DOSAGE AND ADMINISTRATION

For oral inhalation only. Do not swallow SEEBRI capsules, as the intended effects on the lungs will not be obtained. SEEBRI capsules should only be used with the NEOHALER device [see Overdosage (10)].

The recommended dose of SEEBRI NEOHALER is the inhalation of the contents of one SEEBRI capsule twice-daily using the SEEBRI NEOHALER device.

SEEBRI 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 SEEBRI NEOHALER is not recommended.

Store SEEBRI capsules in the blister, and only remove IMMEDIATELY BEFORE USE with the NEOHALER device.

No dosage adjustment is required for geriatric patients, patients with hepatic impairment, or patients with mild to moderate renal impairment.

3 DOSAGE FORMS AND STRENGTHS

Inhalation powder: SEEBRI NEOHALER consists of SEEBRI capsules containing glycopyrrolate powder for oral inhalation and the NEOHALER device. SEEBRI capsules contain 15.6 mcg of glycopyrrolate in an orange transparent hypromellose (HPMC) capsule with the product code “GPL15.6” printed in black and the logo ( ) printed with two radial black bars.

4 CONTRAINDICATIONS

SEEBRI NEOHALER is contraindicated in patients who have demonstrated hypersensitivity to glycopyrrolate or to any of the ingredients [see Warnings and Precautions (5.3)].

5 WARNINGS AND PRECAUTIONS

5.1 Deterioration of Disease and Acute Episodes

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

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

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If SEEBRI NEOHALER no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more inhalation of a 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 SEEBRI NEOHALER beyond the recommended dose is not appropriate in this situation.

5.2 Paradoxical Bronchospasm

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

5.3 Immediate Hypersensitivity Reactions

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

5.4 Worsening of Narrow-Angle Glaucoma

SEEBRI 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.

5.5 Worsening of Urinary Retention

SEEBRI 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.

6 ADVERSE REACTIONS

The following adverse reactions are described in greater detail, in other sections • Paradoxical bronchospasm [see Warnings and Precautions (5.2)].• Immediate hypersensitivity reactions [see Warnings and Precautions (5.3)].• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)].• Worsening of urinary retention [see Warnings and Precautions (5.5)].

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 SEEBRI NEOHALER safety database included 3415 subjects with COPD in four 12-week lung function trials and one 52-week long-term safety study. A total of 1202 subjects received treatment with SEEBRI NEOHALER 15.6 mcg twice-daily (BID). The safety data described below are based on the four 12-week trials and the one 52-week trial.

12-Week Trials

The incidence of adverse reactions associated with SEEBRI NEOHALER in Table 1 is based on four 12-week, placebo-controlled trials in 2908 subjects with COPD. In the total population, 61.2% of patients had moderate COPD and 37.8% had severe COPD. In these trials, 951 subjects received SEEBRI NEOHALER 15.6 mcg BID, 511 subjects received indacaterol 27.5 mcg BID, 508 subjects received a fixed-dose combination of indacaterol/glycopyrrolate 27.5 mcg/15.6 mcg BID, and 938 subjects received placebo. Overall, 62% were males, 90% were Caucasian, and the mean age was 63 years (ranging from 41 to 89 years). In this population, 53% were identified as current smokers with an average smoking history of 48 pack-years.

The most common adverse reactions (incidence greater than or equal to 2% and higher than placebo) were upper respiratory tract infection and nasopharyngitis.

The proportion of subjects who discontinued treatment due to adverse reactions was 2.4% for the SEEBRI NEOHALER-treated patients and 3.8% for placebo-treated patients.

Table 1. Adverse reactions with SEEBRI NEOHALER (greater than or equal to 1% incidence and higher than placebo) in COPD patients

Adverse Reaction

SEEBRI NEOHALER15.6 mcg BID

(N=951)n (%)

Placebo

(N=938)n (%)

Upper respiratory tract infection 32 (3.4) 22 (2.3)

Nasopharyngitis 20 (2.1) 18 (1.9)

Urinary tract infection 13 (1.4) 12 (1.3)

Sinusitis 13 (1.4) 7 (0.7)

Oropharyngeal pain 17 (1.8) 11 (1.2)

Other adverse reactions occurring more frequently with SEEBRI NEOHALER than with placebo, but with an incidence of less than 1% include rash, pruritus, gastroenteritis, hypersensitivity, atrial fibrillation, insomnia, pain in extremity, dysuria, vomiting, productive cough, and diabetes mellitus/hyperglycemia.

52-Week Trial

In a long-term safety trial, 507 subjects were treated for up to 52 weeks with glycopyrrolate 15.6 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 glycopyrrolate 15.6 mcg twice-daily that exceeded the frequency of indacaterol 75 mcg once-daily in this trial were: diarrhea, nausea, upper abdominal pain, fatigue, bronchitis, pneumonia, rhinitis, back pain, arthralgia, dyspnea, and wheezing.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during worldwide post-approval use of glycopyrrolate, the active ingredient in SEEBRI NEOHALER, 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 their frequency or establish a causal relationship to drug exposure. These adverse reactions are: angioedema, paradoxical bronchospasm and dysphonia.

7 DRUG INTERACTIONS

7.1 Sympathomimetics, Methylxanthines, Steroids

In clinical studies, concurrent administration of short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators (including indacaterol), methylxanthines, oral and inhaled steroids with SEEBRI NEOHALER showed no increases in adverse drug reactions.

7.2 Anticholinergics

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of SEEBRI NEOHALER with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects: Pregnancy Category C

There are no adequate and well-controlled studies with SEEBRI NEOHALER in pregnant women. Because animal reproduction studies are not always predictive of human response, SEEBRI NEOHALER should only be used during pregnancy if the potential benefit to the patient justifies the potential risk to the fetus. Women should be advised to contact their physician if they become pregnant while taking SEEBRI NEOHALER.

Glycopyrrolate was not teratogenic in Wistar rats and New Zealand White rabbits at approximately 1400 and 530 times, respectively, the MRHD in adults (on an AUC basis at maternal inhaled doses up to 3.83 mg/kg/day in rats and up to 4.4 mg/kg/day in rabbits).

Non-teratogenic Effects:

Glycopyrrolate had no effects on peri-natal and post-natal developments in rats at approximately 1100 times the MRHD in adults (on an AUC basis at maternal subcutaneous doses up to 1.88 mg/kg/day).

8.2 Labor and Delivery

There are no adequate and well-controlled human trials that have investigated the effects of SEEBRI NEOHALER during labor and delivery. 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

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

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

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

8.5 Geriatric Use

Based on available data, no adjustment of the dosage of SEEBRI NEOHALER in geriatric patients is warranted. SEEBRI 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 SEEBRI NEOHALER, 45% were aged 65 and older, while 10% 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

No dose adjustment is required for patients with mild and moderate renal impairment. SEEBRI NEOHALER should be used in patients with severe renal impairment (estimated GFR less than 30 mL/min/1.73m2), including those with end-stage renal disease requiring dialysis, 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

No dose adjustment is required for patients with hepatic impairment. The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

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 SEEBRI NEOHALER at total doses of 124.8 and 249.6 mcg once-daily for 28 days were well tolerated.

Accidental ingestion: Acute intoxication by inadvertent oral ingestion of SEEBRI NEOHALER capsules is unlikely due to the low oral bioavailability (about 5%) [see Clinical Pharmacology (12.3)].

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.

11 DESCRIPTION

SEEBRI NEOHALER consists of SEEBRI capsules and a NEOHALER device. Each SEEBRI capsule contains a dry powder formulation of glycopyrrolate packaged in orange transparent hypromellose (HPMC) capsules for oral inhalation with the NEOHALER device only.

Each orange transparent HPMC capsule contains 15.6 mcg of glycopyrrolate blended with approximately 25 mg of lactose monohydrate (which contains trace levels of milk protein) and 0.04 mg of magnesium stearate.

Glycopyrrolate, the active component of SEEBRI NEOHALER, is chemically described as (3RS)-3-[(2SR)-(2-cyclopentyl- 2-hydroxy-2-phenylacetyl) oxy]-1,1-dimethylpyrrolidinium bromide. This synthetic quaternary ammonium compound acts as a competitive antagonist at muscarinic acetylcholine receptors, also referred to as anticholinergic. Glycopyrrolate, C19H28BrNO3, is a white powder that is freely soluble in water and sparingly soluble in absolute ethanol. It has a molecular mass of 398.33. The structural formula is:

The NEOHALER device is an inhalation device used to inhale the dry powder within the SEEBRI capsule. The amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow rate and inspiratory time. Under standardized in vitro testing at a fixed flow rate of 90 L/min for 1.3 seconds, the NEOHALER device delivered 13.1 mcg for the 15.6 mcg dose strength (equivalent to 12.5 mcg of glycopyrronium) from the mouthpiece. This in vitro testing revealed that the NEOHALER device had a specific resistance of 0.07 cm H2O1/2/L/min. Peak inspiratory flow rates (PIFR) achievable through the NEOHALER device were evaluated in 26 adult patients with COPD of varying severity. Mean PIFR was 95 L/min (range 52 to 133 L/min) for adult patients. Twenty-five of 26 patients (96%) in this study generated a PIFR through the device exceeding 60 L/min.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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, glycopyrrolate 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 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 effect of SEEBRI NEOHALER on the QTc interval was evaluated in a Phase 1 randomized placebo and positive controlled double-blind, single-dose, crossover thorough QTc study in 73 healthy subjects. At the dose 16-fold the therapeutic daily dose, SEEBRI NEOHALER did not prolong QTc to any clinically relevant extent.

12.3 Pharmacokinetics

Linear pharmacokinetics of glycopyrrolate was observed following inhalation of daily doses of 31.2 mcg to 249.6 mcg.

Absorption

Following oral inhalation using the NEOHALER inhaler, glycopyrrolate was rapidly absorbed and reached peak plasma levels at 5 minutes post dose.

