ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Data from large placebo-controlled US trial that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol [see Warnings and Precautions (5.1)].Systemic and local corticosteroid use may result in the following:Candida albicans infection [see Warnings and Precautions (5.4)] Immunosuppression [see Warnings and Precautions (5.5)] Hypercorticism and adrenal suppression [see Warnings and Precautions (5.7)] Growth effects in pediatrics [see Warnings and Precautions (5.13)] Glaucoma and cataracts [see Warnings and Precautions (5.14)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Candida albicans infection [see Warnings and Precautions (5.4)] Immunosuppression [see Warnings and Precautions (5.5)] Hypercorticism and adrenal suppression [see Warnings and Precautions (5.7)] Growth effects in pediatrics [see Warnings and Precautions (5.13)] Glaucoma and cataracts [see Warnings and Precautions (5.14)] Most common adverse reactions (reported in >=3% of patients) included: Nasopharyngitis, sinusitis and headache. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Nasopharyngitis, sinusitis and headache. (6.1). 6.1Clinical Trials Experience. The safety data described below is based on clinical trials which randomized 1913 patients 12 years of age and older with asthma, including 679 patients exposed to DULERA for 12 to 26 weeks and 271 patients exposed for year. DULERA was studied in two placebo- and active-controlled trials (n=781 and n=728, respectively) and in long-term 52-week safety trial (n=404). In the 12 to 26-week clinical trials, the population was 12 to 84 years of age, 41% male and 59% female, 73% Caucasians, 27% non-Caucasians. Patients received two inhalations twice daily of DULERA (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or 200 mcg), formoterol MDI (5 mcg) or placebo. In the long-term 52-week active-comparator safety trial, the population was 12 years to 75 years of age with asthma, 37% male and 63% female, 47% Caucasians, 53% non-Caucasians and received two inhalations twice daily of DULERA 100 mcg/5 mcg or 200 mcg/5 mcg, or an active comparator.The incidence of treatment emergent adverse reactions associated with DULERA in Table below is based upon pooled data from clinical trials 12 to 26 weeks in duration in patients 12 years and older treated with two inhalations twice daily of DULERA (100 mcg/5 mcg or 200 mcg/5 mcg), mometasone furoate MDI (100 mcg or 200 mcg), formoterol MDI (5mcg) or placebo.Table 1: Treatment-Emergent Adverse Reactions in DULERA Groups Occurring at an Incidence of >=3% and More Commonly than PlaceboAdverse ReactionsDULERAAll treatments were administered as two inhalations twice daily. Mometasone Furoate Formoterol Placebo 100 mcg/5 mcgn=424n (%)200 mcg/5 mcgn=255n (%)100 mcgn=192n (%)200 mcgn=240n (%)5 mcgn=202n (%)n=196n (%)Nasopharyngitis20 (4.7)12 (4.7)15 (7.8)13 (5.4)13 (6.4)7 (3.6)Sinusitis14 (3.3)5 (2.0)6 (3.1)4 (1.7)7 (3.5)2 (1.0)Headache19 (4.5)5 (2.0)10 (5.2)8 (3.3)6 (3.0)7 (3.6)Average Duration of Exposure (days)1168116579131138Oral candidiasis has been reported in clinical trials at an incidence of 0.7% in patients using DULERA 100 mcg/5 mcg, 0.8% in patients using DULERA 200 mcg/5 mcg and 0.5% in the placebo group.. Long-Term Clinical Trial ExperienceIn long-term safety trial in patients 12 years and older treated for 52 weeks with DULERA 100 mcg/5 mcg (n=141), DULERA 200 mcg/5 mcg (n=130) or an active comparator (n=133), safety outcomes in general were similar to those observed in the shorter 12 to 26 week controlled trials. No asthma-related deaths were observed. Dysphonia was observed at higher frequency in the longer term treatment trial at reported incidence of 7/141 (5%) patients receiving DULERA 100 mcg/5 mcg and 5/130 (3.8%) patients receiving DULERA 200 mcg/5 mcg. No clinically significant changes in blood chemistry, hematology, or ECG were observed.. 6.2Postmarketing 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiac disorders: angina pectoris, cardiac arrhythmias, e.g., atrial fibrillation, ventricular extrasystoles, tachyarrhythmia Immune system disorders: immediate and delayed hypersensitivity reactions including anaphylactic reaction, angioedema, severe hypotension, rash, pruritusInvestigations: electrocardiogram QT prolonged, blood pressure increased (including hypertension)Metabolism and nutrition disorders: hypokalemia, hyperglycemiaRespiratory, thoracic and mediastinal disorders: asthma aggravation, which may include cough, dyspnea, wheezing and bronchospasm.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal Toxicology and/or Pharmacology. Animal Pharmacology. Formoterol fumarate: 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.

BOXED WARNING SECTION.

