1.1 Treatment of Asthma

DULERA is indicated for the twice-daily treatment of asthma in patients 5 years of age and older. DULERA should be used for patients not adequately controlled on a long-term asthma-control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta2-adrenergic agonist (LABA).

2.1 Administration Information

Administer DULERA as two inhalations twice daily every day (morning and evening) by the orally inhaled route (see Patient Instructions for Use in the Patient Information leaflet). Do not use more than two inhalations twice daily of the prescribed strength of DULERA as some patients are more likely to experience adverse effects with higher doses of formoterol. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief. Shake well prior to each inhalation. After each dose, advise patients to rinse their mouth with water and, without swallowing, spit out the contents to help reduce the risk of oropharyngeal candidiasis.

Remove the cap from the mouthpiece of the actuator before using DULERA.

Prime DULERA before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray.

Only use the DULERA canister with the DULERA actuator. Do not use the DULERA actuator with any other inhalation drug product. Do not use actuators from other products with the DULERA canister.

2.2 Recommended Dosage

Administer DULERA as two inhalations twice daily every day (morning and evening) by the orally inhaled route. Shake well prior to each inhalation. Individual patients may experience a variable time to onset and degree of symptom relief. If symptoms arise between doses, use an inhaled short-acting beta2-agonist for immediate relief. Improvement in lung function following administration of DULERA can occur within 5 minutes of treatment, although the maximum benefit may not be achieved for 1 week or longer after beginning treatment.

4.1 Status Asthmaticus

DULERA is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.

4.2 Hypersensitivity

DULERA is contraindicated in patients with known hypersensitivity to mometasone furoate, formoterol fumarate, or any of the ingredients in DULERA [see Warnings and Precautions (5.10)].

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

Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death [see Salmeterol Multicenter Asthma Research Trial (SMART)]. 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 to ICS alone [see Serious Asthma-Related Events with ICS/LABA].

5.2 Deterioration of Disease and Acute Episodes

DULERA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. DULERA has not been studied in patients with acutely deteriorating asthma. The initiation of DULERA in this setting is not appropriate.

Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of DULERA.

DULERA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not DULERA, should be used to relieve acute symptoms such as shortness of breath.

When beginning treatment with DULERA, 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.

5.3 Excessive Use of DULERA and Use with Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergic agents, DULERA should not be used more often than recommended, 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. Patients using DULERA should not use an additional long-acting beta2-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma.

5.4 Local Effects

In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with DULERA. If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with DULERA therapy, but at times therapy with DULERA may need to be interrupted. To reduce the risk of oropharyngeal candidiasis, after dosing with DULERA, advise patients to rinse their mouth with water and spit out the contents without swallowing.

5.5 Immunosuppression

Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.

Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.

DULERA should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.6 Transferring Patients from Systemic Corticosteroid Therapy

Particular care is needed for patients who are transferred from systemically active corticosteroids to DULERA because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although DULERA may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies.

During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack.

Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to DULERA. Lung function (FEV1 or PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapy to DULERA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions.

During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function.

5.7 Hypercorticism and Adrenal Suppression

Mometasone furoate, a component of DULERA, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of DULERA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with DULERA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of DULERA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of DULERA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.9 Paradoxical Bronchospasm and Upper Airway Symptoms

DULERA may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening. If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator. DULERA should be discontinued immediately and alternative therapy instituted.

5.10 Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of DULERA, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm.

5.11 Cardiovascular and Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, DULERA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Formoterol fumarate, a component of DULERA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of DULERA at recommended doses, if they occur, the drug 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. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

5.12 Reduction in Bone Mineral Density

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, one of the components of DULERA. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care.

In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 85%–88% predicted), treatment with mometasone furoate dry powder inhaler (DPI) 200 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone furoate group compared to 0.002 (0.25%) for the placebo group. In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 82%–83% predicted), treatment with mometasone furoate 400 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the mometasone furoate group compared to -0.006 (-0.43%) for the placebo group.

5.13 Effect on Growth

Orally inhaled corticosteroids, including DULERA, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving DULERA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, titrate each patient's dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].

5.14 Glaucoma and Cataracts

Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term administration of inhaled corticosteroids, including mometasone furoate, a component of DULERA. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term [see Adverse Reactions (6)].

