Aclidinium Bromide and Formoterol Fumarate

INDICATIONS AND USAGE DUAKLIR PRESSAIR is a combination of aclidinium bromide (an anticholinergic) and formoterol fumarate (a LABA) indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Limitations of Use: DUAKLIR PRESSAIR is not indicated for the relief of acute bronchospasm or for the treatment of asthma [see Warnings and Precautions ( 5.1 , 5.4 )] . DUAKLIR PRESSAIR is a combination of aclidinium bromide an anticholinergic, and formoterol fumarate, a long-acting beta 2 -adrenergic agonist (LABA) indicated for the maintenance treatment of 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 , 5.4 )

DOSAGE AND ADMINISTRATION The recommended dose of DUAKLIR PRESSAIR is one oral inhalation of 400 mcg/12 mcg, twice daily (once in the morning and once in the evening). Do not take more than one inhalation twice daily. • For oral inhalation only. ( 2 ) • 400 mcg/12 mcg, twice daily (once in the morning and once in the evening). ( 2 )

WARNINGS AND PRECAUTIONS • Asthma-related death: Long-acting beta 2 -adrenergic agonists as monotherapy (without an inhaled corticosteroid) for asthma increase 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 a LABA because of risk of overdose. ( 5.3 ) • If paradoxical bronchospasm occurs, discontinue DUAKLIR PRESSAIR and institute alternative therapy. ( 5.4 ) • Use with caution in patients with cardiovascular disorders. ( 5.6 ) • Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus and ketoacidosis. ( 5.7 ) • Be alert to hypokalemia and hyperglycemia. ( 5.8 ) • 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. ( 5.9 ) • Worsening 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. ( 5.10 ) 5.1 Serious Asthma-Related Events-Hospitalizations, Intubations, Death • The safety and efficacy of DUAKLIR PRESSAIR in patients with asthma have not been established. DUAKLIR PRESSAIR is not indicated for the treatment of asthma. [see Contraindications (4) ] . • Use of LABA as monotherapy [without inhaled corticosteroids (ICS)] for asthma is associated with an increased risk of asthma-related death. Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in 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. trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABAs, including formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR. • No trial adequate to determine whether the rate of asthma-related deaths is increased in subjects treated with DUAKLIR PRESSAIR 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 DUAKLIR PRESSAIR should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. DUAKLIR PRESSAIR has not been studied in patients with acutely deteriorating COPD. The use of DUAKLIR PRESSAIR in this setting is inappropriate. DUAKLIR PRESSAIR is intended as twice daily maintenance treatment for COPD and should not be used for the relief of acute symptoms, i.e., as rescue therapy for treatment of acute episodes of bronchospasm. DUAKLIR PRESSAIR has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled short-acting beta 2 -agonist. When beginning treatment with DUAKLIR PRESSAIR, patients who have been taking oral or inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing DUAKLIR PRESSAIR, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient on how it should be used. Increasing inhaled beta 2 -agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If DUAKLIR PRESSAIR no longer controls symptoms of bronchoconstriction; the patient’s inhaled, short-acting beta 2 -agonist becomes less effective; or the patient needs more short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of DUAKLIR PRESSAIR beyond the recommended dose is not appropriate in this situation. 5.3 Excessive Use of DUAKLIR PRESSAIR and Use with Other Long-Acting Beta 2 Agonists As with other inhaled drugs containing beta-agonists, DUAKLIR PRESSAIR 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 DUAKLIR PRESSAIR should not use another medicine containing a LABA for any reason [see Drug Interactions (7.1) ] . 5.4 Paradoxical Bronchospasm Inhaled medicines, including DUAKLIR PRESSAIR, may cause paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with DUAKLIR PRESSAIR, it should be treated immediately with an inhaled, short acting bronchodilator. DUAKLIR PRESSAIR should be discontinued immediately, and alternative therapies should be instituted. 5.5 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions including anaphylaxis, angioedema (including swelling of the lips, tongue, or throat), urticaria, rash, bronchospasm, or itching, have occurred after administration of DUAKLIR PRESSAIR. If such a reaction occurs, therapy with DUAKLIR PRESSAIR should be stopped at once and alternative treatments should be considered. 5.6 Cardiovascular Effects Formoterol fumarate, like other beta agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic or blood pressure, or symptoms [see Clinical Pharmacology (12.2) ] . If such effects occur, DUAKLIR PRESSAIR 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, DUAKLIR PRESSAIR should be used with caution in patients with severe cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.7 Coexisting Conditions DUAKLIR PRESSAIR, like other medications containing sympathomimetic amines, should be used with caution in patients with convulsive disorders, thyrotoxicosis, and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta-agonist albuterol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis. 5.8 Hypokalemia and Hyperglycemia Beta-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. Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 24 to 52 weeks duration evaluating DUAKLIR PRESSAIR in patients with COPD, there was no evidence of a treatment effect on serum glucose or potassium. 5.9 Worsening of Narrow-Angle Glaucoma DUAKLIR PRESSAIR should be used with caution in patients with narrow-