WARNING: ASTHMA-RELATED DEATH. Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. [See Warnings and Precautions (5.1).]. WARNING: ASTHMA-RELATED DEATHSee full prescribing information for complete boxed warning.Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from large placebo-controlled U.S. study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.When treating patients with asthma, prescribe DULERA only for patients with asthma not adequately controlled on long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. (1.1, 5.1). Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from large placebo-controlled U.S. study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients.. When treating patients with asthma, prescribe DULERA only for patients with asthma not adequately controlled on long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. (1.1, 5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Mometasone furoate: In 2-year carcinogenicity study in Sprague Dawley(R) rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 14 times the MRHD on an AUC basis). In 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately times the MRHD on an AUC basis).Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, rat bone marrow chromosomal aberration assay, or mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately times the MRHD on an AUC basis).. Formoterol fumarate: 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 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to mg/kg (AUC exposure approximately 265 times human exposure at the MRHD). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 27 times human exposure at the MRHD). 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 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 350 times human exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to mg/kg in either males or females (AUC exposure approximately 35 times human exposure at the MRHD). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of mg/kg and above (AUC exposure at the low dose of mg/kg was approximately 14 times human exposure at the MRHD). 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 mg/kg (approximately 1200 times the MRHD on mcg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the mechanisms of actions described below for the individual components apply to DULERA. These drugs represent two different classes of medications (a synthetic corticosteroid and selective long-acting beta2-adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.. Mometasone furoate: Mometasone furoate is corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.Mometasone furoate has been shown in vitro to exhibit binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, times that of triamcinolone acetonide, times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown.. Formoterol fumarate: Formoterol fumarate is long-acting selective beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-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 beta2-agonists may have cardiac effects.The pharmacologic effects of beta2-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.. 12.2Pharmacodynamics. Cardiovascular Effects:. DULERA:In single-dose, double-blind placebo-controlled crossover trial in 25 patients with asthma, single-dose treatment of 10 mcg formoterol fumarate in combination with 400 mcg of mometasone furoate delivered via DULERA 200 mcg/5 mcg were compared to formoterol fumarate 10 mcg MDI, formoterol fumarate 12 mcg dry powder inhaler (DPI; nominal dose of formoterol fumarate delivered 10 mcg), or placebo. The degree of bronchodilation at 12 hours after dosing with DULERA was similar to formoterol fumarate delivered alone via MDI or DPI.ECGs and blood samples for glucose and potassium were obtained prior to dosing and post dose. No downward trend in serum potassium was observed and values were within the normal range and appeared to be similar across all treatments over the 12 hour period. Mean blood glucose appeared similar across all groups for each time point. There was no evidence of significant hypokalemia or hyperglycemia in response to formoterol treatment.No relevant changes in heart rate or changes in ECG data were observed with DULERA in the trial. No patients had QTcB (QTc corrected by Bazetts formula) >=500 msec during treatment.In single-dose crossover trial involving 24 healthy subjects, single dose of formoterol fumarate 10, 20, or 40 mcg in combination with 400 mcg of mometasone furoate delivered via DULERA were evaluated for safety (ECG, blood potassium and glucose changes). ECGs and blood samples for glucose and potassium were obtained at baseline and post dose. Decrease in mean serum potassium was similar across all three treatment groups (approximately 0.3 mmol/L) and values were within the normal range. No clinically significant increases in mean blood glucose values or heart rate were observed. No subjects had QTcB >500 msec during treatment.Three active- and placebo-controlled trials (study duration ranging from 12, 26, and 52 weeks) evaluated 1913 patients 12 years of age and older with asthma. No clinically meaningful changes were observed in potassium and glucose values, vital signs, or ECG parameters in patients receiving DULERA.. HPA Axis Effects:The effects of inhaled mometasone furoate administered via DULERA on adrenal function were evaluated in two clinical trials in patients with asthma. HPA-axis function was assessed by 24-hour plasma cortisol AUC. Although both these trials have open-label design and contain small number of subjects per treatment arm, results from these trials taken together demonstrated suppression of 24-hour plasma cortisol AUC for DULERA 200 mcg/5 mcg compared to placebo consistent with the known systemic effects of inhaled corticosteroid.In 42-day, open-label, placebo and active-controlled study 60 patients with asthma 18 years of age and older were randomized to receive two inhalations twice daily of of the following treatments: DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg, or placebo. At Day 42, the mean change from baseline plasma cortisol AUC(0-24 hr) was 8%, 22% and 34% lower compared to placebo for the DULERA 100 mcg/5 mcg (n=13), DULERA 200 mcg/5 mcg (n=15) and fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg (n=16) treatment groups, respectively.In 52-week, open-label safety study, primary analysis of the plasma cortisol 24-hour AUC was performed on 57 patients with asthma who received inhalations twice daily of DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 125/25 mcg, or fluticasone propionate/salmeterol xinafoate 250/25 mcg. At Week 52, the mean plasma cortisol AUC(0-24 hr) was 2.2%, 29.6%, 16.7%, and 32.2% lower from baseline for the DULERA 100 mcg/5 mcg (n=18), DULERA 200 mcg/5 mcg (n=20), fluticasone propionate/salmeterol xinafoate 125/25 mcg (n=8), and fluticasone propionate/salmeterol xinafoate 250/25 mcg (n=11) treatment groups, respectively.. Other Mometasone Products. HPA Axis Effects:The potential effect of mometasone furoate via dry powder inhaler (DPI) on the HPA axis was assessed in 29-day study. total of 64 adult patients with mild to moderate asthma were randomized to one of treatment groups: mometasone furoate DPI 440 mcg twice daily, mometasone furoate DPI 880 mcg twice daily, oral prednisone 10 mg once daily, or placebo. The 30-minute post-Cosyntropin stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dl for the mometasone furoate DPI 440 mcg twice daily group and 20.8 mcg/dl for the mometasone furoate DPI 880 mcg twice daily group, compared to 14.5 mcg/dl for the oral prednisone 10 mg group and 25 mcg/dl for the placebo group. The difference between mometasone furoate DPI 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.. 12.3Pharmacokinetics. Absorption. Mometasone furoate:. Healthy Subjects: The systemic exposures to mometasone furoate from DULERA versus mometasone furoate delivered via DPI were compared. Following oral inhalation of single and multiple doses of the DULERA, mometasone furoate was absorbed in healthy subjects with median Tmax values ranging from 0.50 to hours. Following single-dose administration of higher than recommended dose of DULERA (4 inhalations of DULERA 200 mcg/5 mcg) in healthy subjects, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for MF were 67.8 (49) pg/mL and 650 (51) pghr/mL, respectively while the corresponding estimates following days of BID dosing of DULERA 800 mcg/20 mcg were 241 (36) pg/mL and 2200 (35) pghr/mL. Exposure to mometasone furoate increased with increasing inhaled dose of DULERA 100 mcg/5 mcg to 200 mcg/5 mcg. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of mometasone furoate is negligible (<1%).The above study demonstrated that the systemic exposure to mometasone furoate (based on AUC) was approximately 52% and 25% lower on Day and Day 5, respectively, following DULERA administration compared to mometasone furoate via DPI.. Asthma Patients: Following oral inhalation of single and multiple doses of the DULERA, mometasone furoate was absorbed in asthma patients with median Tmax values ranging from to hours. Following single-dose administration of DULERA 400 mcg/10 mcg, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for MF were 20 (88) pg/mL and 170 (94) pghr/mL, respectively while the corresponding estimates following BID dosing of DULERA 400 mcg/10 mcg at steady-state were 60 (36) pg/mL and 577 (40) pghr/mL.. Formoterol fumarate: Healthy Subjects: When DULERA was administered to healthy subjects, formoterol was absorbed with median Tmax values ranging from 0.167 to 0.5 hour. In single-dose study with DULERA 400 mcg/10 mcg in healthy subjects, arithmetic mean (CV%) Cmax and AUC for formoterol were 15 (50) pmol/L and 81 (51) pmolh/L, respectively. Over the dose range of 10 to 40 mcg for formoterol from DULERA, the exposure to formoterol was dose proportional.. Asthma Patients: When DULERA was administered to patients with asthma, formoterol was absorbed with median Tmax values ranging from 0.58 to 1.97 hours. In single-dose study with DULERA 400 mcg/10 mcg in patients with asthma, arithmetic mean (CV%) Cmax and AUC(0-12 hr) for formoterol were 22 (29) pmol/L and 125 (42) pmolh/L, respectively. Following multiple-dose administration of DULERA 400 mcg/10 mcg, the steady-state arithmetic mean (CV%) Cmax and AUC(0-12 hr) for formoterol were 41 (59) pmol/L and 226 (54) pmolhr/L.. Distribution. Mometasone furoate: Based on the study employing 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder in humans, no appreciable accumulation of mometasone furoate in the red blood cells was found. Following an intravenous 400 mcg dose of mometasone furoate, the plasma concentrations showed biphasic decline, with mean steady-state volume of distribution of 152 liters. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% (in concentration range of to 500 ng/mL).. Formoterol fumarate: The binding of formoterol to human plasma proteins in vitro was 61% to 64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31% to 38% over range of to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of single 120 mcg dose.. Metabolism. Mometasone furoate: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. In-vitro studies have confirmed the primary role of human liver cytochrome P-450 3A4 (CYP3A4) in the metabolism of this compound, however, no major metabolites were identified. Human liver CYP3A4 metabolizes mometasone furoate to 6-beta hydroxy mometasone furoate.. Formoterol fumarate: Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.. Excretion. Mometasone furoate: Following an intravenous dosing, the terminal half-life was reported to be about hours. Following the inhaled dose of tritiated 1000 mcg mometasone furoate, the radioactivity is excreted mainly in the feces (a mean of 74%), and to small extent in the urine (a mean of 8%) up to days. No radioactivity was associated with unchanged mometasone furoate in the urine. Absorbed mometasone furoate is cleared from plasma at rate of approximately 12.5 mL/min/kg, independent of dose. The effective 1/2 for mometasone furoate following inhalation with DULERA was 25 hours in healthy subjects and in patients with asthma.. Formoterol fumarate: Following oral administration of 80 mcg of radiolabeled formoterol fumarate to healthy subjects, 59% to 62% of the radioactivity was eliminated in the urine and 32% to 34% in the feces over period of 104 hours. In an oral inhalation study with DULERA, renal clearance of formoterol from the blood was 217 mL/min. In single-dose studies, the mean 1/2 values for formoterol in plasma were 9.1 hours and 10.8 hours from the urinary excretion data. The accumulation of formoterol in plasma after multiple dose administration was consistent with the increase expected with drug having terminal 1/2 of to 11 hour.Following single inhaled doses ranging from 10 to 40 mcg to healthy subjects from the MFF MDI, 6.2% to 6.8% of the formoterol dose was excreted in urine unchanged. The (R,R) and (S,S)-enantiomers accounted, respectively, for 37% and 63% of the formoterol recovered in urine. From urinary excretion rates measured in healthy subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13 and 9.5 hours, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied.. Special Populations. Hepatic/Renal Impairment: There are no data regarding the specific use of DULERA in patients with hepatic or renal impairment.A study evaluating the administration of single inhaled dose of 400 mcg mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only or subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50-105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.. Gender and Race: Specific studies to examine the effects of gender and race on the pharmacokinetics of DULERA have not been specifically studied.. Geriatrics: The pharmacokinetics of DULERA have not been specifically studied in the elderly population.. Drug-Drug InteractionsA single-dose crossover study was conducted to compare the pharmacokinetics of inhalations of the following: mometasone furoate MDI, formoterol MDI, DULERA (mometasone furoate/formoterol fumarate MDI), and mometasone furoate MDI plus formoterol fumarate MDI administered concurrently. The results of the study indicated that there was no evidence of pharmacokinetic interaction between the two components of DULERA.. Inhibitors of Cytochrome P450 Enzymes: Ketoconazole: In drug interaction study, an inhaled dose of mometasone furoate 400 mcg delivered by dry powder inhaler was given to 24 healthy subjects twice daily for days and ketoconazole 200 mg (as well as placebo) were given twice daily concomitantly on Days to 9. Mometasone furoate plasma concentrations were <150 pcg/mL on Day prior to coadministration of ketoconazole or placebo. Following concomitant administration of ketoconazole, out of 12 subjects in the ketoconazole treatment group (n=12) had peak plasma concentrations of mometasone furoate >200 pcg/mL on Day (211-324 pcg/mL). Mometasone furoate plasma levels appeared to increase and plasma cortisol levels appeared to decrease upon concomitant administration of ketoconazole.Specific drug-drug interaction studies with formoterol have not been performed.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. 14.1 Asthma. 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 2 to 3-week run-in period with mometasone furoate to establish 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 mcgThis 26-week, placebo-controlled trial 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 mcg (n=202 patients) and placebo (n=196 patients); each administered as inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This study included 2 to 3-week run-in period with mometasone furoate 100 mcg, 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 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure.FEV1 AUC(0-12 hr) was assessed as 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 shows the change from baseline post-dose serial FEV1 evaluations in Trial 1.Figure 1Trial - DULERA 100 mcg/5 mcg FEV1 Serial Evaluations for Observed Cases at Week 12 Change from Baseline by TreatmentClinically 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: 20% decrease in FEV1; 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 mcg (p<0.001).Table 2: Trial - Clinically Judged Deterioration in Asthma or Reduction in Lung FunctionIncludes only the first event day for each patient. Patients could have experienced more than one event criterion. DULERA100 mcg/5 mcgTwo inhalations, twice daily. (n=191)MometasoneFuroate100 mcg (n=192)Formoterol5 mcg (n=202)Placebo (n=196)Clinically judged deterioration in asthma or reduction in lung function 58(30%)65(34%)109(54%)109(56%) Decrease in FEV1 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). 18(9%)19(10%)31(15%)41(21%) Decrease in PEFDecrease in AM or PM peak expiratory flow (PEF) on or more consecutive days below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last days of the run-in period). 37(19%)41(21%)62(31%)61(31%) Emergency treatment01(<1%)4(2%)1(<1%) Hospitalization1(<1%)000 Treatment with excluded asthma medicationThirty patients received glucocorticosteroids; patient received formoterol via dry powder inhaler in the Formoterol mcg group. 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. significantly greater increase in mean trough FEV1 was observed for DULERA 100 mcg/5 mcg compared to formoterol mcg (the primary treatment comparison) as well as to placebo (Table 3).Table 3: Trial - Change in Trough FEV1 from Baseline to Week 12Treatment ArmNBaseline (L)Change From Baseline at Week 12 (L)Treatment Difference from Placebo (L)P-Valuevs. PlaceboP-Valuevs. FormoterolLS means and p-values are from Week 12 estimates of longitudinal analysis model.DULERA 100 mcg/5 mcg1672.330.130.18<0.001<0.001Mometasone furoate 100 mcg1752.360.070.12<0.0010.058Formoterol fumarate mcg1412.290.000.050.170Placebo1452.30-0.05The 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 7-point scale where = maximum impairment and = no impairment). change from baseline >=0.5 points is considered 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].. Image of Figure 1. Trial 2: Clinical Trial With DULERA 200 mcg/5 mcgThis 12-week double-blind trial 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 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This trial included 2 to 3-week run-in period with mometasone furoate 200 mcg, 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, (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 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 4). 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 4: Trial - Change in Trough FEV1 from Baseline to Week 12Treatment ArmNBaseline(L)Change from Baseline at Week 12 (L)DULERA 100 mcg/5 mcg2322.100.14DULERA 200 mcg/5 mcg2552.050.19Mometasone furoate 200 mcg2392.070.10Clinically 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 by any of the following: 20% decrease in FEV1; 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 5: Trial - Clinically Judged Deterioration in Asthma or Reduction in Lung FunctionIncludes only the first event day for each patient. Patients could have experienced more than one event criterion. DULERA 100 mcg/5 mcgTwo inhalations, twice daily. (n=233)DULERA200 mcg/5 mcg (n=255)MometasoneFuroate200 mcg (n=240)Clinically judged deterioration in asthma or reduction in lung function 29(12%)31(12%)44(18%) Decrease in FEV1 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). 23(10%)17(7%)33(14%) Decrease in PEF on two consecutive daysDecrease 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 days of the run-in period). 2(1%)4(2%)3(1%) Emergency treatment2(1%)1(<1%)1(<1%) Hospitalization0 1(<1%)0 Treatment with excluded asthma medicationTwenty four patients received glucocorticosteroids; patient received albuterol in the DULERA 200 mcg 5 mcg group. 5(2%)8(3%)12(5%). Other StudiesIn addition to Trial and Trial 2, the safety and efficacy of the individual components, mometasone furoate MDI 100 mcg and 200 mcg, in comparison to placebo were demonstrated in three other, 12-week, placebo controlled trials which evaluated the mean change in FEV1 from baseline as primary endpoint. The safety and efficacy of formoterol MDI mcg alone in comparison to placebo was replicated in another 26-week trial that evaluated lower dose of mometasone furoate MDI in combination with formoterol.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4.1)Hypersensitivity to any of the ingredients of DULERA. (4.2). Primary treatment of status asthmaticus or acute episodes of asthma requiring intensive measures. (4.1). Hypersensitivity to any of the ingredients of DULERA. (4.2). 4.1Status Asthmaticus. DULERA is contraindicated in the primary treatment of status asthmaticus or other acute episodes of asthma where intensive measures are required.. 4.2Hypersensitivity. 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)].