The absolute bioavailability of glycopyrrolate inhaled via SEEBRI NEOHALER was estimated to be about 40%. About 90% of systemic exposure following inhalation is due to lung absorption and 10% is due to gastrointestinal absorption.

Following repeated once-daily inhalation in patients with COPD, PK steady-state of glycopyrrolate was reached within 1 week of treatment. There was no indication that the glycopyrrolate pharmacokinetics changes over time.

Distribution

After intravenous administration, the steady-state volume of distribution of glycopyrrolate was 83 L and the volume of distribution in the terminal phase was 376 L. The in vitro human plasma protein binding of glycopyrrolate was 38% to 41% at concentrations of 1 to 10 ng/mL.

Metabolism

In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis-hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9). Further in vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrrolate and the hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family pre-systemically and/or via first pass metabolism from the swallowed dose fraction of orally inhaled glycopyrrolate. Glucuronide and/or sulfate conjugates of glycopyrrolate were found in urine of humans after repeated inhalation, accounting for about 3% of the dose.

Elimination

Renal elimination of parent drug accounts for about 60% to 70% of total clearance of systemically available glycopyrrolate whereas non-renal clearance processes account for about 30% to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.

Following inhalation of single and repeated once-daily doses between 62.4 mcg and 249.6 mcg glycopyrrolate by healthy volunteers and patients with COPD, mean renal clearance of glycopyrrolate was in the range of 17.4 L/h and 24.4 L/h indicating active tubular secretion contributes to the renal elimination of glycopyrrolate.

Glycopyrrolate plasma concentrations declined in a multi-phasic manner. The mean terminal elimination half-life was much longer after inhalation (33 to 53 hours) than after intravenous (6.2 hours) and oral (2.8 hours) administration.

Drug Interactions

In vitro inhibition studies demonstrated that glycopyrrolate has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrrolate for any of the cytochrome P450 isoenzymes tested as well as for UGT1A1 and the transporters MDR1 and MRP2.

In a clinical study in healthy volunteers, cimetidine, an inhibitor of organic cation transport which is thought to contribute to the renal excretion of glycopyrrolate, increased total systemic exposure (AUC) to glycopyrrolate by 22% and decreased renal clearance by 23%.

Specific Populations

Population pharmacokinetic analysis showed no evidence of a clinically relevant effect of age (40 to 85 years) or body weight (45 to 120 kg) on systemic exposure to glycopyrrolate. In addition, there was no evidence of a clinically significant ethnic/race effect (across Caucasian, Chinese, Hispanic/Latino, Japanese subjects). Gender, smoking status, and baseline FEV1 have no apparent effect on maximal or average glycopyrrolate systemic exposure.

Renal Impairment: Renal impairment has an impact on the systemic exposure to glycopyrrolate. A moderate mean increase in total systemic exposure (AUClast) of up to 1.4-fold was seen in subjects with mild and moderate renal impairment [estimated GFR greater than or equal to 30 mL/min/1.73m2] and up to 2.2-fold in subjects with severe renal impairment and end stage renal disease [estimated GFR less than 30 mL/min/1.73m2] [see Use in Specific Populations (8.6)].

Hepatic Impairment: The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied. Glycopyrrolate is cleared predominantly from systemic circulation by renal excretion [see Use in Specific Populations (8.7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Glycopyrrolate produced no treatment-related increases in the incidence of tumors in a 2-year inhalation study in Wistar rats at inhaled doses up to 0.56 mg/kg/day (approximately 170 times the MRHD in adults on an AUC basis, respectively). A 26-week oral (gavage) study in male and female TgrasH2 mice that received glycopyrrolate at doses up to 93.8 and 125.1 mg/kg/day, respectively, did not show any evidence of tumorigenicity.

Glycopyrrolate tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro human lymphocyte chromosomal aberration assay, and in vivo rat bone marrow micronucleus assay.

Impairment of fertility was observed in male and female Wistar rats at a subcutaneous dose of 1.88 mg/kg/day (approximately 1900 and 1100 times the MRHD in adults on an AUC basis) based upon findings of decreased implantation sites and live fetuses. No effects on fertility and reproductive performance in male and female rats were observed at a subcutaneous dose of 0.63 mg/kg/day (approximately 350 times the MRHD in adults on an AUC basis).

13.2 Animal Toxicology

Eye findings 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 CLINICAL STUDIES

The safety and efficacy of SEEBRI NEOHALER were evaluated in a clinical development program that included 2 dose-ranging trials, 4 efficacy and safety trials of 12 weeks duration (placebo-controlled), and a 52-week long-term safety trial. Two of these efficacy and safety trials were conducted in support of the UTIBRON NEOHALER clinical development program, included glycopyrrolate 15.6 mcg twice daily (BID) treatment arms, and are included in the overall safety database. Therefore, the efficacy of SEEBRI NEOHALER is based primarily on the dose-ranging trials in 471 subjects with COPD and the 2 placebo-controlled confirmatory trials in 867 subjects with COPD.

14.1 Dose Ranging Trial

Dose selection for glycopyrrolate 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 (QD) 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 1. Adjusted mean change from baseline in FEV1 (L) over 24 hours on Days 1 and 28

14.2 Confirmatory Trials

The clinical development program for SEEBRI NEOHALER included two (Trial 1 and Trial 2) similar 12-week, randomized, double-blinded, placebo-controlled, parallel-group trials in subjects with COPD designed to evaluate the efficacy of SEEBRI NEOHALER on lung function.

The 12-week trials treated 867 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-bronchodilator 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 867 subjects included in the efficacy analysis, 58% were male and 89% were Caucasian. They had a mean age of 63 years and an average smoking history of 53 pack-years, with 57% identified as current smokers, and 29% using inhaled corticosteroids. At screening, the mean post-bronchodilator percent predicted FEV1 was 55% (range: 30% to 83%), the mean post-bronchodilator percent FEV1/FVC was 51% (range: 24% to 69%), and the mean percent reversibility was 20% (0% to 169%).

Trial 1 and Trial 2 evaluated SEEBRI NEOHALER (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. In both trials, SEEBRI NEOHALER twice-daily demonstrated a larger increase in mean change from baseline in FEV1 AUC0-12h compared to placebo (see Table 2).

Table 2. Least Squares (LS) mean change from baseline in FEV1 (L) AUC(0-12h) at Day 85 in Trials 1 and 2 (Intent-to-Treat Population)

Treatment N

Change from baseline

LS Mean (SE)

Comparison Treatment difference

LS Mean (SE)

(95% CI)

Trial 1

SEEBRI NEOHALER

222 0.125 L (0.0162)

SEEBRI NEOHALER - Placebo

0.139 L (0.0225) (0.095, 0.184)

Placebo 216 -0.014 L (0.0165)

Trial 2

SEEBRI NEOHALER

215 0.115 L (0.0153)

SEEBRI NEOHALER - Placebo

0.123 L (0.0213) (0.081, 0.165)

Placebo 213 - 0.008 L (0.0153)

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 2. In Trial 2, the results for SEEBRI NEOHALER in FEV1 AUC0-12h were similar to those observed in Trial 1.

Figure 2. Adjusted mean change from baseline in FEV1 (L) over 12 hours on Days 1 and 85 in Trial 1 (All Patient Population)

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use SEEBRI NEOHALER safely and effectively. See full prescribing information for SEEBRI NEOHALER.

SEEBRI™ NEOHALER® (glycopyrrolate) inhalation powder, for oral inhalation useInitial U.S. Approval: 1961

INDICATIONS AND USAGE

SEEBRI NEOHALER is an anticholinergic indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). (1)

DOSAGE AND ADMINISTRATION

• For oral inhalation only. Do not swallow SEEBRI capsules. Only use SEEBRI capsules with the NEOHALER device. (2)

• Maintenance treatment of COPD: The inhalation of the powder contents of one SEEBRI capsule (15.6 mcg) twice-daily (2)

DOSAGE FORMS AND STRENGTHS

• Inhalation powder: SEEBRI capsules contain 15.6 mcg of glycopyrrolate inhalation powder for use with the NEOHALER device. (3)

CONTRAINDICATIONS

• History of known hypersensitivity to glycopyrrolate or to any of the ingredients. (4, 5.3)

WARNINGS AND PRECAUTIONS

• Do not initiate in acutely deteriorating COPD or to treat acute symptoms. (5.1)• If paradoxical bronchospasm occurs, discontinue SEEBRI NEOHALER immediately and institute

alternative therapy. (5.2)• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and

instruct patients to contact a physician immediately if symptoms occur. (5.4)• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder neck

obstruction and instruct patients to consult a physician immediately if symptoms occur. (5.5)

ADVERSE REACTIONS

Most common adverse reactions (incidence greater than or equal to 2% and higher than placebo) are upper respiratory tract infection and nasopharyngitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

• Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of SEEBRI NEOHALER with other anticholinergic-containing drugs. (7.2)

USE IN SPECIFIC POPULATIONS

• Use in patients with severe renal impairment should be considered if the potential benefit of the treatment outweighs the risk. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 1/2018

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Deterioration of Disease and Acute Episodes 5.2 Paradoxical Bronchospasm 5.3 Immediate Hypersensitivity Reactions 5.4 Worsening of Narrow-Angle Glaucoma 5.5 Worsening of Urinary Retention

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience7 DRUG INTERACTIONS 7.1 Sympathomimetics,

Methylxanthines, Steroids 7.2 Anticholinergics8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers

8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis,

Impairment of Fertility 13.2 Animal Toxicology14 CLINICAL STUDIES 14.1 Dose Ranging Trial 14.2 Confirmatory Trials16 HOW SUPPLIED/STORAGE

AND HANDLING17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

• Do not stop using SEEBRI NEOHALER or other medicines to control or treat your COPD unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.

• Call your healthcare provider or get emergency medical care right away if your breathing problems worsen with SEEBRI NEOHALER, you need to use your rescue medicine more often than usual, or your rescue inhaler medicine does not work as well for you at relieving your symptoms.