CONTRAINDICATIONS Use of a long-acting beta 2 -adrenergic agonist (LABA), including formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR, without an inhaled corticosteroid is contraindicated in patients with asthma [see Warnings and Precautions (5.1) ] . DUAKLIR PRESSAIR is not indicated for the treatment of asthma. DUAKLIR PRESSAIR is contraindicated in patients with: • Severe hypersensitivity to milk proteins [see Warnings and Precautions (5.5) ] . • Hypersensitivity to aclidinium bromide, formoterol fumarate, or to any component of the product [see Warnings and Precautions (5.5) ] . • Use of a long-acting beta 2 -adrenergic agonist (LABA), including formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR, without an inhaled corticosteroid is contraindicated in patients with asthma. ( 1 , 4 ) • Hypersensitivity to aclidinium bromide or formoterol fumarate or to any component of this product. ( 4 , 5.5 )

DRUG INTERACTIONS No formal drug interaction studies have been performed with DUAKLIR PRESSAIR. • Use of other adrenergic by any route may potentiate the effect of DUAKLIR PRESSAIR. 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 ) • Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium sparing diuretics may worsen with concomitant beta 2 -agonists. ( 7.3 ) • Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol fumarate on cardiovascular system. ( 7.4 ) • Beta-blockers: Use with caution and only when medically necessary. ( 7.5 ) • Anticholinergics: May interact additively with concomitantly used anticholinergic medications. Avoid administrations of DUAKLIR PRESSAIR with other anticholinergic-containing drugs. ( 7.6 ) 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 formoterol, a component of DUAKLIR PRESSAIR, may be potentiated [see Warnings and Precautions (5.7) ] . 7.2 Xanthine Derivatives, Steroids Concomitant treatment with xanthine derivatives, or steroids may potentiate any hypokalemic effect of beta-adrenergic agonists such as formoterol, a component of DUAKLIR PRESSAIR. 7.3 Non-Potassium Sparing Diuretics The electrocardiographic 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, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics. 7.4 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants, QTc Prolonging Drugs DUAKLIR PRESSAIR, as with other drugs containing beta 2 -agonists, should be administered with 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 have an increased risk of ventricular arrhythmias. 7.5 Beta-Blockers Beta-adrenergic receptor antagonists (beta-blockers) and DUAKLIR PRESSAIR may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta 2 -agonists, such as formoterol, a component of DUAKLIR PRESSAIR, 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 a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of DUAKLIR PRESSAIR with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects [see Warnings and Precautions ( 5.3 , 5.4 ) and Adverse Reactions (6) ] .