DESCRIPTION SECTION.

11DESCRIPTION. DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg are combinations of mometasone furoate and formoterol fumarate dihydrate for oral inhalation only.One active component of DULERA is mometasone furoate, corticosteroid having the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16 (alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) with the following chemical structure:Mometasone furoate is white powder with an empirical formula of C27H30Cl2O6, and molecular weight 521.44. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone.One active component of DULERA is formoterol fumarate dihydrate, racemate. Formoterol fumarate dihydrate is selective beta2-adrenergic bronchodilator having the chemical name of (+-)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate with the following chemical structure:Formoterol fumarate dihydrate has molecular weight of 840.9, and its empirical formula is (C19H24N2O4)2oC4H4O4o2H2O. Formoterol fumarate dihydrate is white to yellowish powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether.Each DULERA 100 mcg/5 mcg and 200 mcg/5 mcg is hydrofluoroalkane (HFA-227) propelled pressurized metered dose inhaler containing sufficient amount of drug for 60 or 120 inhalations [see How Supplied/Storage and Handling (16)]. After priming, each actuation of the inhaler delivers 115 or 225 mcg of mometasone furoate and 5.5 mcg of formoterol fumarate dihydrate in 69.6 mg of suspension from the valve and delivers 100 or 200 mcg of mometasone furoate and mcg of formoterol fumarate dihydrate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. DULERA also contains anhydrous alcohol as cosolvent and oleic acid as surfactant.DULERA should be primed before using for the first time by releasing 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 days, prime the inhaler again by releasing test sprays into the air, away from the face, shaking well before each spray.. Image of Mometasone Furoate Chemical Structure. Image of Formoterol Fumarate Dihydrate Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2DOSAGE AND ADMINISTRATION. For oral inhalation only. (2.1)Treatment of asthma in patients >=12 years: inhalations twice daily of DULERA 100 mcg/5 mcg or 200 mcg/5 mcg. Starting dosage is based on prior asthma therapy and disease severity. (2.2). 2.1Administration Information. DULERA should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route (see Patient Instructions for Use in the Medication Guide). Shake well prior to each inhalation. After each dose, the patient should be advised to rinse his/her mouth with water without swallowing.The cap from the mouthpiece of the actuator should be removed before using DULERA.DULERA should be primed before using for the first time by releasing 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 days, prime the inhaler again by releasing test sprays into the air, away from the face, shaking well before each spray.The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister.. 2.2Recommended Dosage. Adults and Adolescents 12 Years of Age and OlderThe dosage is either inhalations twice daily of DULERA 100 mcg/5 mcg or DULERA 200 mcg/5 mcg. The maximum recommended dosage is two inhalations of DULERA 200 mcg/5 mcg twice daily (maximum daily dosage 800 mcg/20 mcg).When choosing the starting dosage strength of DULERA, consider the patients disease severity, based on their previous asthma therapy, including the inhaled corticosteroid dosage, as well as the patients current control of asthma symptoms and risk of future exacerbation.The maximum benefit may not be achieved for week or longer after beginning treatment. Individual patients may experience variable time to onset and degree of symptom relief. For patients who do not respond adequately after weeks of therapy with two inhalations of DULERA 100 mcg/5 mcg twice daily (morning and evening), increasing the dosage to two inhalations of DULERA 200 mcg/5 mcg twice daily (morning and evening) may provide additional asthma control.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.If previously effective dosage regimen of DULERA fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength of DULERA with higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered.

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. DULERA is pressurized metered dose inhaler that is available in strengths.DULERA 100 mcg/5 mcg delivers 100 mcg of mometasone furoate and mcg of formoterol fumarate dihydrate per actuation.DULERA 200 mcg/5 mcg delivers 200 mcg of mometasone furoate and mcg of formoterol fumarate dihydrate per actuation.. Inhalation aerosol containing combination of mometasone furoate (100 or 200 mcg) and formoterol fumarate dihydrate (5 mcg) per actuation. (3).

DRUG INTERACTIONS SECTION.

7DRUG INTERACTIONS. In clinical trials, concurrent administration of DULERA and other drugs, such as short-acting beta2-agonist and intranasal corticosteroids have not resulted in an increased frequency of adverse drug reactions. No formal drug interaction studies have been performed with DULERA. The drug interactions of the combination are expected to reflect those of the individual components.. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (7.1)Adrenergic agents: Use with caution. Additional adrenergic drugs may potentiate sympathetic effects. (7.2)Xanthine derivatives and diuretics: Use with caution. May potentiate ECG changes and/or hypokalemia. (7.3, 7.4)MAO inhibitors, tricyclic antidepressants, macrolides, and drugs that prolong QTc interval: Use with extreme caution. May potentiate effect on the cardiovascular system. (7.5)Beta-blockers: Use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm. (7.6)Halogenated hydrocarbons: There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons. (7.7). Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (7.1). Adrenergic agents: Use with caution. Additional adrenergic drugs may potentiate sympathetic effects. (7.2). Xanthine derivatives and diuretics: Use with caution. May potentiate ECG changes and/or hypokalemia. (7.3, 7.4). MAO inhibitors, tricyclic antidepressants, macrolides, and drugs that prolong QTc interval: Use with extreme caution. May potentiate effect on the cardiovascular system. (7.5). Beta-blockers: Use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm. (7.6). Halogenated hydrocarbons: There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons. (7.7). 7.1Inhibitors of Cytochrome P450 3A4. The main route of metabolism of corticosteroids, including mometasone furoate, component of DULERA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, 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. Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)].. 7.2Adrenergic 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, component of DULERA, may be potentiated.. 7.3Xanthine Derivatives. Concomitant treatment with xanthine derivatives may potentiate any hypokalemic effect of formoterol, component of DULERA.. 7.4Diuretics. 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.. 7.5Monoamine 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 weeks of discontinuation of such agents, because the action of formoterol, 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.. 7.6Beta-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, 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.. 7.7Halogenated Hydrocarbons. There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

GERIATRIC USE SECTION.

