formoterol fumarate 0.01 MG/ML Inhalation Solution

INDICATIONS AND USAGE Formoterol fumarate inhalation solution is a long-acting beta 2 -adrenergic agonist (beta 2 -agonist) indicated for: • Long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. ( 1.1 ) Important limitations of use: • Formoterol fumarate inhalation solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease. ( 1.2 , 5.2 ) •Formoterol fumarate inhalation solution is not indicated to treat asthma. ( 1.2 ) 1.1 Maintenance Treatment of COPD Formoterol fumarate inhalation solution is indicated for the long-term, twice daily (morning and evening) administration in the maintenance treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. 1.2 Important Limitations of Use Formoterol fumarate inhalation solution is not indicated to treat acute deteriorations of chronic obstructive pulmonary disease [ see WARNINGS AND PRECAUTIONS (5.2) ]. Formoterol fumarate inhalation solution is not indicated to treat asthma. The safety and effectiveness of formoterol fumarate inhalation solution in asthma have not been established.

DOSAGE AND ADMINISTRATION The recommended dose of Formoterol Fumarate Inhalation Solution is one 20 mcg unit-dose vial administered twice daily (morning and evening) by nebulization. A total daily dose greater than 40 mcg is not recommended. Formoterol Fumarate Inhalation Solution should be administered by the orally inhaled route via a standard jet nebulizer connected to an air compressor. The safety and efficacy of Formoterol Fumarate Inhalation Solution have been established in clinical trials when administered using the PARI-LC Plus ® nebulizer (with a facemask or mouthpiece) and the PRONEB ® Ultra compressor. The safety and efficacy of Formoterol Fumarate Inhalation Solution delivered from non-compressor based nebulizer systems have not been established. Formoterol Fumarate Inhalation Solution should always be stored in the foil pouch, and only removed IMMEDIATELY BEFORE USE. Contents of any partially used container should be discarded. If the recommended maintenance treatment regimen fails to provide the usual response, medical advice should be sought immediately, as this is often a sign of destabilization of COPD. Under these circumstances, the therapeutic regimen should be re-evaluated and additional therapeutic options should be considered. The drug compatibility (physical and chemical), efficacy, and safety of Formoterol Fumarate Inhalation Solution when mixed with other drugs in a nebulizer have not been established. For oral inhalation only. • One 20 mcg/2 mL vial every 12 hours ( 2 ) • For use with a standard jet nebulizer (with a facemask or mouthpiece) connected to an air compressor ( 2 )

WARNINGS AND PRECAUTIONS • LABA as monotherapy (without inhaled corticosteroid) for asthma increases the risk of serious asthma-related events. ( 5.1 ) • Do not initiate formoterol fumarate inhalation solution in acutely deteriorating patients. ( 5.2 ) • Do not use for relief of acute symptoms. Concomitant short-acting beta 2 -agonists can be used as needed for acute relief. ( 5.2 ) • Do not exceed the recommended dose. Excessive use of formoterol fumarate inhalation solution or use in conjunction with other medications containing long-acting beta 2 -agonists, can result in clinically significant cardiovascular effects, and may be fatal. ( 5.3 , 5.5 ) • Life-threatening paradoxical bronchospasm can occur. Discontinue formoterol fumarate inhalation 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 ) 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death The safety and efficacy of formoterol fumarate inhalation solution in patients with asthma have not been established. Formoterol fumarate inhalation solution is not indicated for the treatment of asthma [ see CONTRAINDICATIONS (4) ]. Use of long-acting beta 2 -adrenergic agonists (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 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 the long-acting beta 2 -adrenergic agonists, including formoterol fumarate inhalation solution. No study adequate to determine whether the rate of asthma related death is increased in patients treated with formoterol fumarate inhalation solution has been conducted. Clinical studies with formoterol fumarate administered as a dry powder inhaler suggested a higher incidence of serious asthma exacerbations in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. 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 Formoterol fumarate inhalation solution should not be initiated in patients with acutely deteriorating COPD, which may be a life-threatening condition. Formoterol fumarate inhalation solution has not been studied in patients with acutely deteriorating COPD. The use of formoterol fumarate inhalation solution in this setting is inappropriate. Formoterol fumarate inhalation solution should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Formoterol fumarate inhalation solution 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 formoterol fumarate inhalation solution, patients who have been taking inhaled, short-acting beta 2 -agonists on a regular basis (e.g., four times a day) should be instructed to discontinue the regular use of these drugs and use them only for symptomatic relief of acute respiratory symptoms. When prescribing formoterol fumarate inhalation solution, the healthcare provider should also prescribe an inhaled, short-acting beta 2 -agonist and instruct the patient 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 formoterol fumarate inhalation solution no longer controls the symptoms of bronchoconstriction, or the patient's inhaled, short-acting beta 2 -agonist becomes less effective or the patient needs more inhalation of short-acting beta 2 -agonist than usual, these may be markers of deterioration of disease. In this setting, a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dosage of formoterol fumarate inhalation solution beyond the recommended 20 mcg twice daily dose is not appropriate in this situation. 5.3 Excessive Use and Use with Other Long-Acting Beta 2 -Agonists As with other inhaled beta 2 -adrenergic drugs, formoterol fumarate inhalation solution should not be used more often, at higher doses than recommended, or in conjunction with other medications containing long-acting beta 2 -agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.4 Paradoxical Bronchospasm As with other inhaled beta 2 -agonists, formoterol fumarate inhalation solution can produce paradoxical bronchospasm that may be life-threatening. If paradoxical bronchospasm occurs, formoterol fumarate inhalation solution should be discontinued immediately and alternative therapy instituted. 5.5 Cardiovascular Effects Formoterol fumarate inhalation solution, like other beta 2 -agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic and/or diastolic blood pressure, and/or symptoms. If such effects occur, formoterol fumarate inhalation solution 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. The clinical significance of these findings is unknown. Therefore, formoterol fumarate inhalation solution, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.6 Coexisting Conditions Formoterol fumarate inhalation solution, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.7 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. Clinically significant changes in serum potassium and blood glucose were infrequent during clinical studies with long-term administration of formoterol fumarate inhalation solution at the recommended dose. 5.8 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of formoterol fumarate inhalation solution, as demonstrated by cases of anaphylactic reactions, urtic

CONTRAINDICATIONS Use of a long-acting beta 2 -adrenergic agonists (LABA), including formoterol fumarate inhalation solution, without an inhaled corticosteroid is contraindicated in patients with asthma [see WARNINGS and PRECAUTIONS ( 5.1 )] . Formoterol fumarate inhalation solution is not indicated for the treatment of asthma. Use of a long-acting beta 2 -agonist (LABA), including formoterol fumarate inhalation solution, without an inhaled corticosteroid is contraindicated in patients with asthma. ( 4 )

Mechanism of Action Formoterol fumarate is a long-acting, beta 2 -adrenergic receptor agonist (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. 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 adenylyl 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 with COPD is unknown.