What are the possible side effects of SEEBRI NEOHALER?SEEBRI NEOHALER can cause serious side effects, including:• sudden shortness of breath immediately after use of SEEBRI NEOHALER. Sudden

shortness of breath may be life-threatening. If you have sudden breathing problems immediately after inhaling your medicine, stop taking SEEBRI NEOHALER and call your healthcare provider or go to the nearest hospital emergency room right away.

• serious allergic reactions. Stop using SEEBRI NEOHALER and call your healthcare provider or get emergency medical care right away if you get any of the following symptoms of a serious allergic reaction:

○ rash ○ hives ○ swelling of the tongue, lips, and face ○ difficulty breathing or swallowing• new or worsened eye problems including acute narrow-angle glaucoma. Acute

narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include:

○ eye pain or discomfort ○ nausea or vomiting ○ blurred vision ○ seeing halos or bright colors around lights ○ red eyes If you have these symptoms, stop taking SEEBRI NEOHALER and call your healthcare

provider right away before using another dose.• new or worsened urinary retention. People who use SEEBRI NEOHALER may develop

new or worse urinary retention. Urinary retention can be caused by a blockage in your bladder. Urinary retention can also happen in men who have a larger than normal prostate. Symptoms of urinary retention may include:

○ difficulty urinating ○ painful urination ○ urinating frequently ○ urination in a weak stream or drips If you have these symptoms, stop taking SEEBRI NEOHALER and call your healthcare

provider right away before taking another dose.

Common side effects of SEEBRI NEOHALER include upper respiratory tract infection, sore throat and runny nose.

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all of the possible side effects of SEEBRI NEOHALER. For more information, ask your healthcare provider or pharmacist.

Call your doctor or pharmacist for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SEEBRI NEOHALER?

• Store SEEBRI NEOHALER (inhaler and blister-packaged capsules) at room temperature between 68°F and 77°F (20°C and 25°C).

• Do not remove SEEBRI capsules from the blister card until you are ready to use a dose of SEEBRI NEOHALER.

• Do not store SEEBRI capsules in the NEOHALER inhaler.• Keep SEEBRI NEOHALER in a dry place away from moisture.• Keep SEEBRI NEOHALER and all medicines out of the reach of children.

General information about the safe and effective use of SEEBRI NEOHALER.

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information. Do not use SEEBRI NEOHALER for a condition for which it was not prescribed. Do not give SEEBRI NEOHALER to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information summarizes the most important information about SEEBRI NEOHALER. If you would like more information, talk with your healthcare provider or pharmacist. You can ask your healthcare provider or pharmacist for information that was written for healthcare professionals.

For more information about SEEBRI NEOHALER or to report side effects, go to www.Seebri.com or call 1-888-394-7377.

What are the ingredients in SEEBRI NEOHALER?Active ingredient: glycopyrrolateInactive ingredients: lactose monohydrate (contains milk proteins) and magnesium stearate.

Revised: July 2017

This Patient Information has been approved by the U.S. Food and Drug Administration. January 2017

Instructions for Use SEEBRI™ NEOHALER®

(SEE-Bri) (glycopyrrolate)

inhalation powder, for oral inhalation use

For Oral Inhalation OnlyDo not swallow SEEBRI capsules.

Follow the instructions below for using SEEBRI NEOHALER. You will breathe in (inhale) the medicine in the SEEBRI capsules from the NEOHALER inhaler. If you have any questions, ask your healthcare provider or pharmacist.

Your SEEBRI NEOHALER

SEEBRI NEOHALER consists of both the inhaler and the blister-packaged capsules. Each package contains SEEBRI capsules and a NEOHALER inhaler.• ( 1) NEOHALER inhaler which consists of a cap and a base (see figure below)• SEEBRI capsules come in blister cards to be used only in the NEOHALER inhaler

(see figure below)

Your inhaler is made to give you the medicine contained in the capsules.

Only use the NEOHALER inhaler contained in this pack. Do not use SEEBRI NEOHALER capsules with any other inhaler; do not use NEOHALER inhaler to take any other capsule medicine.

How to use your inhaler:

Step 1. Pull off cap.

Step 2. Open inhaler:

Hold the base of the inhaler firmly and tilt the mouthpiece to open the inhaler.

Step 3. Prepare capsule:

Separate 1 of the blisters from the blister card by tearing along the perforation.

Take 1 blister and peel away the protective backing to expose the capsule.

Do not push the capsule through the foil to remove it from the blister.

Step 4. Remove a SEEBRI capsule:

Capsules should always be stored in the blister and only removed immediately before use.

With dry hands, remove 1 capsule from the blister. Do not swallow the SEEBRI capsule.

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 SEEBRI NEOHALER compared with placebo at Day 1 and at Day 85 was 0.142L and 0.163L (Trial 1), and 0.137L and 0.148L (Trial 2), respectively.

In Trials 1 and 2, patients treated with SEEBRI NEOHALER used less daily rescue albuterol during the trial compared to patients treated with placebo.

The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Trials 1 and 2. In Trial 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) for the SEEBRI NEOHALER treatment arm was 49% compared to 41% for placebo [Odds Ratio: 1.43, 95% CI: 0.95, 2.15]. In Trial 2, the SGRQ responder rate for the SEEBRI NEOHALER treatment arm was 55% compared to 42% for placebo [Odds Ratio: 1.78; 95% CI: 1.17, 2.71].

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

SEEBRI NEOHALER contains SEEBRI (glycopyrrolate (15.6 mcg) inhalation powder) orange transparent capsules packaged in aluminum blister cards, one NEOHALER device, and FDA approved Patient Labeling.

Unit Dose (blister pack), Box of 60 (10 blister cards with 6 orange transparent capsules each) NDC 63402-815-60

Unit Dose (blister pack), Box of 6 (1 blister card with 6 orange transparent capsules) NDC 63402-815-06

The NEOHALER device consists of a white protective cap and a base with mouthpiece, capsule chamber and 2 orange 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].

• SEEBRI capsules should be used with the NEOHALER device only. Do not use the NEOHALER device with any other capsules.

• Store SEEBRI capsules in the blister protected from moisture. Remove the SEEBRI 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.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Not for Acute Symptoms

Inform patients that SEEBRI 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 in how it should be used [see Warnings and Precautions (5.1)].

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 SEEBRI NEOHALER without physician/healthcare provider guidance since symptoms may recur after discontinuation.

Paradoxical Bronchospasm

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

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.

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.

Instructions for Administering SEEBRI NEOHALER

It is important for patients to understand how to correctly administer SEEBRI capsules using the NEOHALER device [see Instructions for Use]. Instruct patients that SEEBRI 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 SEEBRI capsules are for oral inhalation only and must not be swallowed.

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

Inform patients to use one inhalation of SEEBRI 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 SEEBRI 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

© 2018 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: January 2018 902046R01-MKT1

PATIENT INFORMATIONSEEBRI™ NEOHALER®

(SEE-Bri)(glycopyrrolate)

inhalation powder, for oral inhalation use

Important: Do not swallow SEEBRI capsules. SEEBRI capsules are used only with the NEOHALER inhaler that comes with SEEBRI NEOHALER. Do not place a capsule in the mouthpiece of the NEOHALER inhaler.

Read this Patient Information that comes with SEEBRI NEOHALER before you start using it and each time you get a refill. There may be new information. This Patient Information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is SEEBRI NEOHALER?

SEEBRI NEOHALER is an anticholinergic medicine known as glycopyrrolate. • Anticholinergic medicines such as SEEBRI NEOHALER help the muscles around the airways

in your lungs stay relaxed to prevent symptoms such as wheezing, coughing, chest tightness, and shortness of breath. This makes it hard to breathe.

• SEEBRI NEOHALER is used for maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD). COPD is a chronic lung disease that includes chronic bronchitis, emphysema, or both.

• SEEBRI NEOHALER is for long-term use and should be taken 2 times each day to improve symptoms of COPD for better breathing.

• SEEBRI NEOHALER is not used to treat sudden symptoms of COPD. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden symptoms of COPD. If you do not have a rescue inhaler, contact your healthcare provider to have one prescribed for you.

• SEEBRI NEOHALER should not be used in children. It is not known if SEEBRI NEOHALER is safe and effective in children younger than 18 years of age.

Who should not use SEEBRI NEOHALER?

Do not use SEEBRI NEOHALER if you:• are allergic to glycopyrrolate, or any of the ingredients in SEEBRI NEOHALER.

Ask your healthcare provider if you are not sure. See “What are the ingredients in SEEBRI NEOHALER?” at the end of this leaflet for a complete list of ingredients in SEEBRI NEOHALER.

What should I tell my healthcare provider before using SEEBRI NEOHALER?

Before you use SEEBRI NEOHALER, tell your healthcare provider if you:• have kidney problems.• have eye problems such as glaucoma. SEEBRI NEOHALER may make your glaucoma worse.• have prostate or bladder problems, or problems passing urine. SEEBRI NEOHALER may make

these problems worse.• have any other medical conditions.• are pregnant or plan to become pregnant. It is not known if SEEBRI NEOHALER can harm

your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if the medicine in SEEBRI NEOHALER

passes into your breast milk and if it can harm your baby. You and your healthcare provider should decide if you will take SEEBRI NEOHALER or breastfeed.

• are allergic to SEEBRI NEOHALER or any of its ingredients, any other medicines, or food products.

SEEBRI NEOHALER contains lactose (milk sugar) and a small amount of milk proteins. It is possible that allergic reactions may happen in people who have a severe milk protein allergy.

Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. SEEBRI NEOHALER may affect the way other medicines work, and other medicines can affect how SEEBRI NEOHALER works. Using SEEBRI NEOHALER with other medicines may cause serious side effects.

Especially tell your healthcare provider if you take anticholinergics (including umeclidinium, tiotropium, ipratropium, aclidinium, glycopyrrolate).

Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use SEEBRI NEOHALER?