8.5Geriatric Use. total of 77 patients 65 years of age and older (11 of whom were 75 years and older) have been treated with DULERA in 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.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. Product: 50090-1916NDC: 50090-1916-0 60 AEROSOL in CANISTER.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. DULERA is combination product containing corticosteroid and long-acting beta2-adrenergic agonist indicated for:Treatment of asthma in patients 12 years of age and older. (1.1)Important limitations:Not indicated for the relief of acute bronchospasm. (1.1). Treatment of asthma in patients 12 years of age and older. (1.1). Not indicated for the relief of acute bronchospasm. (1.1). 1.1Treatment of Asthma. DULERA is indicated for the treatment of asthma in patients 12 years of age and older.Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.. Important Limitation of UseDULERA is NOT indicated for the relief of acute bronchospasm.. DULERA is NOT indicated for the relief of acute bronchospasm.

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).. Asthma-Related DeathPatients should be informed that formoterol, one of the active ingredients in DULERA, increases the risk of asthma-related death. In pediatric and adolescent patients, formoterol may increase the risk of asthma-related hospitalization. They should also be informed that data are not adequate to determine whether the concurrent use of inhaled corticosteroids, the other component of DULERA, or other long-term asthma-control therapy mitigates or eliminates this risk [see Warnings and Precautions (5.1)]. Not for Acute SymptomsDULERA is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated 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).Patients should be instructed to seek medical attention immediately if they experience any of the following:If their symptoms worsenSignificant decrease in lung function as outlined by the physicianIf they need more inhalations of short-acting beta2-agonist than usualPatients should be advised not to increase the dose or frequency of DULERA. The daily dosage of DULERA should not exceed two inhalations twice daily. If they miss dose, they should be instructed to take their next dose at the same time they normally do. DULERA provides bronchodilation for up to 12 hours.Patients should not stop or reduce DULERA therapy without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2)].. If their symptoms worsen. Significant decrease in lung function as outlined by the physician. If they need more inhalations of short-acting beta2-agonist than usual. Do Not Use Additional Long-Acting Beta2-AgonistsWhen patients are prescribed DULERA, other long-acting beta2-agonists should not be used [see Warnings and Precautions (5.3)].. Risks Associated With Corticosteroid Therapy. Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with DULERA therapy, but at times therapy with DULERA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.4)]. Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.5)]. Hypercorticism and Adrenal Suppression: Patients should be advised that DULERA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to DULERA [see Warnings and Precautions (5.7)]. Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and, where appropriate, be treated for this condition [see Warnings and Precautions (5.12)]. Reduced Growth Velocity: Patients should be informed that orally inhaled corticosteroids, component of DULERA, may cause reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.13)]. Glaucoma and Cataracts: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (glaucoma or cataracts); regular eye examinations should be considered [see Warnings and Precautions (5.14)]. Risks Associated With Beta-Agonist TherapyPatients should be informed 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 UsePatients should be instructed regarding the following:Read the Medication Guide before use and follow the Instructions for Use carefully. Patients should be reminded to: Remove the cap from the mouthpiece of the actuator before use. Not remove the canister from the actuator.Not wash inhaler in water. The mouthpiece should be cleaned using dry wipe after every days of use. Read the Medication Guide before use and follow the Instructions for Use carefully. Patients should be reminded to: Remove the cap from the mouthpiece of the actuator before use. Not remove the canister from the actuator.Not wash inhaler in water. The mouthpiece should be cleaned using dry wipe after every days of use. Remove the cap from the mouthpiece of the actuator before use. Not remove the canister from the actuator.. Not wash inhaler in water. The mouthpiece should be cleaned using dry wipe after every days of use.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are no available data on the presence of DULERA, mometasone furoate, or formoterol fumarate in human milk, the effects on the breastfed child, or the effects on milk production. Other inhaled corticosteroids, similar to mometasone furoate, are present in human milk. Formoterol fumarate is present in rat milk; however, due to species specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DULERA and any potential adverse effects on the breastfed infant from DULERA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the mechanisms of actions described below for the individual components apply to DULERA. These drugs represent two different classes of medications (a synthetic corticosteroid and selective long-acting beta2-adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.. Mometasone furoate: Mometasone furoate is corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.Mometasone furoate has been shown in vitro to exhibit binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, times that of triamcinolone acetonide, times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown.. Formoterol fumarate: Formoterol fumarate is long-acting selective beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-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 beta2-agonists may have cardiac effects.The pharmacologic effects of beta2-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.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Mometasone furoate: In 2-year carcinogenicity study in Sprague Dawley(R) rats, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 67 mcg/kg (approximately 14 times the MRHD on an AUC basis). In 19-month carcinogenicity study in Swiss CD-1 mice, mometasone furoate demonstrated no statistically significant increase in the incidence of tumors at inhalation doses up to 160 mcg/kg (approximately times the MRHD on an AUC basis).Mometasone furoate increased chromosomal aberrations in an in vitro Chinese hamster ovary cell assay, but did not have this effect in an in vitro Chinese hamster lung cell assay. Mometasone furoate was not mutagenic in the Ames test or mouse lymphoma assay, and was not clastogenic in an in vivo mouse micronucleus assay, rat bone marrow chromosomal aberration assay, or mouse male germ-cell chromosomal aberration assay. Mometasone furoate also did not induce unscheduled DNA synthesis in vivo in rat hepatocytes.In reproductive studies in rats, impairment of fertility was not produced by subcutaneous doses up to 15 mcg/kg (approximately times the MRHD on an AUC basis).. Formoterol fumarate: 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 mg/kg and above in the drinking water study and at 20 mg/kg in the dietary study, but not at dietary doses up to mg/kg (AUC exposure approximately 265 times human exposure at the MRHD). In the dietary study, the incidence of benign ovarian theca-cell tumors was increased at doses of 0.5 mg/kg and above (AUC exposure at the low dose of 0.5 mg/kg was approximately 27 times human exposure at the MRHD). 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 mg/kg and above in the drinking water study, but not at doses up to 50 mg/kg (AUC exposure approximately 350 times human exposure at the MRHD) in the dietary study. The incidence of hepatocarcinomas was increased in the dietary study at doses of 20 and 50 mg/kg in females and 50 mg/kg in males, but not at doses up to mg/kg in either males or females (AUC exposure approximately 35 times human exposure at the MRHD). Also in the dietary study, the incidence of uterine leiomyomas and leiomyosarcomas was increased at doses of mg/kg and above (AUC exposure at the low dose of mg/kg was approximately 14 times human exposure at the MRHD). 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 mg/kg (approximately 1200 times the MRHD on mcg/m2 basis).. 13.2Animal Toxicology and/or Pharmacology. Animal Pharmacology. Formoterol fumarate: 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.