5.15 Coexisting Conditions

DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, 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.

5.16 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. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with DULERA at recommended doses.

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

The following adverse reactions have been reported during post-approval use of DULERA or post-approval use with inhaled mometasone furoate or inhaled formoterol fumarate. 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.

Cardiac disorders: angina pectoris, cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia

Eye disorders: vision blurred [see Warnings and Precautions (5.14)]

Immune system disorders: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema, severe hypotension, rash, pruritus

Investigations: electrocardiogram QT prolonged, blood pressure increased (including hypertension)

Metabolism and nutrition disorders: hypokalemia, hyperglycemia

Respiratory, thoracic and mediastinal disorders: asthma aggravation, which may include cough, dyspnea, wheezing and bronchospasm

7.1 Inhibitors of Cytochrome P450 3A4

The main route of metabolism of corticosteroids, including mometasone furoate, a component of DULERA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased. Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate and potentially increase the risk for systemic corticosteroid side effects. Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)]. Consider the benefit of coadministration versus the potential risk of systemic corticosteroid effects, in which case patients should be monitored for systemic corticosteroid side effects.

7.2 Adrenergic Agents

If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol, a component of DULERA, may be potentiated.

7.3 Xanthine Derivatives

Concomitant treatment with xanthine derivatives may potentiate any hypokalemic effect of formoterol, a component of DULERA.

7.4 Diuretics

Concomitant treatment with diuretics may potentiate the possible hypokalemic effect of adrenergic agonists. 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 coadministration of DULERA with non-potassium-sparing diuretics.

7.5 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and Drugs Known to Prolong the QTc Interval

DULERA should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of DULERA, 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.

7.6 Beta-Adrenergic Receptor Antagonists

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 beta2-agonists, such as formoterol, a component of DULERA, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma 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 asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution.

7.7 Halogenated Hydrocarbons

There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of DULERA have been established in patients 12 years of age and older in 3 clinical trials up to 52 weeks in duration. In the 3 clinical trials, 101 patients 12 to 17 years of age were treated with DULERA. Patients in this age-group demonstrated efficacy results similar to those observed in patients 18 years of age and older. There were no obvious differences in the type or frequency of adverse reactions reported in this age group compared to patients 18 years of age and older. Similar efficacy and safety results were observed in an additional 22 patients 12 to 17 years of age who were treated with DULERA in another clinical trial.

The safety and effectiveness of DULERA 50 mcg/5 mcg, two inhalations twice daily, have been established in patients with asthma aged 5 to less than 12 years in clinical trials up to 24 weeks of treatment duration. Patients in this age group demonstrated efficacy and safety results similar to those observed in patients aged 12 years and older who were treated with DULERA [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

The safety and effectiveness of DULERA have not been established in children younger than 5 years of age.

Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8 per year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for "catch up" growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.

The growth of children and adolescents receiving orally inhaled corticosteroids, including DULERA, should be monitored routinely (e.g., via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2.2)].

8.5 Geriatric Use

A total of 77 patients 65 years of age and older (11 of whom were 75 years and older) have been treated with DULERA in 3 clinical trials up to 52 weeks in duration. Similar efficacy and safety results were observed in an additional 28 patients 65 years of age and older who were treated with DULERA in another clinical trial. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other products containing beta2-agonists, special caution should be observed when using DULERA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for DULERA or its active components, no adjustment of dosage of DULERA in geriatric patients is warranted.

8.6 Hepatic Impairment

Concentrations of mometasone furoate appear to increase with severity of hepatic impairment [see Clinical Pharmacology (12.3)].

10.1 Signs and Symptoms

10.2 Treatment

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Asthma

Adult and Adolescent Patients Aged 12 Years of Age and Older

The safety and efficacy of DULERA were demonstrated in two randomized, double-blind, parallel group, multicenter clinical trials of 12 to 26 weeks in duration involving 1509 patients 12 years of age and older with persistent asthma uncontrolled on medium or high dose inhaled corticosteroids (baseline FEV1 means of 66% to 73% of predicted normal). These studies included a 2 to 3-week run-in period with mometasone furoate to establish a certain level of asthma control. One clinical trial compared DULERA to placebo and the individual components, mometasone furoate and formoterol (Trial 1) and one clinical trial compared two different strengths of DULERA to mometasone furoate alone (Trial 2).