Read the step-by-step instructions for using SEEBRI NEOHALER at the end of this Patient Information.• Do not use SEEBRI NEOHALER unless your healthcare provider has taught you how to use

the inhaler and you understand how to use it correctly.• Use SEEBRI NEOHALER exactly as your healthcare provider tells you to use it. Do not use

SEEBRI NEOHALER more often than prescribed for you.• Do not swallow SEEBRI capsules. Only use SEEBRI capsules with the NEOHALER inhaler.• Use 1 SEEBRI capsule inhaled through the NEOHALER inhaler 2 times each day

(1 capsule in the morning and 1 capsule in the evening).• To make sure the full dose has been taken, you should open the inhaler to check that there is

no powder left in the capsule. As long as the capsule is empty, you have received 1 full dose. • If you miss a dose of SEEBRI NEOHALER, take it as soon as you remember. Take your next

dose at your usual time. ○ Do not use 2 capsules at 1 time. ○ Do not use more than 2 capsules in a day.• SEEBRI capsules should always be stored in the blister strip and only removed immediately

before use. Peel the backing foil away from the blister to open it, do not push the capsule through the foil.

• Always use the new NEOHALER inhaler that is provided with each new prescription.• SEEBRI NEOHALER does not relieve sudden symptoms of COPD. Always have a rescue

inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler medicine, call your healthcare provider to have a rescue inhaler prescribed for you.

Step 5. Insert capsule:

Place the capsule into the capsule chamber.

Do not place a capsule directly into the mouthpiece.

Step 6. Close the inhaler:

Close the inhaler fully. You should hear a ‘click’ as it fully closes.

Step 7. Pierce the capsule:

Hold the inhaler upright with the mouthpiece pointing up.

Press both piercing buttons together firmly at the same time. You should hear a ‘click’ as the capsule is being pierced.

Do not press the piercing buttons more than 1 time.

Step 8. Release the piercing buttons fully.

Step 9. Breathe out:

Before placing the mouthpiece in your mouth, breathe out fully.

Do not blow into the mouthpiece.

Step 10. Inhale the medicine:

Before breathing in: • Hold the inhaler as shown in the figure for Step 10. Make sure

that the piercing buttons are to the left and right of the inhaler (not up and down).

• Place the mouthpiece in your mouth and close your lips firmly around the mouthpiece.

• Breathe in rapidly but steadily, as deeply as you can. Do not press the piercing buttons.

Step 11. Note: As you breathe in through the inhaler, the capsule spins around in the

chamber and you should hear a whirring noise. You may experience a sweet flavor as you inhale the medicine.

If you do not hear a whirring noise, the capsule may be stuck in the capsule chamber. If this occurs, open the inhaler and carefully loosen the capsule by tapping the base of the inhaler. Do not press the piercing buttons to loosen the capsule. (Repeat steps 9 and 10 if necessary).

Step 12. Hold breath:

Continue to hold your breath for at least 5 to 10 seconds or as long as comfortably possible while removing the inhaler from your mouth. Then breathe out.

Open the inhaler to see if any powder is left in the capsule. If there is powder left in the capsule, close the inhaler and repeat steps 9 to 12. Most people are able to empty the capsule with 1 or 2 inhalations.

Some people may cough soon after inhaling the medicine. If you cough, don’t worry; as long as the capsule is empty, you have received 1 full dose.

Step 13. Remove capsule:

After you have finished taking your dose of SEEBRI NEOHALER, open the mouthpiece again, remove the empty capsule by tipping it out of the capsule chamber, and throwing it away. Close the inhaler and replace the cap.

Do not leave the used capsules in the NEOHALER inhaler.

Additional Information:

Occasionally, very small pieces of the capsule can get past the screen and enter your mouth. If this happens, you may be able to feel these pieces on your tongue. It is not harmful if these pieces are swallowed or inhaled. The chances of the capsule shattering (breaking apart) will be increased if the capsule is pierced more than once (see Step 7). Therefore, it is recommended that you follow the storage directions, remove the capsule from the blister immediately before use, and pierce each capsule only once.

How to clean your inhaler:

Cleaning the inhaler device is not necessary; however, if you want to clean your inhaler, wipe the mouthpiece inside and outside with a clean, dry, lint-free cloth, or you may use a clean, dry, soft brush to wipe the inhaler between uses to remove any powder residue. Keep the inhaler dry.

REMEMBER:

• Do not swallow SEEBRI capsules.• Only use the NEOHALER inhaler contained in this pack.• Do not place a SEEBRI NEOHALER capsule directly into the mouthpiece of the NEOHALER inhaler.• Do not blow into the mouthpiece of the NEOHALER inhaler.• Always release the piercing buttons before inhalation.• Do not press the piercing buttons more than once.• Do not take the NEOHALER inhaler apart.• Always use the new NEOHALER inhaler that comes with your new SEEBRI NEOHALER

medication pack.• Do not use SEEBRI capsules with inhalers from other medicines.

How should I store SEEBRI NEOHALER?

• Store SEEBRI NEOHALER (inhaler and blister-packaged capsules) at room temperature between 68°F and 77°F (20°C and 25°C).

• Do not remove SEEBRI capsules from the blister card until you are ready to use a dose of SEEBRI NEOHALER.

• Do not store SEEBRI capsules in the NEOHALER inhaler.• Keep SEEBRI NEOHALER in a dry place away from moisture.• Keep SEEBRI NEOHALER and all medicines out of the reach of children.

SEEBRI is a trademark of Novartis AG. NEOHALER is a registered trademark of Novartis AG.

Manufactured for Sunovion Pharmaceuticals Inc. Marlborough MA 01752 USA

© 2017 Sunovion Pharmaceuticals Inc.

Revised: July 2017

This Instructions for Use has been approved by the U.S. Food and Drug Administration. January 2017

Cap

Base BlistersCapsule chamber

Mouthpiece

Screen

Piercing button

Inhaler Blister card Inhaler base

FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

LONHALA MAGNAIR is indicated for the long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

2. DOSAGE AND ADMINISTRATION

For oral inhalation only. Do not swallow LONHALA solution. LONHALA vials should only be used with MAGNAIR [see Overdosage (10)].

The recommended dose of LONHALA is the inhalation of the contents of one LONHALA vial twice-daily using MAGNAIR. LONHALA vials should only be administered with MAGNAIR. Patients should be instructed on the correct use of this drug product and device.

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

Store LONHALA vials in the foil pouch, and only remove IMMEDIATELY BEFORE USE with MAGNAIR.

No dosage adjustment is required for geriatric patients, patients with hepatic impairment, or patients with mild to moderate renal impairment.

3. DOSAGE FORMS AND STRENGTHS

LONHALA Inhalation Solution is supplied as a sterile, clear, colorless, aqueous solution for inhalation in a unit-dose single-use low-density polyethylene (LDPE) vial. Each 1 mL vial contains 25 mcg of glycopyrrolate.

4. CONTRAINDICATIONS

LONHALA MAGNAIR is contraindicated in patients with a hypersensitivity to glycopyrrolate or any of the ingredients [see Warnings and Precautions (5.3)].

5. WARNINGS AND PRECAUTIONS

5.1 Deterioration of Disease and Acute Episodes

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

LONHALA MAGNAIR should not be used as rescue therapy for the treatment of acute episodes of bronchospasm. LONHALA MAGNAIR 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.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If LONHALA MAGNAIR no longer controls symptoms of bronchoconstriction the patient’s inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more inhalations of a 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 LONHALA MAGNAIR beyond the recommended dose is not appropriate in this situation.

5.2 Paradoxical Bronchospasm

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

5.3 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of LONHALA MAGNAIR. If signs suggesting allergic reactions occur, in particular, angioedema (including difficulties in breathing or swallowing, swelling of the tongue, lips, and face), urticaria, or skin rash, LONHALA MAGNAIR should be discontinued immediately and alternative therapy instituted.

5.4 Worsening of Narrow-Angle Glaucoma

LONHALA MAGNAIR 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.

5.5 Worsening of Urinary Retention

LONHALA MAGNAIR 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.

6. ADVERSE REACTIONS

The following adverse reactions are described in greater detail in other sections: • Paradoxical bronchospasm [see Warnings and Precautions (5.2)] • Immediate hypersensitivity reactions [see Warnings and Precautions (5.3)]• Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.4)] • Worsening of urinary retention [see Warnings and Precautions (5.5)]

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The LONHALA MAGNAIR safety database included 2379 subjects with COPD in two 12-week efficacy studies and one 48-week long-term safety study. A total of 431 subjects received treatment with LONHALA MAGNAIR 25 mcg twice-daily (BID). The safety data described below are based on the two 12-week trials and the one 48-week trial.

12-Week Trials

LONHALA MAGNAIR was studied in two 12-week placebo-controlled trials in subjects with COPD. In these trials, 431 subjects were treated with LONHALA MAGNAIR at the recommended dose of 25 mcg twice daily. The population had a mean age of 63 years (ranging from 40 to 87 years), with 56% males, 90% Caucasian, and a mean post-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 52% of predicted normal value (20%-80%) at study entry. The study population also included subjects with pre-existing cardiovascular disease as well as subjects with continued use of stable long-acting bronchodilator (LABA) +/- inhaled corticosteroid (ICS) and ipratropium bromide background therapy. Subjects with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these studies.

Table 1 shows the most common adverse reactions incidence greater than or equal to 2.0% in the LONHALA MAGNAIR group and higher than placebo in the two 12-week placebo-controlled trials.

The proportion of subjects who discontinued treatment due to adverse reactions was 5% for the LONHALA MAGNAIR-treated subjects and 9% for placebo-treated subjects.