OVERDOSAGE SECTION.

10OVERDOSAGE. 10.1Signs and Symptoms. DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to DULERA.. Mometasone Furoate: Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.7)]. Single oral doses up to 8000 mcg of mometasone furoate have been studied on human volunteers with no adverse reactions reported.. Formoterol Fumarate: The expected signs and symptoms with overdosage of formoterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the following signs and symptoms: angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of formoterol.The minimum acute lethal inhalation dose of formoterol fumarate in rats is 156 mg/kg (approximately 63,000 times the MRHD on mcg/m2 basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the MRHD.. 10.2Treatment. DULERA: Treatment of overdosage consists of discontinuation of DULERA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of DULERA. Cardiac monitoring is recommended in cases of overdosage.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

mometasone furoate and formoterol fumarate dihydrate. Label Image.

PEDIATRIC USE SECTION.

8.4Pediatric Use. The safety and effectiveness of DULERA have been established in patients 12 years of age and older in clinical trials up to 52 weeks in duration. In the 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 drug 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 efficacy of DULERA have not been established in children less than 12 years of age.Controlled clinical studies have shown that inhaled corticosteroids may cause reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 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 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 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)].

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics. Cardiovascular Effects:. DULERA:In single-dose, double-blind placebo-controlled crossover trial in 25 patients with asthma, single-dose treatment of 10 mcg formoterol fumarate in combination with 400 mcg of mometasone furoate delivered via DULERA 200 mcg/5 mcg were compared to formoterol fumarate 10 mcg MDI, formoterol fumarate 12 mcg dry powder inhaler (DPI; nominal dose of formoterol fumarate delivered 10 mcg), or placebo. The degree of bronchodilation at 12 hours after dosing with DULERA was similar to formoterol fumarate delivered alone via MDI or DPI.ECGs and blood samples for glucose and potassium were obtained prior to dosing and post dose. No downward trend in serum potassium was observed and values were within the normal range and appeared to be similar across all treatments over the 12 hour period. Mean blood glucose appeared similar across all groups for each time point. There was no evidence of significant hypokalemia or hyperglycemia in response to formoterol treatment.No relevant changes in heart rate or changes in ECG data were observed with DULERA in the trial. No patients had QTcB (QTc corrected by Bazetts formula) >=500 msec during treatment.In single-dose crossover trial involving 24 healthy subjects, single dose of formoterol fumarate 10, 20, or 40 mcg in combination with 400 mcg of mometasone furoate delivered via DULERA were evaluated for safety (ECG, blood potassium and glucose changes). ECGs and blood samples for glucose and potassium were obtained at baseline and post dose. Decrease in mean serum potassium was similar across all three treatment groups (approximately 0.3 mmol/L) and values were within the normal range. No clinically significant increases in mean blood glucose values or heart rate were observed. No subjects had QTcB >500 msec during treatment.Three active- and placebo-controlled trials (study duration ranging from 12, 26, and 52 weeks) evaluated 1913 patients 12 years of age and older with asthma. No clinically meaningful changes were observed in potassium and glucose values, vital signs, or ECG parameters in patients receiving DULERA.. HPA Axis Effects:The effects of inhaled mometasone furoate administered via DULERA on adrenal function were evaluated in two clinical trials in patients with asthma. HPA-axis function was assessed by 24-hour plasma cortisol AUC. Although both these trials have open-label design and contain small number of subjects per treatment arm, results from these trials taken together demonstrated suppression of 24-hour plasma cortisol AUC for DULERA 200 mcg/5 mcg compared to placebo consistent with the known systemic effects of inhaled corticosteroid.In 42-day, open-label, placebo and active-controlled study 60 patients with asthma 18 years of age and older were randomized to receive two inhalations twice daily of of the following treatments: DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg, or placebo. At Day 42, the mean change from baseline plasma cortisol AUC(0-24 hr) was 8%, 22% and 34% lower compared to placebo for the DULERA 100 mcg/5 mcg (n=13), DULERA 200 mcg/5 mcg (n=15) and fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg (n=16) treatment groups, respectively.In 52-week, open-label safety study, primary analysis of the plasma cortisol 24-hour AUC was performed on 57 patients with asthma who received inhalations twice daily of DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 125/25 mcg, or fluticasone propionate/salmeterol xinafoate 250/25 mcg. At Week 52, the mean plasma cortisol AUC(0-24 hr) was 2.2%, 29.6%, 16.7%, and 32.2% lower from baseline for the DULERA 100 mcg/5 mcg (n=18), DULERA 200 mcg/5 mcg (n=20), fluticasone propionate/salmeterol xinafoate 125/25 mcg (n=8), and fluticasone propionate/salmeterol xinafoate 250/25 mcg (n=11) treatment groups, respectively.. Other Mometasone Products. HPA Axis Effects:The potential effect of mometasone furoate via dry powder inhaler (DPI) on the HPA axis was assessed in 29-day study. total of 64 adult patients with mild to moderate asthma were randomized to one of treatment groups: mometasone furoate DPI 440 mcg twice daily, mometasone furoate DPI 880 mcg twice daily, oral prednisone 10 mg once daily, or placebo. The 30-minute post-Cosyntropin stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dl for the mometasone furoate DPI 440 mcg twice daily group and 20.8 mcg/dl for the mometasone furoate DPI 880 mcg twice daily group, compared to 14.5 mcg/dl for the oral prednisone 10 mg group and 25 mcg/dl for the placebo group. The difference between mometasone furoate DPI 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. Absorption. Mometasone furoate:. Healthy Subjects: The systemic exposures to mometasone furoate from DULERA versus mometasone furoate delivered via DPI were compared. Following oral inhalation of single and multiple doses of the DULERA, mometasone furoate was absorbed in healthy subjects with median Tmax values ranging from 0.50 to hours. Following single-dose administration of higher than recommended dose of DULERA (4 inhalations of DULERA 200 mcg/5 mcg) in healthy subjects, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for MF were 67.8 (49) pg/mL and 650 (51) pghr/mL, respectively while the corresponding estimates following days of BID dosing of DULERA 800 mcg/20 mcg were 241 (36) pg/mL and 2200 (35) pghr/mL. Exposure to mometasone furoate increased with increasing inhaled dose of DULERA 100 mcg/5 mcg to 200 mcg/5 mcg. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of mometasone furoate is negligible (<1%).The above study demonstrated that the systemic exposure to mometasone furoate (based on AUC) was approximately 52% and 25% lower on Day and Day 5, respectively, following DULERA administration compared to mometasone furoate via DPI.. Asthma Patients: Following oral inhalation of single and multiple doses of the DULERA, mometasone furoate was absorbed in asthma patients with median Tmax values ranging from to hours. Following single-dose administration of DULERA 400 mcg/10 mcg, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for MF were 20 (88) pg/mL and 170 (94) pghr/mL, respectively while the corresponding estimates following BID dosing of DULERA 400 mcg/10 mcg at steady-state were 60 (36) pg/mL and 577 (40) pghr/mL.. Formoterol fumarate: Healthy Subjects: When DULERA was administered to healthy subjects, formoterol was absorbed with median Tmax values ranging from 0.167 to 0.5 hour. In single-dose study with DULERA 400 mcg/10 mcg in healthy subjects, arithmetic mean (CV%) Cmax and AUC for formoterol were 15 (50) pmol/L and 81 (51) pmolh/L, respectively. Over the dose range of 10 to 40 mcg for formoterol from DULERA, the exposure to formoterol was dose proportional.. Asthma Patients: When DULERA was administered to patients with asthma, formoterol was absorbed with median Tmax values ranging from 0.58 to 1.97 hours. In single-dose study with DULERA 400 mcg/10 mcg in patients with asthma, arithmetic mean (CV%) Cmax and AUC(0-12 hr) for formoterol were 22 (29) pmol/L and 125 (42) pmolh/L, respectively. Following multiple-dose administration of DULERA 400 mcg/10 mcg, the steady-state arithmetic mean (CV%) Cmax and AUC(0-12 hr) for formoterol were 41 (59) pmol/L and 226 (54) pmolhr/L.. Distribution. Mometasone furoate: Based on the study employing 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder in humans, no appreciable accumulation of mometasone furoate in the red blood cells was found. Following an intravenous 400 mcg dose of mometasone furoate, the plasma concentrations showed biphasic decline, with mean steady-state volume of distribution of 152 liters. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% (in concentration range of to 500 ng/mL).. Formoterol fumarate: The binding of formoterol to human plasma proteins in vitro was 61% to 64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31% to 38% over range of to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of single 120 mcg dose.. Metabolism. Mometasone furoate: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. In-vitro studies have confirmed the primary role of human liver cytochrome P-450 3A4 (CYP3A4) in the metabolism of this compound, however, no major metabolites were identified. Human liver CYP3A4 metabolizes mometasone furoate to 6-beta hydroxy mometasone furoate.. Formoterol fumarate: Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.. Excretion. Mometasone furoate: Following an intravenous dosing, the terminal half-life was reported to be about hours. Following the inhaled dose of tritiated 1000 mcg mometasone furoate, the radioactivity is excreted mainly in the feces (a mean of 74%), and to small extent in the urine (a mean of 8%) up to days. No radioactivity was associated with unchanged mometasone furoate in the urine. Absorbed mometasone furoate is cleared from plasma at rate of approximately 12.5 mL/min/kg, independent of dose. The effective 1/2 for mometasone furoate following inhalation with DULERA was 25 hours in healthy subjects and in patients with asthma.. Formoterol fumarate: Following oral administration of 80 mcg of radiolabeled formoterol fumarate to healthy subjects, 59% to 62% of the radioactivity was eliminated in the urine and 32% to 34% in the feces over period of 104 hours. In an oral inhalation study with DULERA, renal clearance of formoterol from the blood was 217 mL/min. In single-dose studies, the mean 1/2 values for formoterol in plasma were 9.1 hours and 10.8 hours from the urinary excretion data. The accumulation of formoterol in plasma after multiple dose administration was consistent with the increase expected with drug having terminal 1/2 of to 11 hour.Following single inhaled doses ranging from 10 to 40 mcg to healthy subjects from the MFF MDI, 6.2% to 6.8% of the formoterol dose was excreted in urine unchanged. The (R,R) and (S,S)-enantiomers accounted, respectively, for 37% and 63% of the formoterol recovered in urine. From urinary excretion rates measured in healthy subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13 and 9.5 hours, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied.. Special Populations. Hepatic/Renal Impairment: There are no data regarding the specific use of DULERA in patients with hepatic or renal impairment.A study evaluating the administration of single inhaled dose of 400 mcg mometasone furoate by dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only or subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50-105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.. Gender and Race: Specific studies to examine the effects of gender and race on the pharmacokinetics of DULERA have not been specifically studied.. Geriatrics: The pharmacokinetics of DULERA have not been specifically studied in the elderly population.. Drug-Drug InteractionsA single-dose crossover study was conducted to compare the pharmacokinetics of inhalations of the following: mometasone furoate MDI, formoterol MDI, DULERA (mometasone furoate/formoterol fumarate MDI), and mometasone furoate MDI plus formoterol fumarate MDI administered concurrently. The results of the study indicated that there was no evidence of pharmacokinetic interaction between the two components of DULERA.. Inhibitors of Cytochrome P450 Enzymes: Ketoconazole: In drug interaction study, an inhaled dose of mometasone furoate 400 mcg delivered by dry powder inhaler was given to 24 healthy subjects twice daily for days and ketoconazole 200 mg (as well as placebo) were given twice daily concomitantly on Days to 9. Mometasone furoate plasma concentrations were <150 pcg/mL on Day prior to coadministration of ketoconazole or placebo. Following concomitant administration of ketoconazole, out of 12 subjects in the ketoconazole treatment group (n=12) had peak plasma concentrations of mometasone furoate >200 pcg/mL on Day (211-324 pcg/mL). Mometasone furoate plasma levels appeared to increase and plasma cortisol levels appeared to decrease upon concomitant administration of ketoconazole.Specific drug-drug interaction studies with formoterol have not been performed.

