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.

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 beta2-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, urticaria, angioedema, rash, and bronchospasm.

6.1 Beta 2-Agonist Adverse Reaction Profile

Adverse reactions to Formoterol Fumarate Inhalation Solution are expected to be similar in nature to other beta 2-adrenergic receptor agonists including: angina, hypertension or hypotension, tachycardia, arrhythmias, nervousness, headache, tremor, dry mouth, muscle cramps, palpitations, nausea, dizziness, fatigue, malaise, insomnia, hypokalemia, hyperglycemia, and metabolic acidosis.

6.2 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.

6.3 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of Formoterol Fumarate Inhalation Solution. 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.

Anaphylactic reactions, urticaria, angioedema (presenting as face, lip, tongue, eye, pharyngeal, or mouth edema), rash, and bronchospasm

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 may be potentiated [see WARNINGS AND PRECAUTIONS (5.3, 5.5, 5.6, 5.7)].

7.2 Xanthine Derivatives, Steroids, or Diuretics

Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of adrenergic agonists [see WARNINGS AND PRECAUTIONS (5.7)].

7.3 Non-potassium Sparing Diuretics

The 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, 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 co-administration of beta-agonists with non-potassium sparing diuretics.

7.4 MAO Inhibitors, Tricyclic Antidepressants, QTc Prolonging Drugs

Formoterol, as with other beta 2-agonists, 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 the effect 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 formoterol 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 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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Formoterol Fumarate Inhalation Solution is not indicated for use in children. The safety and effectiveness of  Formoterol Fumarate Inhalation Solution in pediatric patients have not been established. The pharmacokinetics of formoterol fumarate has not been studied in pediatric patients.

8.5 Geriatric Use

Of the 586 subjects who received Formoterol Fumarate Inhalation Solution in clinical studies, 284 were 65 years and over, while 89 were 75 years and over. Of the 123 subjects who received Formoterol Fumarate Inhalation Solution in the 12-week safety and efficacy trial, 48 (39%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

The pharmacokinetics of Formoterol Fumarate Inhalation Solution has not been studied in elderly subjects.

12.1 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 vitrostudies 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 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 vitrotests 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 vitroand animal findings to humans with COPD is unknown.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Information on the pharmacokinetics of formoterol (dry powder and/or inhalation solution) in plasma and/or urine is available in healthy subjects as well as patients with chronic obstructive pulmonary disease after oral inhalation of doses at and above the therapeutic dose.

Urinary excretion of unchanged formoterol was used as an indirect measure of systemic exposure. Plasma drug disposition data parallel urinary excretion, and the elimination half-lives calculated for urine and plasma are similar.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of formoterol fumarate has been evaluated in 2-year drinking water and dietary studies in both rats and mice. In rats, the incidence of ovarian leiomyomas was increased at doses of 15,000 mcg/kg and above in the drinking water study and at 20,000 mcg/kg in the dietary study (AUC exposure approximately 2,300 times human exposure at the maximum recommended daily inhalation dose), but not at dietary doses up to 5,000 mcg/kg (AUC exposure approximately 570 times human exposure at the maximum recommended daily inhalation dose). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 500 mcg/kg (AUC exposure was approximately 57 times human exposure at the maximum recommended daily inhalation dose) and above. This finding was not observed in the drinking water study, nor was it seen in mice (see below).

In mice, the incidence of adrenal subcapsular adenomas and carcinomas was increased in males at doses of 69,000 mcg/kg (AUC exposure approximately 1000 times human exposure at the maximum recommended daily inhalation dose) and above in the drinking water study, but not at doses up to 50,000 mcg/kg (AUC exposure approximately 750 times human exposure at the maximum recommended daily inhalation dose) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20,000 and 50,000 mcg/kg in females (AUC exposures approximately 300 and 750 times human exposure at the maximum recommended daily inhalation dose, respectively) and 50,000 mcg/kg in males, but not at doses up to 5,000 mcg/kg (AUC exposure approximately 75 times human exposure at the maximum recommended daily inhalation dose). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of 2,000 mcg/kg (AUC exposure was approximately 30 times human exposure at the maximum recommended daily inhalation dose) and above. Increases in leiomyomas of the rodent female genital tract have been similarly demonstrated with other beta-agonist drugs.

Formoterol fumarate was not mutagenic or clastogenic in the following tests: mutagenicity tests in bacterial and mammalian cells, chromosomal analyses in mammalian cells, unscheduled DNA synthesis repair tests in rat hepatocytes and human fibroblasts, transformation assay in mammalian fibroblasts and micronucleus tests in mice and rats.

Reproduction studies in rats revealed no impairment of fertility at oral doses up to 3,000 mcg/kg (approximately 730 times the maximum recommended daily inhalation powder dose in humans on a mcg/m 2basis).

13.2 Animal Pharmacology

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown [see DRUG INTERACTIONS, Xanthine Derivatives, Steroids, or Diuretics (7.2)].

14.1 Adult COPD Trial

Formoterol Fumarate Inhalation Solution was evaluated in a 12-week, double-blind, placebo- and active-controlled, randomized, parallel-group, multicenter trial conducted in the United States. Of a total enrollment of 351 adults (age range: 40 to 86 years; mean age: 63 years) with COPD who had a mean pre-bronchodilator FEV 1of 1.34 liters (44% of predicted), 237 patients were randomized to Formoterol Fumarate Inhalation Solution 20 mcg or placebo, administered twice daily via a PARI-LC Plus ®nebulizer with a PRONEB ®Ultra compressor. The diagnosis of COPD was based upon a prior clinical diagnosis of COPD, a smoking history (at least 10 pack-years), age (at least 40 years), and spirometry results (pre-bronchodilator baseline FEV 1at least 30% and less than 70% of the predicted value, and the FEV 1/FVC less than 70%). About 58% of patients had bronchodilator reversibility, defined as a 10% or greater increase in FEV 1after inhalation of 2 actuations (180 mcg) of albuterol from a metered dose inhaler. About 86% (106) of patients treated with Formoterol Fumarate Inhalation Solution and 74% (84) of placebo patients completed the trial.

Formoterol Fumarate Inhalation Solution 20 mcg twice daily resulted in significantly greater post-dose bronchodilation (as measured by serial FEV 1for 12 hours post-dose; the primary efficacy analysis) compared to placebo when evaluated at endpoint (week 12 for completers and last observation for dropouts). Similar results were seen on Day 1 and at subsequent timepoints during the trial.

Mean FEV 1measurements at Day 1 (Figure 1) and at endpoint (Figure 2) are shown below.

*Figures show least-squares means adjusted for baseline FEV 1

Patients treated with Formoterol Fumarate Inhalation Solution used less rescue albuterol during the trial compared to patients treated with placebo.

Examination of age (≥ 65 or younger) and gender subgroups did not identify differences in response to Formoterol Fumarate Inhalation Solution. There were too few non-Caucasian subjects to assess differences in populations defined by race adequately.

In the 12-week study, 78% of subjects achieved a 15% increase from baseline FEV 1following the first dose of Formoterol Fumarate Inhalation Solution 20 mcg. In these subjects, the median time to onset of bronchodilation, defined as 15% increase in FEV 1, was 11.7 minutes. When defined as an increase in FEV 1of 12% and 200 mL, the time to onset of bronchodilation was 13.1 minutes after dosing. The median time to peak bronchodilator effect was 2 hours after dosing.