Table 1. Adverse Reactions with LONHALA MAGNAIR ≥2.0% Incidence and Higher than Placebo

Placebo(N=430)

N (%)

LONHALA MAGNAIR 25 mcg BID(N=431)

N (%)

Dyspnea 13 (3.0) 21 (4.9)

Urinary Tract Infection 6 (1.4) 9 (2.1)

Other adverse reactions defined as events with an incidence of ≥1.0% but less than 2.0% with LONHALA MAGNAIR but more common than with placebo included the following: wheezing, upper respiratory tract infection, nasopharyngitis, oedema peripheral, and fatigue.

48-Week Trial

In a long-term open-label safety trial, 1086 subjects were treated for up to 48-weeks with LONHALA MAGNAIR 50 mcg twice-daily (N=620) or tiotropium (N=466). The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy studies described above. The adverse reactions reported in the long-term safety trial were consistent with those observed in the placebo-controlled studies of 12-weeks. Adverse reactions that occurred at a frequency greater than that seen in either active treatment dose in the pooled 12-week placebo controlled studies and ≥ 2.0% were: diarrhea, edema peripheral, bronchitis, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, urinary tract infection, back pain, headache, Chronic Obstructive Pulmonary Disease, cough, dyspnea, oropharyngeal pain, and hypertension.

7. DRUG INTERACTIONS

7.1 Sympathomimetics and Steroids

In clinical studies, concurrent administration of glycopyrrolate and other drugs commonly used in the treatment of COPD including sympathomimetics (long and short-acting beta2 agonists), anticholinergics (short-acting anti-muscarinic antagonists) and oral and inhaled steroids showed no increases in adverse drug reactions.

7.2 Anticholinergics

There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid unnecessary co-administration of LONHALA MAGNAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies in pregnant women. LONHALA MAGNAIR should only be used during pregnancy if the expected benefit to the patient outweighs the potential risk to the fetus. Women should be advised to contact their physician if they become pregnant while taking LONHALA MAGNAIR. In animal reproduction studies, there were no teratogenic effects in Wistar rats and New Zealand White rabbits at inhaled doses approximating 1521 and 580 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) based on an AUC comparison [see Data].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Labor or Delivery

The potential effect of LONHALA MAGNAIR on labor and delivery is unknown. LONHALA MAGNAIR should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.

Data

Animal Data

Developmental studies in Wistar rats and New Zealand White rabbits in which glycopyrrolate was administered by inhalation during the period of organogenesis did not result in evidence of teratogenicity at exposures approximately 1521 and 580 times, respectively, the MRHDID of LONHALA MAGNAIR based on a comparison of plasma AUC levels (maternal doses up to 3.8 mg/kg/day in rats and 4.4 mg/kg/day in rabbits).

Glycopyrrolate had no effects on peri-natal and post-natal development in rats following subcutaneous exposure of approximately 1137 times the MRHDID of LONHALA MAGNAIR based on an AUC comparison (at a maternal dose of up to 1.885 mg/kg/day).

8.2 Lactation

Risk Summary

There are no data on the presence of glycopyrrolate or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. However, in a study of lactating rats, glycopyrrolate was present in the milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LONHALA MAGNAIR and any potential adverse effects on the breastfed infant from LONHALA MAGNAIR or from the underlying maternal condition.

Data

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

8.4 Pediatric Use

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

8.5 Geriatric Use

Based on available data, no adjustment of the dosage of LONHALA MAGNAIR in geriatric patients is warranted. LONHALA MAGNAIR 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 LONHALA MAGNAIR, 41% were aged 65 and older, while 8% 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

No dose adjustment is required for patients with mild and moderate renal impairment. The effects of renal impairment on the pharmacokinetics of glycopyrrolate have not been studied [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is required for patients with hepatic impairment. The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied [see Clinical Pharmacology (12.3)].

10. OVERDOSAGE

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, orally inhaled administration of LONHALA MAGNAIR at a total daily dose of 200 mcg for 28 consecutive days (maximum of 1 mg) was well tolerated. Pharmacokinetic results from several studies conducted in COPD patients showed that a single, well tolerated dose of 1000 mcg had a Cmax of 1534 pg/mL and AUC0-inf of 5271 pg*hr/mL. These values are approximately 44 fold and 21 fold higher, respectively, than the estimated daily Cmax of 34.5 pg/mL and AUC0-inf of 255 pg*hr/mL for a 25 mcg BID dose regimen at steady-state.

11. DESCRIPTION

LONHALA MAGNAIR consists of LONHALA vials and a MAGNAIR nebulization system. LONHALA (glycopyrrolate) Inhalation Solution is a sterile, clear, colorless, aqueous solution for oral inhalation.

Glycopyrrolate USP, the active component of LONHALA Inhalation Solution, is chemically described as (3RS)-3-[(2SR)-(2-cyclopentyl-2-hydroxy-2-penylacetyl)oxy]-1,1-dimethlypyrrolidinium bromide. Glycopyrrolate is a synthetic quaternary ammonium compound that acts as a competitive antagonist at muscarinic acetylcholine receptors, also referred to as an anticholinergic. Glycopyrrolate, C19H28BrNO3, is a white, odorless, crystalline powder that is soluble in water and in alcohol. It has a molecular mass of 398.33. The structural formula is:

The inactive ingredients in LONHALA are: citric acid monohydrate, sodium chloride, sodium hydroxide and water for injection.

LONHALA Inhalation Solution is supplied in low-density polyethylene (LDPE) unit dose vials, each containing 1.0 mL of the solution. Each unit-dose vial contains 25 mcg of glycopyrrolate in a sterile, isotonic saline solution, pH-adjusted to 4.0 with citric acid and sodium hydroxide.

Like all other nebulized treatments, the amount delivered to the lungs will depend upon patient factors. Under standardized in vitro testing per USP<1601> adult breathing pattern (500 mL tidal volume, 15 breaths per minute, and inhalation: exhalation ratio of 1:1), the mean delivered dose from the mouthpiece was approximately 14.2 mcg of glycopyrrolate (equivalent to 11.4 mcg glycopyrronium and 56.8% label claim). The mass median aerodynamic diameter (MMAD) of the nebulized aerosol particles/droplets is 3.71 μm 95% CI (2.92 - 4.49 μm) as determined using the Next Generation Impactor (NGI) method. The mean nebulization time was approximately 2 to 3 minutes.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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:

In the dose ranging and confirmatory clinical studies, the administration of LONHALA MAGNAIR did not demonstrate any clinically relevant changes in cardiac function including: vital signs (heart rate, blood pressure), electrocardiograms (including QTc) and Holter monitoring. In addition, no major adverse cardiovascular events (MACE) were reported following the administration of LONHALA MAGNAIR 25 mcg in any clinical study.

12.3 Pharmacokinetics

Absorption

Following oral inhalation using MAGNAIR, glycopyrrolate was rapidly absorbed and reached peak plasma levels <20 minutes post dose.

In patients with COPD, pharmacokinetic steady-state plasma levels of glycopyrrolate were reached within one week of the start of treatment. A twice daily dose regimen leads to approximately 2-3 fold accumulation of systemic glycopyrrolate exposure at steady-state.

Distribution

The in vitro human plasma protein binding of glycopyrrolate was 38% to 41% at concentrations of 1 to 10 ng/mL.

Metabolism

In vitro metabolism studies show glycopyrrolate hydroxylation resulting in a variety of mono- and bis- hydroxylated metabolites and direct hydrolysis resulting in the formation of a carboxylic acid derivative (M9). Further in vitro investigations showed that multiple CYP isoenzymes contribute to the oxidative biotransformation of glycopyrrolate and the hydrolysis to M9 is likely to be catalyzed by members from the cholinesterase family pre-systemically and/or via first pass metabolism from the swallowed dose fraction of orally inhaled glycopyrrolate.

Elimination

After intravenous administration of [3H]-labelled glycopyrrolate to humans, the mean urinary excretion of radioactivity in 48 hours amounted to 85% of the dose. A further 5% of the dose was found in the bile.

Renal elimination of parent drug accounts for about 60 to 70% of total clearance of systemically available glycopyrrolate whereas non-renal clearance processes account for about 30 to 40%. Biliary clearance contributes to the non-renal clearance, but the majority of non-renal clearance is thought to be due to metabolism.

Drug Interactions

In vitro inhibition studies demonstrated that glycopyrrolate has no relevant capacity to inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5, the efflux transporters MDR1, MRP2 or MXR, and the uptake transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. In vitro enzyme induction studies did not indicate a clinically relevant induction by glycopyrrolate for cytochrome P450 isoenzymes, or for UGT1A1 and the transporters MDR1 and MRP2.

There is potential for additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of LONHALA MAGNAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects [see Warnings and Precautions (5.4, 5.5) and Adverse Reactions (6)].

Specific Populations

A population pharmacokinetic analysis of data in COPD patients indicated no clinically relevant effect of age (41 to 80 years) or body weight (40.1 to 154.8 kg) on systemic exposure to glycopyrrolate. In addition, there was no evidence of clinically significant ethnic/race effect.

Renal Impairment

The effects of renal impairment on the pharmacokinetics of glycopyrrolate have not been studied [see Use in Specific Populations (8.6)].

Hepatic Impairment

The effects of hepatic impairment on the pharmacokinetics of glycopyrrolate have not been studied. Glycopyrrolate is cleared predominantly from systemic circulation by renal excretion [see Use in Specific Populations (8.7)].

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies of glycopyrrolate did not result in an increase in the incidence of tumors in a 2-year inhalation study of glycopyrrolate in Wistar rats at doses up to 0.56 mg/kg/day, approximately 143 times the MRHDID of LONHALA MAGNAIR in adults on an AUC basis. Also, no evidence of tumorigenicity occurred in a 26-week oral (gavage) study in male and female TgrasH2 mice that received glycopyrrolate at doses up to 93.8 and 125.1 mg/kg/day, respectively, approximately 66 times the MRHDID of LONHALA MAGNAIR.

Glycopyrrolate was not mutagenic in the following genotoxicity assays: the in vitro Ames assay, in vitro human lymphocyte chromosomal aberration assay, and in vivo rat bone marrow micronucleus assay.