ADVERSE REACTIONS LABAs, such as formoterol fumarate, one of the active ingredients in DUAKLIR PRESSAIR, increase the risk of asthma-related death. DUAKLIR PRESSAIR is not indicated for the treatment of asthma [see Warnings and Precautions (5.1) ] . The following adverse reactions are described in greater detail elsewhere in the labeling: • Paradoxical bronchospasm [see Warnings and Precautions (5.4) ] • Immediate hypersensitivity reactions [see Contraindications (4) , Warnings and Precautions (5.5) ] • Cardiovascular effects [see Warnings and Precautions (5.6)] • Worsening of narrow-angle glaucoma [see Warnings and Precautions (5.9) ] • Worsening of urinary retention [see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence ≥ 3% and more common than with placebo) include: upper respiratory tract infection, headache and, back pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma at 1-877-411-2510 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for DUAKLIR PRESSAIR included 6501 subjects with COPD in 2 placebo-controlled and 1 active-controlled 24-week lung function trials, one long-term safety extension study of 28 weeks and 2 other clinical trials. A total of 1893 subjects have received at least 1 dose of DUAKLIR PRESSAIR. 24-Week Trials The frequency of common adverse reactions in Table 1 below is based upon pooled data from two, double-blind, placebo-controlled parallel group clinical trials (Trials 1 and 2, n=1729 and n=1669) in 3398 adult patients with moderate to severe COPD. Of these, 60% were male and 94% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack-years, with 49% identified as current smokers. At screening, the mean post-bronchodilator percent predicted forced expiratory volume in 1 second (FEV 1 ) was 54% (range: 28% to 80%) and the mean percent reversibility was 15% (range: -19% to 69%). Table 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 3% in the DUAKLIR PRESSAIR group in the two 24-week placebo-controlled trials where the rates in the DUAKLIR PRESSAIR group exceeded placebo. Table 1: Adverse Reactions with DUAKLIR PRESSAIR ≥3% Incidence and More Common than with Placebo in Subjects with COPD Treatment Adverse Reactions Preferred Term DUAKLIR PRESSAIR (N=720) % Aclidinium (N=722) % Formoterol (N=716) % Placebo (N=526) % Upper respiratory tract infection Includes Viral Upper Respiratory Tract Infection and Upper Respiratory Tract Infection 8.9 7.6 8.9 6.3 Headache 6.3 6.6 7.7 5.1 Back pain 3.8 3.3 3.5 3.4 Other adverse reactions reported in clinical studies with an incidence of >1% but less than 3% with DUAKLIR PRESSAIR but more common than with placebo were cough, sinusitis, influenza, tooth abscess, insomnia, dizziness, dry mouth, oropharyngeal pain, muscle spasms, musculoskeletal pain, arthralgia, pain in extremity, urinary tract infection, and blood creatine phosphokinase increased. The adverse events reported in the 24-week active-controlled trial were consistent with those observed in 24-week placebo-controlled trials. Long-Term Safety Extension Trial In a 28-week safety extension trial, 918 subjects who successfully completed Trial 2 were treated for up to an additional 28 weeks for a total treatment period of up to 52 weeks with DUAKLIR PRESSAIR, aclidinium 400 mcg, formoterol fumarate 12 mcg administered twice daily or placebo. Because the subjects continued from Trial 2 into the safety extension trial, the demographic and baseline characteristics of the long-term safety extension 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 24-week placebo-controlled trials.

Mechanism of Action DUAKLIR PRESSAIR DUAKLIR PRESSAIR contains two bronchodilators: aclidinium a long-acting muscarinic antagonist (also known as an anticholinergic) and formoterol a long-acting beta 2 -adrenergic agonist. Further information regarding these two substances is provided below. The mechanism of action described below for the individual components apply to DUAKLIR PRESSAIR. These drugs represent two different classes of medications (a long-acting antimuscarinic agent and a selective long-acting beta 2 -adrenergic receptor agonist) that have different effects on clinical and physiological indices of COPD. Aclidinium bromide Aclidinium bromide is a long-acting antimuscarinic agent, 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 receptors 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 acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of aclidinium bromide is predominantly a site-specific effect. Formoterol fumarate Formoterol fumarate is a long-acting selective beta 2 -adrenergic receptor agonist (LABA) (beta 2 -agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In-vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors. The in-vitro binding selectivity to beta 2 -over beta 1 -adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta‑selectivity ratio than formoterol. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in 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 the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper responsiveness. The relevance of these in vitro and animal findings to humans is unknown.