Trial 1: Clinical Trial with DULERA 100 mcg/5 mcg

This 26-week, placebo-controlled trial (NCT00383240) evaluated 781 patients 12 years of age and older comparing DULERA 100 mcg/5 mcg (n=191 patients), mometasone furoate 100 mcg (n=192 patients), formoterol fumarate 5 mcg (n=202 patients) and placebo (n=196 patients); each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This study included a 2 to 3-week run-in period with mometasone furoate 100 mcg, 2 inhalations twice daily. This trial included patients ranging from 12 to 76 years of age, 41% male and 59% female, and 72% Caucasian and 28% non-Caucasian. Patients had persistent asthma and were not well controlled on medium dose of inhaled corticosteroids prior to randomization. All treatment groups were balanced with regard to baseline characteristics. Mean FEV1 and mean percent predicted FEV1 were similar among all treatment groups (2.33 L, 73%). Eight (4%) patients receiving DULERA 100 mcg/5 mcg, 13 (7%) patients receiving mometasone furoate 100 mcg, 47 (23%) patients receiving formoterol fumarate 5 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure.

FEV1 AUC(0-12 hr) was assessed as a co-primary efficacy endpoint to evaluate the contribution of the formoterol component to DULERA. Patients receiving DULERA 100 mcg/5 mcg had significantly higher increases from baseline at Week 12 in mean FEV1 AUC(0-12 hr) compared to mometasone furoate 100 mcg (the primary treatment comparison) and vs. placebo (both p<0.001) (Figure 1). These differences were maintained through Week 26. Figure 1 shows the change from baseline post-dose serial FEV1 evaluations in Trial 1.

Figure 1

Trial 1 - DULERA 100 mcg/5 mcg - FEV1 Serial Evaluations for Observed Cases at Week 12 Change from Baseline by Treatment

Clinically judged deteriorations in asthma or reductions in lung function were assessed as another primary endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg (primary treatment comparison DULERA vs. formoterol). Deteriorations in asthma were defined as any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Fewer patients who received DULERA 100 mcg/5 mcg reported an event compared to patients who received formoterol 5 mcg (p<0.001).

Table 3: Trial 1 - Clinically Judged Deterioration in Asthma or Reduction in Lung Function*

	DULERA 100 mcg/ 5 mcg† (n=191)	Mometasone Furoate 100 mcg† (n=192)	Formoterol 5 mcg† (n=202)	Placebo† (n=196)
* Includes only the first event day for each patient. Patients could have experienced more than one event criterion. † Two inhalations, twice daily. ‡ Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication). § Decrease in AM or PM peak expiratory flow (PEF) on 2 or more consecutive days below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period). ¶ Thirty patients received glucocorticosteroids; 1 patient received formoterol via dry powder inhaler in the Formoterol 5 mcg group.
Clinically judged deterioration in asthma or reduction in lung function*	58 (30%)	65 (34%)	109 (54%)	109 (56%)
Decrease in FEV1‡	18 (9%)	19 (10%)	31 (15%)	41 (21%)
Decrease in PEF§	37 (19%)	41 (21%)	62 (31%)	61 (31%)
Emergency treatment	0	1 (<1%)	4 (2%)	1 (<1%)
Hospitalization	1 (<1%)	0	0	0
Treatment with excluded asthma medication¶	2 (1%)	4 (2%)	17 (8%)	8 (4%)

The change in mean trough FEV1 from baseline to Week 12 was assessed as another endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg. A significantly greater increase in mean trough FEV1 was observed for DULERA 100 mcg/5 mcg compared to formoterol 5 mcg (the primary treatment comparison) as well as to placebo (Table 4).