Impairment of fertility was observed in male and female Wistar rats at a subcutaneous glycopyrrolate dose of 1.88 mg/kg/day (approximately and 2035 and 1136 times, respectively, the MRHD of LONHALA MAGNAIR on an AUC basis) based upon findings of decreased implantation sites and corresponding reduction of live fetuses. No effects on fertility and reproductive performance occurred in male and female rats at a subcutaneous glycopyrrolate dose of 0.63 mg/kg/day, approximately 384 times the MRHD of LONHALA MAGNAIR on an AUC basis).

14. CLINICAL STUDIES

The safety and efficacy of LONHALA MAGNAIR were evaluated in 2 dose-ranging studies, 2 placebo-controlled confirmatory studies (12-week studies), and a 48-week long-term safety study. The efficacy of LONHALA MAGNAIR is based primarily on the dose-ranging studies in 378 subjects with COPD and the 2 placebo-controlled confirmatory studies in 1293 subjects with COPD.

14.1 Dose Ranging Studies

Dose selection for the confirmatory COPD studies for LONHALA MAGNAIR was supported by two studies. Study A was a randomized, double-blind, placebo-controlled, parallel arm study with a 28-day treatment period. The study included LONHALA MAGNAIR doses of placebo, 12.5 mcg, 25 mcg, 50 mcg, and 100 mcg twice daily. The Study demonstrated a dose-response effect on peak and trough FEV1 over 24-hour dosing period in subjects treated with LONHALA MAGNAIR twice daily [Figure 1 (Day 1) and Figure 2 (Day 28)]. The LS mean differences in trough FEV1 from baseline after 28 days compared to placebo for the 12.5 mcg, 25 mcg, 50 mcg, and 100 mcg twice daily doses were 0.117 L (95% CI: 0.037, 0.197); 0.128 L (95% CI: 0.048, 0.209), 0.146 L (95% CI: 0.067, 0.226), and 0.177 L (95% CI: 0.099, 0.255), respectively. In Study A, all subjects in each treatment group (N=282) had FEV1 AUC0-12h serial spirometry assessments while a subset of subjects (N=125; shown in Figure 1 and Figure 2 below) had extended FEV1 AUC12-24h assessments on Days 1 and 28.

Study B was a randomized, six-way, crossover study with 7-day treatment periods separated by 5-7-day washout periods. Study B included LONHALA MAGNAIR doses of placebo, 3 mcg, 6.25 mcg, 12.5 mcg, and 50 mcg twice daily with aclidinium bromide 400 mcg BID as an active control.

The dose-ranging results from Study A and Study B supported the evaluation of LONHALA MAGNAIR 25 mcg and 50 mcg twice-daily in the confirmatory COPD trials. The results of Study A are reported in Figure 1 below.

Figure 1: LS Mean Change from Baseline in FEV1 (L) Over Time on Day 1 (Study A)

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LONHALA® MAGNAIR® safely and effectively. See full prescribing information for LONHALA MAGNAIR.

LONHALA MAGNAIR (glycopyrrolate) inhalation solution, for oral inhalation use Initial U.S. Approval: 1961

INDICATIONS AND USAGE

LONHALA MAGNAIR is an anticholinergic indicated for the long-term, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). (1)

DOSAGE AND ADMINISTRATION

• For oral inhalation only. Do not swallow LONHALA solution. Only use LONHALA vials with MAGNAIR. (2)• Maintenance treatment of COPD: The contents of one LONHALA vial twice-daily. (2)

DOSAGE FORMS AND STRENGTHS

LONHALA Inhalation Solution is supplied as a sterile solution for inhalation in a unit-dose single-use low-density polyethylene (LDPE) vial. Each 1 mL vial contains 25 mcg of glycopyrrolate. (3)

CONTRAINDICATIONS

LONHALA MAGNAIR is contraindicated in patients with a hypersensitivity to glycopyrrolate or any of the ingredients. (4)

WARNINGS AND PRECAUTIONS

• Do not initiate in acutely deteriorating COPD or to treat acute symptoms. (5.1)• If paradoxical bronchospasm occurs, discontinue LONHALA MAGNAIR immediately and institute

alternative therapy. (5.2)• Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma

and instruct patients to contact a physician immediately if symptoms occur. (5.4)• Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder

neck obstruction and instruct patients to consult a physician immediately if symptoms occur. (5.5)

ADVERSE REACTIONS

Most common adverse reactions (incidence greater than or equal to 2.0% and higher than placebo) are dyspnea and urinary tract infection. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administration of LONHALA MAGNAIR with other anticholinergic-containing drugs. (7.2)

USE IN SPECIFIC POPULATIONS

Use in patients with severe renal impairment should be considered if the potential benefit of the treatment outweighs the risk. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 06/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE2. DOSAGE AND ADMINISTRATION3. DOSAGE FORMS AND STRENGTHS4. CONTRAINDICATIONS5. WARNINGS AND PRECAUTIONS 5.1 Deterioration of Disease and Acute Episodes 5.2 Paradoxical Bronchospasm 5.3 Immediate Hypersensitivity Reactions

5.4 Worsening of Narrow-Angle Glaucoma 5.5 Worsening of Urinary Retention6. ADVERSE REACTIONS 6.1 Clinical Trials Experience7. DRUG INTERACTIONS 7.1 Sympathomimetics and Steroids 7.2 Anticholinergics8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation

8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 10. OVERDOSAGE11. DESCRIPTION12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis,

Impairment of Fertility14. CLINICAL STUDIES 14.1 Dose Ranging Studies 14.2 Confirmatory Studies16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage and Handling17. PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

Figure 2: LS Mean Change from Baseline in FEV1 (L) Over Time on Day 28 (Study A)

14.2 Confirmatory Studies

There were 2 confirmatory studies (Study 1 and Study 2) for LONHALA MAGNAIR. Both studies were randomized, double-blind, placebo-controlled, parallel-group 12-week studies in subjects with COPD designed to evaluate the efficacy of LONHALA MAGNAIR on lung function. These studies treated subjects who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than or equal to 10 pack-years, a post-bronchodilator FEV1 less than or equal to 80% of predicted, and an FEV1/FVC ratio less than 0.7. Subjects also had pre-existing or concurrent cardiovascular disease and stable, background LABA ± ICS and SAMA use were permitted. Subjects in Study 1 and Study 2 had a mean age of 63 years, were primarily male (56%), Caucasian (90%), and current smokers (53%) with an average smoking history of 52 pack-years. At screening, the mean post-bronchodilator percent predicted FEV1 was 52% (range: 20% to 80%), the mean post-bronchodilator percent FEV1/FVC was 54% (range: 20% to 71%), and the mean percent reversibility was 18% (range: -33% to 86%).

Study 1 and Study 2 evaluated LONHALA MAGNAIR (glycopyrrolate) 25 mcg and 50 mcg twice-daily and placebo twice-daily. The primary endpoint was the change from baseline in trough FEV1 at Day 84 compared with placebo. LONHALA MAGNAIR twice-daily demonstrated a larger increase in LS mean change from baseline in trough FEV1 compared to placebo. Compared to LONHALA MAGNAIR 25 mcg twice daily, LONHALA MAGNAIR 50 mcg twice daily did not provide sufficient additional benefit on a variety of endpoints, including FEV1, to support use of higher doses. Table 2 presents the results from Studies 1 and 2 for LONHALA MAGNAIR 25 mcg twice daily.

Table 2. LS Mean change from baseline in Trough FEV1 (L) on Day 84 (ITT Population*)

Treatment N Change from baseline LS Mean (SE)

Comparison Treatment Difference LS Mean (SE)

95% CI

Study 1

LONHALA MAGNAIR 25 mcg BID

217 0.089 (0.014)

LONHALA MAGNAIR - Placebo

0.096 (0.019)

0.059, 0.133

Placebo 218 -0.008 (0.014)

Study 2

LONHALA MAGNAIR 25 mcg BID

214 0.092 (0.014)

LONHALA MAGNAIR - Placebo

0.081 (0.020)

0.042, 0.120

Placebo 212 0.011 (0.015)

*Study results are from a treatment policy strategy which analyzes all collected data, including data for some patients who discontinued study treatment prior to Week 12 and may have received other COPD treatment but were followed. Analyses of efficacy data measured only while on randomized blinded study treatment showed similar results.

In Study 1, serial spirometric evaluations throughout the 12-hour dosing interval were performed in a subset of subjects on Day 1 and Day 84. The spirometric curves from Study 1 on Day 1 and Day 84 are displayed in Figure 3 and Figure 4.

Figure 3: Mean Change from Baseline in FEV1 (L) Over Time on Day 1 (Substudy Population)

Figure 4: Mean Change from Baseline in FEV1 (L) Over Time on Day 84 (Substudy Population)

The peak FEV1 was defined as the highest postdose FEV1 within the first 12 hours after morning dosing for each subject on Days 1 and 84, respectively, for the substudy population.

The mean peak FEV1 improvement from baseline for LONHALA MAGNAIR on Day 1 and on Day 84 in the subset of subjects was 0.228 L and 0.214 L (Study 1) respectively.

The St. George’s Respiratory Questionnaire (SGRQ) was assessed in Studies 1 and 2. In Study 1, the SGRQ responder rate (defined as an improvement in score of 4 or more as threshold) for the LONHALA MAGNAIR 25 mcg treatment arm was 51% compared to 40% for placebo [Odds Ratio:1.55; 95% CI: 1.03, 2.33]. In Study 2, the SGRQ responder rate for the LONHALA MAGNAIR 25 mcg treatment arm was 41% compared to 29% for placebo [Odds Ratio: 1.72; 95% CI: 1.11, 2.67].

16. HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

LONHALA MAGNAIR is supplied as a 1 mL sterile, clear, colorless, aqueous solution in low-density polyethylene (LDPE) unit-dose vials overwrapped in foil. LONHALA MAGNAIR is available in a Starter Kit containing 60 unit-dose vials packaged with one MAGNAIR, and FDA approved patient labeling. LONHALA MAGNAIR is also supplied in a Refill Kit containing 60 unit-dose vials packaged with a MAGNAIR Replacement Handset and FDA approved patient labeling.