Table 4: Trial 1 – Change in Trough FEV1 from Baseline to Week 12

Treatment Arm	N	Baseline (L)	Change From Baseline at Week 12 (L)	Treatment Difference from Placebo (L)	P-Value vs. Placebo	P-Value vs. Formoterol
LS means and p-values are from Week 12 estimates of a longitudinal analysis model.
DULERA 100 mcg/5 mcg	167	2.33	0.13	0.18	<0.001	<0.001
Mometasone furoate 100 mcg	175	2.36	0.07	0.12	<0.001	0.058
Formoterol fumarate 5 mcg	141	2.29	0.00	0.05	0.170
Placebo	145	2.30	-0.05

The effect of DULERA 100 mcg/5 mcg, two inhalations twice daily on selected secondary efficacy endpoints, including proportion of nights with nocturnal awakenings (-60% vs. -15%), change in total rescue medication use (-0.6 vs. +1.1 puffs/day), change in morning peak flow (+18.1 vs. -28.4 L/min) and evening peak flow (+10.8 vs. -32.1 L/min) further supports the efficacy of DULERA 100 mcg/5 mcg compared to placebo.

The subjective impact of asthma on patients' health-related quality of life was evaluated by the Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). A change from baseline ≥0.5 points is considered a clinically meaningful improvement. The mean difference in AQLQ between patients receiving DULERA 100 mcg/5 mcg and placebo was 0.5 [95% CI 0.32, 0.68].

Trial 2: Clinical Trial With DULERA 200 mcg/5 mcg

This 12-week double-blind trial (NCT00381485) evaluated 728 patients 12 years of age and older comparing DULERA 200 mcg/5 mcg (n=255 patients) with DULERA 100 mcg/5 mcg (n=233 patients) and mometasone furoate 200 mcg (n=240 patients), each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This trial included a 2 to 3-week run-in period with mometasone furoate 200 mcg, 2 inhalations twice daily. Patients had persistent asthma and were uncontrolled on high dose inhaled corticosteroids prior to study entry. All treatment groups were balanced with regard to baseline characteristics. This trial included patients ranging from 12 to 84 years of age, 44% male and 56% female, and 89% Caucasian and 11% non-Caucasian. Mean FEV1 and mean percent predicted FEV1 values were similar among all treatment groups (2.05 L, 66%). Eleven (5%) patients receiving DULERA 100 mcg/5 mcg, 8 (3%) patients receiving DULERA 200 mcg/5 mcg and 13 (5%) patients receiving mometasone furoate 200 mcg discontinued the trial early due to treatment failure.

The primary efficacy endpoint was the mean change in FEV1 AUC(0-12 hr) from baseline to Week 12. Patients receiving DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg had significantly greater increases from baseline at Day 1 in mean FEV1 AUC(0-12 hr) compared to mometasone furoate 200 mcg. The difference was maintained over 12 weeks of therapy.

Mean change in trough FEV1 from baseline to Week 12 was also assessed to evaluate the relative contribution of mometasone furoate to DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg (Table 5). A greater numerical increase in the mean trough FEV1 was observed for DULERA 200 mcg/5 mcg compared to DULERA 100 mcg/5 mcg and mometasone furoate 200 mcg.

Table 5: Trial 2 – Change in Trough FEV1 from Baseline to Week 12

Treatment Arm	N	Baseline (L)	Change from Baseline at Week 12 (L)
DULERA 100 mcg/5 mcg	232	2.10	0.14
DULERA 200 mcg/5 mcg	255	2.05	0.19
Mometasone furoate 200 mcg	239	2.07	0.10

Clinically judged deterioration in asthma or reduction in lung function was assessed as an additional endpoint. Fewer patients who received DULERA 200 mcg/5 mcg or DULERA 100/5 mcg compared to mometasone furoate 200 mcg alone reported an event, defined as in Trial 1 by any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol.

Table 6: Trial 2 - Clinically Judged Deterioration in Asthma or Reduction in Lung Function*

	DULERA 100 mcg/ 5 mcg† (n=233)	DULERA 200 mcg/ 5 mcg† (n=255)	Mometasone Furoate 200 mcg† (n=240)
* Includes only the first event day for each patient. Patients could have experienced more than one event criterion. † Two inhalations, twice daily. ‡ Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication). § Decrease in AM or PM peak expiratory flow (PEF) below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period). ¶ Twenty four patients received glucocorticosteroids; 1 patient received albuterol in the DULERA 200 mcg / 5 mcg group.
Clinically judged deterioration in asthma or reduction in lung function*	29 (12%)	31 (12%)	44 (18%)
Decrease in FEV1‡	23 (10%)	17 (7%)	33 (14%)
Decrease in PEF on two consecutive days§	2 (1%)	4 (2%)	3 (1%)
Emergency treatment	2 (1%)	1 (<1%)	1 (<1%)
Hospitalization	0	1 (<1%)	0
Treatment with excluded asthma medication¶	5 (2%)	8 (3%)	12 (5%)

Other Studies in Adults

In addition to Trial 1 and Trial 2, the safety and efficacy of the individual components, mometasone furoate MDI 100 mcg and 200 mcg (each administered as 2 inhalations by MDI), in comparison to placebo were demonstrated in two other, 12-week, placebo-controlled trials that evaluated the mean change in FEV1 from baseline as a primary endpoint. The safety and efficacy of formoterol MDI 5 mcg (administered as 2 inhalations twice daily) alone in comparison to placebo was replicated in another 26-week trial (NCT00383552) that also evaluated the same endpoint with a lower dose of mometasone furoate MDI in combination with formoterol.

16.1 How Supplied

DULERA is available in three strengths and supplied in the following package sizes (Table 8):

Each strength is supplied as a pressurized aluminum canister that has a blue plastic actuator integrated with a dose counter and a green dust cap. Each 120-inhalation canister has a net fill weight of 13 grams and each 60-inhalation canister has a net fill weight of 8.8 grams. Each canister is placed into a carton. Each carton contains 1 canister and a Patient Information leaflet.

Initially the dose counter will display "64" or "124" actuations. After the initial priming with 4 actuations, the dose counter will read "60" or "120" and the inhaler is now ready for use.

16.2 Storage and Handling

Only use the DULERA canister with the DULERA actuator. Do not use the DULERA actuator with any other inhalation drug product. Do not use actuators from other products with the DULERA canister.

Do not remove the canister from the actuator because the correct amount of medication may not be discharged; the dose counter may not function properly; reinsertion may cause the dose counter to count down by 1 and discharge a puff.

The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate. Discard the inhaler when the labeled number of actuations has been used (the dose counter will read "0").

Store at controlled room temperature 20°C–25°C (68°F–77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].

The 120-inhalation inhaler does not require specific storage orientation. For the 60-inhalation inhaler, after priming, store the inhaler with the mouthpiece down or in a horizontal position.

For best results, keep the canister at room temperature before use. Shake well and remove the cap from the mouthpiece of the actuator before using. Keep out of reach of children. Avoid spraying in eyes.

Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator.

Serious Asthma-Related Events

Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization, or asthma-related death. Available data show that when ICS and LABA are used together, such as with DULERA, there is not a significant increase in risk of these events.

Not for Acute Symptoms

DULERA is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose. Treat acute symptoms with an inhaled, short-acting, beta2-agonist (the health care provider should prescribe the patient with such medication and instruct the patient in how it should be used).

Instruct patients to seek medical attention immediately if they experience any of the following:

• If their symptoms worsen
• Significant decrease in lung function as outlined by the physician
• If they need more inhalations of a short-acting beta2-agonist than usual

Advise patients not to increase the dose or frequency of DULERA. Do not exceed the daily dosage of DULERA of two inhalations twice daily. If they miss a dose, instruct patients to take their next dose at the same time they normally do. DULERA provides bronchodilation for up to 12 hours.

Instruct patients not to stop or reduce DULERA therapy without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2)].

Do Not Use Additional Long-Acting Beta2-Agonists

When patients are prescribed DULERA, other long-acting beta2-agonists should not be used [see Warnings and Precautions (5.3)].

Risks Associated With Corticosteroid Therapy

Risks Associated With Beta-Agonist Therapy

Inform patients that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness [see Warnings and Precautions (5.11)].

Instructions for Use

Instruct patients regarding the following:

• Read the Patient Information before use and follow the Instructions for Use carefully.
• Remind patients to:
  • Remove the cap from the mouthpiece of the actuator before use.
  • After dosing, rinse their mouth with water without swallowing and spit out after breathing in the medicine. This will help reduce the risk of oropharyngeal candidiasis.
  • Not remove the canister from the actuator.
  • Not wash inhaler in water. The mouthpiece should be cleaned using a dry wipe after every 7 days of use.