Package Configuration Dosage Strength NDC

Starter Kit with 30 day supply (30 foil pouches with 2 vials per pouch) and complete MAGNAIR Nebulizer System

25 mcg NDC: 63402-201-00

Refill Kit with 30 day supply (30 foil pouches with 2 vials per pouch) and MAGNAIR Replacement Handset

25 mcg NDC: 63402-301-01

10140-02-MKT1

®®

16.2 Storage and Handling

Store LONHALA Inhalation Solution in the protective foil pouch at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].

• LONHALA vials should be used with MAGNAIR only. Do not use MAGNAIR with any other vials.• Store LONHALA vials in the protective foil pouch. After opening the foil pouch, unused unit-dose vials

should be returned to, and stored in, the foil pouch. Once a foil pouch is opened, discard the vials if not used within 7 days. An opened unit-dose vial should be used right away. Discard any unit-dose vial if the solution is not colorless.

Always use the MAGNAIR Replacement Handset parts that come with each LONHALA MAGNAIR refill prescription.

Keep out of the reach of children.

17. PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Not for Acute Symptoms: Inform patients that LONHALA MAGNAIR 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 in how it should be used [see Warnings and Precautions (5.1)].

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 LONHALA MAGNAIR without physician/provider guidance since symptoms may recur after discontinuation.

Paradoxical Bronchospasm: Inform patients that LONHALA MAGNAIR can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue LONHALA MAGNAIR.

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 if any of these signs or symptoms develop.

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 if any of these signs or symptoms develop.

Instructions for Administering LONHALA MAGNAIR

It is important for patients to understand how to correctly administer LONHALA vials using MAGNAIR [see Instructions for Use]. Instruct patients that LONHALA vials should only be administered via MAGNAIR and MAGNAIR should not be used for administering other medications. Patients should be instructed not to inject or swallow the LONHALA solution.

Instruct patients to store LONHALA vials in the sealed foil pouch and to only open the foil pouch to remove a LONHALA vial immediately before use. Inform patients that unopened vials should be returned to the opened foil pouch for use at their next treatment and discarded if not used within 7 days or it may not be as effective.

Inform patients to use one inhalation of LONHALA MAGNAIR orally twice daily (1 vial in the morning and 1 vial in the evening) at the same time every day.

Inform patients that if they miss a dose of LONHALA MAGNAIR, they should use their next vial at the usual time. Instruct patients to not use 2 vials at one time and to not use more than 2 vials in a day. Patients should throw the plastic dispensing vials away immediately after use. Due to their small size, the vials pose a danger of choking to young children.

Inform patients treated with LONHALA MAGNAIR that a Refill Kit will be provided to them on a monthly basis. The Refill Kit will include foil pouches containing 60 vials of LONHALA (2 vials of LONHALA in each pouch; 1 vial per dose), and 1 MAGNAIR Replacement Handset (containing only these replacement parts: Medication cap, Handset body, Mouthpiece, and Aerosol head; Manufacturer’s Instructions for Use booklet).

Important: Instruct patients to throw away the old Handset parts after using 60 vials of LONHALA and use the replacement Handset parts with the next 60 vials of LONHALA.

Manufactured for Sunovion Respiratory Development Inc., 84 Waterford Drive Marlborough, MA 01752 USA a direct wholly-owned subsidiary of Sunovion Pharmaceuticals Inc. Made in Germany.

For Sunovion 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.

©2019 Sunovion Pharmaceuticals Inc. All rights reserved.

PATIENT INFORMATION LONHALA MAGNAIR (lon-HAH-luh MAGG-nair)

(glycopyrrolate) inhalation solution, for oral inhalation use

Important: For oral inhalation only. Do not inject or swallow the LONHALA medicine. LONHALA vials are used only with the MAGNAIR device. Do not use MAGNAIR with any other medicine.

Read this Patient Information that comes with LONHALA MAGNAIR before you start using it and each time you get a refill. There may be new information. This Patient Information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is LONHALA MAGNAIR?

LONHALA MAGNAIR is an anticholinergic medicine known as glycopyrrolate. • Anticholinergic medicines such as LONHALA MAGNAIR help the muscles

around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, coughing, chest tightness, and shortness of breath. This makes it hard to breathe.

• LONHALA MAGNAIR is used for maintenance treatment of Chronic Obstructive Pulmonary Disease (COPD). COPD is a long-term (chronic) lung disease that includes chronic bronchitis, emphysema, or both.

• LONHALA MAGNAIR is for long-term use and should be taken 2 times each day to improve symptoms of COPD for better breathing.

• LONHALA MAGNAIR is not used to treat sudden symptoms of COPD. Always have a short-acting beta2-agonist medicine (rescue inhaler) with you to treat sudden symptoms of COPD. If you do not have a rescue inhaler, contact your healthcare provider to have one prescribed for you.

• LONHALA MAGNAIR should not be used in children. It is not known if LONHALA MAGNAIR is safe and effective in children younger than 18 years of age.

Do not use LONHALA MAGNAIR if you: • are allergic to glycopyrrolate, or any of the ingredients in LONHALA MAGNAIR.

Ask your healthcare provider if you are not sure. See “What are the ingredients in LONHALA MAGNAIR?” at the end of this Patient Information leaflet for a complete list of ingredients in LONHALA MAGNAIR.

Before using LONHALA MAGNAIR, tell your healthcare provider about all of your medical conditions, including if you: • have kidney problems. • have eye problems such as glaucoma. LONHALA MAGNAIR may make your

glaucoma worse. • have prostate or bladder problems, or problems passing urine. LONHALA

MAGNAIR may make these problems worse. • are pregnant or plan to become pregnant. It is not known if LONHALA MAGNAIR

can harm your unborn baby. • are breastfeeding or plan to breastfeed. It is not known if the medicine in

LONHALA MAGNAIR passes into your breast milk and if it can harm your baby. You and your healthcare provider should decide if you will take LONHALA MAGNAIR or breastfeed.

• are allergic to LONHALA MAGNAIR or any of its ingredients or any other medicines.

Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. LONHALA MAGNAIR may affect the way other medicines work, and other medicines can affect how LONHALA MAGNAIR works. Using LONHALA MAGNAIR with other medicines may cause serious side effects.

Especially tell your healthcare provider if you take anticholinergics (including umeclidinium, tiotropium, ipratropium, aclidinium, glycopyrrolate).

Know the medicines you take. Keep a list of your medicines with you and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I use LONHALA MAGNAIR?

Read the step-by-step instructions for using LONHALA MAGNAIR at the end of this Patient Information leaflet and the Manufacturer’s Instructions for Use booklet. The Manufacturer’s Instructions for Use booklet provides complete information about how to put together (assemble), prepare, use, care for, and trouble-shoot your MAGNAIR nebulizer system. • Do not use LONHALA MAGNAIR unless your healthcare provider has taught you

how to use the device and you understand how to use it correctly. • Use LONHALA MAGNAIR exactly as your healthcare provider tells you to use it.

Do not use LONHALA MAGNAIR more often than prescribed for you. • Only use LONHALA vials with the MAGNAIR device. • Do not inject or swallow the LONHALA medicine. • Inhale the medicine in 1 LONHALA vial through the MAGNAIR device 2 times

each day (1 vial in the morning and 1 vial in the evening) at the same time each day.

• If you miss a dose of LONHALA MAGNAIR, take your next dose at your usual time. ○ Do not use 2 vials at 1 time. ○ Do not use more than 2 vials in a day. • Do not stop using LONHALA MAGNAIR or other medicines to control or treat your

COPD unless told to do so by your healthcare provider because your symptoms might get worse. Your healthcare provider will change your medicines as needed.

• Call your healthcare provider or get emergency medical care right away if your breathing problems worsen with LONHALA MAGNAIR, you need to use your rescue medicine more often than usual, or your rescue inhaler medicine does not work as well for you at relieving your symptoms.

What are the possible side effects of LONHALA MAGNAIR?

LONHALA MAGNAIR can cause serious side effects, including: • sudden shortness of breath immediately after use of LONHALA MAGNAIR.

Sudden shortness of breath may be life-threatening. If you have sudden breathing problems immediately after inhaling your medicine, stop taking LONHALA MAGNAIR and call your healthcare provider or go to the nearest hospital emergency room right away.

• serious allergic reactions. Stop using LONHALA MAGNAIR and call your healthcare provider or get emergency medical care right away if you get any of the following symptoms of a serious allergic reaction:

○ rash ○ hives ○ swelling of the tongue, lips, ○ difficulty breathing and face or swallowing

• new or worsened eye problems including acute narrow-angle glaucoma. Acute narrow-angle glaucoma can cause permanent loss of vision if not treated. Symptoms of acute narrow-angle glaucoma may include:

○ eye pain or discomfort ○ red eyes ○ blurred vision ○ seeing halos or bright ○ nausea or vomiting colors around lights

If you have any of these symptoms, stop taking LONHALA MAGNAIR and call your healthcare provider right away before using another dose.

• new or worsened problems emptying your bladder (urinary retention). People who use LONHALA MAGNAIR may develop new or worsened urinary retention. Urinary retention can be caused by a blockage in your bladder. Urinary retention can also happen in men who have a larger than normal prostate. Symptoms of urinary retention may include:

○ difficulty urinating ○ painful urination ○ urinating frequently ○ urination in a weak stream or drips

If you have any of these symptoms, stop taking LONHALA MAGNAIR and call your healthcare provider right away before taking another dose.

Common side effects of LONHALA MAGNAIR include shortness of breath, and urinary tract infections.

These are not all of the possible side effects of LONHALA MAGNAIR.

Call your doctor or pharmacist for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store LONHALA MAGNAIR?

• Store LONHALA vials in the protective foil pouch at room temperature between 68°F and 77°F (20°C and 25°C).

• LONHALA vials should be used with the MAGNAIR device only. Do not use MAGNAIR with any other medicine.

After opening the protective foil pouch, unused LONHALA vials should be returned to, and stored in, the opened foil pouch. Once a foil pouch is opened, discard the vials if not used within 7 days.

• An opened LONHALA vial should be used right away. • Throw away the LONHALA vial right away after use. • The medicine in the LONHALA vial should be colorless. Throw away the

LONHALA vial if the medicine is not colorless. • Always use the MAGNAIR Replacement Handset parts that come with each

LONHALA MAGNAIR refill prescription. • Keep LONHALA MAGNAIR and all medicines out of the reach of children.

General information about the safe and effective use of LONHALA MAGNAIR.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LONHALA MAGNAIR for a condition for which it was not prescribed. Do not give LONHALA MAGNAIR to other people, even if they have the same symptoms you have. It may harm them.

You can ask your healthcare provider or pharmacist for information about LONHALA MAGNAIR that is written for healthcare professionals.

What are the ingredients in LONHALA MAGNAIR?

Active ingredient: glycopyrrolate

Inactive ingredients: citric acid monohydrate, sodium chloride, sodium hydroxide and water for injection.

Manufactured for: Sunovion Respiratory Development Inc., a wholly-owned subsidiary of Sunovion Pharmaceuticals Inc. Made in Germany.

©2019 Sunovion Pharmaceuticals Inc. All rights reserved.

For more information, go to www.LonhalaMagnair.com or call Sunovion Customer Service at 1-888-394-7377.

This Patient information has been approved by the U.S. Food and Drug Administration

Revised: June 2019

INSTRUCTIONS FOR USE LONHALA MAGNAIR (lon-HAH-luh MAGG-nair)

(glycopyrrolate) inhalation solution, for oral inhalation use

Read this Instructions for Use leaflet and the Manufacturer’s Instructions for Use booklet before you start using LONHALA MAGNAIR and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. If you have any questions, ask your healthcare provider or pharmacist. The Manufacturer’s Instructions for Use booklet provides complete information about how to put together (assemble), prepare, use, care for, and troubleshoot your MAGNAIR nebulizer system.

Your LONHALA MAGNAIR:MAGNAIR is a nebulizer system to be used by the patient, caregiver, or healthcare provider to deliver the medicine LONHALA. LONHALA MAGNAIR consists of both the MAGNAIR nebulizer system and the medicine LONHALA.

The following supplies come with your LONHALA MAGNAIR:

Starter Kit: Foil pouches containing 60 vials of LONHALA (2 vials of LONHALA in each pouch; 1 vial per dose), Instructional video, and 1 MAGNAIR Nebulizer System with carrying bag (including Manufacturer’s Instructions for Use booklet and Quick Reference Guide) (see the figure below). Refill Kit: Foil pouches containing 60 vials of LONHALA (2 vials of LONHALA in each pouch; 1 vial per dose), and 1 MAGNAIR refill Handset (containing only these replacement parts: Medication cap, Handset body, Mouthpiece, and Aerosol head; Manufacturer’s Instructions for Use booklet).

Important: Throw away the old Handset parts after using 60 vials of LONHALA and use the replacement Handset parts in the Refill Kit with the next 60 vials of LONHALA.

Important: Check to make sure that your MAGNAIR nebulizer system is working properly before you use LONHALA MAGNAIR for the first time. See the Manufacturer’s Instructions for Use that come with your MAGNAIR nebulizer system.

Steps for Using Batteries with MAGNAIR

Step 1: Open the battery door on the Controller. Place your thumb on the black tab of the battery door and firmly push the tab to open the door.

Step 2: Put 4 AA batteries in the Controller as shown.

Step 3: Close the battery door. You may hear a “Click”. Important: Make sure to have an extra set of batteries with you at all times if you choose not to use the AC adapter.

Steps for Using the AC Adapter with MAGNAIR

Step 1: Plug the AC adapter into the Inlet on the battery door of the Controller.Step 2: Plug the AC adapter into the wall outlet.

Assembling Your MAGNAIR

Step 1: Wash your hands.Step 2: Open the top of the Handset body by lifting the clasp.

Step 3: Insert the Aerosol head into the Handset body as shown. Do not touch the center of the Aerosol head. Notice that the Aerosol head has a small tab on the side. Align the small tab with the matching notch in the Handset body.

Step 4: Close the Handset body. You may hear a “Click”.

Step 5: Attach the Mouthpiece to the Handset body. Make sure the Blue valve is pressed down.

Step 6: Connect the Controller to the Handset body using the Connection cord. You may hear a “Click”.

Step 7: Connect the Controller to the Handset body using the Connection cord as shown.

Using LONHALA MAGNAIR

Step 1: Open the foil pouch, enough to remove the 2 LONHALA vials and separate them. Return 1 vial to the opened foil pouch and store in the carrying bag to be used at the next treatment. Discard the vial if not used within 7 days.

Step 2: Insert one LONHALA vial into the bottom of the Medication cap until it “Clicks”.

Important: Do not touch the part of the Handset body that pierces the vial.

Step 3: Make sure the Aerosol head is installed before attaching the Medication cap because your medicine could leak and you will not get your full treatment.Place the Medication cap with LONHALA vial on the top of the Handset body.

Step 4: To attach the Medication cap to the Handset body, turn the Medication cap in a clockwise direction as shown, until you hear a “Click”. The notch in the Medication cap (at the base of the opening) should line up with the blue line on the Handset body.

Step 5: Insert the Mouthpiece into your mouth. Important: Do not tilt the Handset, loosen or remove the Medication cap, or unclasp the Handset body until the treatment is complete because you will not get your full treatment.

Step 6: Press the On/Off button to turn on the Controller as shown, and start your treatment.

Step 7: Breathe in (inhale) and breathe out (exhale) normally through the Mouthpiece.

2-3minutes

At the end of your treatment, you will hear a beeping sound and the Controller will automatically shut off. Your treatment should take about 2 to 3 minutes.

Cleaning the Handset

Step 1: Disconnect the Handset from the Connection cord.

Step 2: Turn the Medication cap in a counterclockwise direction as shown, to remove it from the Handset body.

Step 3: Place the top of the Medication cap into the palm of your hand and push up as shown to remove the LONHALA vial. Throw away the LONHALA vial into the wastebasket.

Step 4: Remove the Mouthpiece from the Handset body by giving it a gentle twist and pull to separate from the Handset body.

Step 5: Carefully loosen the Blue valve from the slot in the Mouthpiece. Make sure the valve is still attached on one side to the Mouthpiece.

Step 6: Remove the Aerosol head from the Handset body by lifting the clasp on the side of the Handset body as shown. Do not touch the center of the Aerosol head.

Step 7: Set aside the Aerosol head to be cleaned separately (see Step 10). Rinse all Handset parts well with warm running water for about 10 seconds.

Step 8: Wash all Handset parts in warm soapy water (water and clear liquid dishwashing soap) for about 10 seconds.

Step 9: Rinse the Handset parts well with warm running water for about 10 seconds to remove all of the soap.

Step 10: Clean the Aerosol head using the instructions in Steps 7 through 10.

10A. Rinse each side of the Aerosol head well with warm running water for about 10 seconds.

10B. Hold the Aerosol head by the handle and swish it back and forth in the warm soapy water for about 10 seconds.

10C. Then, rinse both sides of the Aerosol head well with warm running water for about 10 seconds on each side.

Rinsing the Aerosol head well helps prevent clogging and ensure proper operation.

Step 11: Inspect all Handset parts to make sure they are completely clean. If any Handset parts are still dirty, soak the parts in warm soapy water for 5 more minutes. Rinse well with warm running water until the Handset parts are clean.Shake Handset parts to remove excess water. Air-dry all Handset parts on a lint-free towel.Do not put the Handset parts back together until ready to use again for your next treatment of LONHALA.

Step 12: Store the Handset parts in the carrying bag provided.

Warnings and Precautions:Failure to follow the Warnings and Precautions below could cause serious injury or may lead to death in some cases: • Check all parts of your LONHALA MAGNAIR to make sure that they are clean

and not damaged. • Clean the Handset before the first use and after every use. If you do not clean

the Handset after every use, your treatment could take more than 3 minutes. • Do not leave the Aerosol head in your Handset. • Do not wash the Controller, Connection cord, or AC adapter. • Only use clear liquid dishwashing soap to wash the Handset parts.

Do not use any other type of soap. ○ Do not use antibacterial soap. Antibacterial soap can damage the

Aerosol head. • Do not use a microwave oven to dry any parts of your LONHALA MAGNAIR. • Allow all parts of your LONHALA MAGNAIR to air dry completely.

If you have any questions, contact Sunovion Customer Service at 1-888-394-7377.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

LONHALA and are registered trademarks of Sunovion Pharmaceuticals Inc. MAGNAIR is a registered trademark of PARI Pharma GmbH, used under license.

SUNOVION and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd.

PARI and are registered trademarks of PARI GmbH.eFlow is a registered trademark of PARI Pharma GmbH. Made under license of The Technology Partnership plc.

Manufactured for:Sunovion Respiratory Development Inc.,a wholly-owned subsidiary of Sunovion Pharmaceuticals Inc. Made in Germany.

©2019 Sunovion Pharmaceuticals Inc. All rights reserved.

Revised: June 2019

10140-02-MKT1

Controller

AC adapterAerosol head

Connection cord

Medication cap

Handset body

Mouthpiece

Carrying bag

4 AA batteries

MAGNAIR Nebulizer System

4 AA batteries

Black battery doorInlet

AC adapter

Clasp

Notch

Text side Tab Clasp

Blue inletConnection cord

Blue valve Blue mark

Gray mark

Connection cord

Medication cap: topMedication cap: bottom

LONHALA vial

Line up notch in cap with blue line on Handset body.

On/Off button

Clasp