PREGNANCY SECTION.

8.1Pregnancy. Risk SummaryThere are no randomized clinical studies of DULERA, mometasone furoate, or formoterol fumarate in pregnant women. There are clinical considerations with the use of DULERA in pregnant women [see Clinical Considerations]. Animal reproduction studies with DULERA are not available; however, studies are available with its individual components, mometasone furoate and formoterol fumarate. In animal reproduction studies, subcutaneous administration of mometasone furoate to pregnant mice, rats, or rabbits caused increased fetal malformations and decreased fetal survival and growth following administration of doses that produced exposures approximately 1/3 to times the maximum recommended human dose (MRHD) on mcg/m2 or AUC basis [see Data]. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 1200 to 49,000 times the MRHD on mg/m2 or AUC basis [see Data]. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 500 times the MRHD.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskIn women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.. Labor or deliveryThere are no adequate and well-controlled human studies that have studied the effects of DULERA during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of DULERA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.. Data. Animal Data. Mometasone FuroateIn an embryofetal development study with pregnant mice dosed throughout the period of organogenesis, mometasone furoate produced cleft palate at an exposure approximately one-third of the MRHD (on mcg/m2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at an exposure approximately equivalent to the MRHD (on mcg/m2 basis with maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with dose that produced an exposure approximately one-tenth of the MRHD (on mcg/m2 basis with maternal topical dermal doses of 20 mcg/kg and above).In an embryofetal development study with pregnant rats dosed throughout the period of organogenesis, mometasone furoate produced fetal umbilical hernia at exposures approximately times the MRHD (on mcg/m2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at exposures approximately times the MRHD (on mcg/m2 basis with maternal topical dermal doses of 300 mcg/kg and above).In another reproductive toxicity study, pregnant rats were dosed with mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at an exposure that was approximately times the MRHD (on an area under the curve (AUC) basis with maternal subcutaneous dose of 15 mcg/kg). There were no findings with an exposure approximately times the MRHD (on an AUC basis with maternal subcutaneous dose of 7.5 mcg/kg).Embryofetal development studies were conducted with pregnant rabbits dosed with mometasone furoate by either the topical dermal route or oral route throughout the period of organogenesis. In the study using the topical dermal route, mometasone furoate caused multiple malformations in fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at an exposure approximately times the MRHD (on mcg/m2 basis with maternal topical dermal doses of 150 mcg/kg and above). In the study using the oral route, mometasone furoate caused increased fetal resorptions and cleft palate and/or head malformations (hydrocephaly and domed head) at an exposure approximately 1/2 of the MRHD (on AUC basis with maternal oral dose of 700 mcg/kg). At an exposure approximately times the MRHD (on an AUC basis with maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No effects were observed at an exposure approximately 1/10 of the MRHD (on an AUC basis with maternal oral dose of 140 mcg/kg).. Formoterol FumarateIn embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species. However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 80 times the MRHD (on mcg/m2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 2400 times the MRHD (on mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). In pre- and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 2400 times the MRHD (on mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). However, no effects were observed in this study at an exposure approximately 80 times the MRHD (on mcg/m2 basis with maternal oral dose of 200 mcg/kg).In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species. Umbilical hernia, malformation, was observed in rat fetuses at exposures approximately 1200 times the MRHD (on mcg/m2 basis with maternal oral doses of 3000 mcg/kg/day and above). Brachygnathia, skeletal malformation, was observed in rat fetuses at an exposure approximately 6100 times the MRHD (on mcg/m2 basis with maternal oral dose of 15,000 mcg/kg/day). In another study with rats, no teratogenic effects were observed with exposures up to approximately 500 times the MRHD (on mcg/m2 basis with maternal inhalation dose of 1200 mcg/kg/day). Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 49,000 times the MRHD (on mcg/m2 basis with maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed with exposures up to approximately 3000 times the MRHD (on mcg/m2 basis with maternal oral dose of 3500 mcg/kg).

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1, 2.2)06/2017Warnings and Precautions Deterioration of Disease and Acute Episodes (5.2)06/2017.

SPL MEDGUIDE SECTION.

Medication GuideDULERA(R) [dew-LAIR-ah] 100 mcg/5 mcg(mometasone furoate 100 mcg and formoterol fumarate dihydrate mcg) Inhalation AerosolDULERA(R) 200 mcg/5 mcg(mometasone furoate 200 mcg and formoterol fumarate dihydrate mcg) Inhalation AerosolRead the Medication Guide that comes with DULERA(R) before you start using it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.What is the most important information should know about DULERADULERA can cause serious side effects, including:1.People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines such as formoterol (one of the medicines in DULERA), have an increased risk of death from asthma problems. It is not known whether mometasone furoate, the other medicine in DULERA, reduces the risk of death from asthma problems seen with formoterol. Call your healthcare provider if breathing problems worsen over time while using DULERA. You may need different treatment.Get emergency medical care if:breathing problems worsen quickly, andyou use your rescue inhaler medicine, but it does not relieve your breathing problems. 2.DULERA should be used only if your healthcare provider decides that your asthma is not well controlled with long-term asthma control medicine, such as an inhaled corticosteroid.3.When your asthma is well controlled, your healthcare provider may tell you to stop taking DULERA. Your healthcare provider will decide if you can stop DULERA without loss of asthma control. Your healthcare provider may prescribe different long-term asthma-control medicine for you, such as an inhaled corticosteroid.4.Children and adolescents who take LABA medicines may have an increased risk of being hospitalized for asthma problems.What is DULERADULERA combines an inhaled corticosteroid medicine, mometasone furoate (the same medicine found in ASMANEX TWISTHALER), and long-acting beta2-agonist medicine (LABA), formoterol (the same medicine found in FORADIL(R) AEROLIZER(R)).Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms.LABA medicines are used in people with asthma. LABA medicines help the muscles around the airways in your lungs stay relaxed to prevent asthma symptoms, such as wheezing and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. In severe cases, wheezing can stop your breathing and may lead to death if not treated right away.DULERA is used to control symptoms of asthma and prevent symptoms such as wheezing in people 12 years of age and older.DULERA should not be used as rescue inhaler.DULERA contains formoterol (the same medicine found in FORADIL AEROLIZER). LABA medicines such as formoterol increase the risk of death from asthma problems. DULERA is not for children and adults with asthma who:are well controlled with an asthma-control medicine, such as low to medium dose of an inhaled corticosteroid medicineonly need rescue inhaler once in awhileIt is not known if DULERA is safe and effective in children less than 12 years of age.Who should not use DULERADo not use DULERA:to treat sudden severe symptoms of asthmaif you are allergic to any of the ingredients in DULERA. See the end of the Medication Guide for list of ingredients in DULERA.What should tell my healthcare provider before using DULERATell your healthcare provider about all of your health conditions, including if you:have heart problems have high blood pressure have seizures have thyroid problems have diabetes have liver problems have osteoporosis have an immune system problem have eye problems such as increased pressure in the eye, glaucoma, or cataractsare allergic to any medicinesare exposed to chickenpox or measleshave an aneurysm (swelling of an artery)have pheochromocytoma (a tumor of the adrenal gland that can affect your blood pressure)are scheduled to have surgeryhave any other medical problemsare pregnant or planning to become pregnant. It is not known if DULERA may harm your unborn baby.are breastfeeding. It is not known if DULERA passes into your milk and if it can harm your baby. You and your healthcare provider should decide if you will take DULERA while breastfeeding.Tell your healthcare provider about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. DULERA and certain other medicines may interact with each other. This may cause serious side effects.Especially, tell your healthcare provider if you take antifungal medicines, such as ketoconazole, or anti-HIV medicines, such as ritonavir. The anti-HIV medicines NORVIR(R) (ritonavir capsules) Soft Gelatin, NORVIR(R) (ritonavir oral solution), and KALETRA(R) (lopinavir/ritonavir) Tablets contain ritonavir.Know the medicines you take. Keep list and show it to your healthcare provider and pharmacist each time you get new medicine.How should use DULERASee the step-by-step instructions for using DULERA at the end of this Medication Guide. Do not use DULERA unless your healthcare provider has taught you and you understand everything. Ask your healthcare provider or pharmacist if you have any questions.Use DULERA exactly as prescribed. Do not use DULERA more often than prescribed. DULERA comes in strengths. Your healthcare provider has prescribed the strength that is best for you. Note the differences between DULERA and your other inhaled medications, including the differences in prescribed use and physical appearance.DULERA should be taken every day as puffs in the morning and puffs in the evening.If you miss dose of DULERA, skip your missed dose and take your next dose at your regular time. Do not take DULERA more often or use more puffs than you have been prescribed.While you are using DULERA times each day, do not use other medicines that contain long-acting beta2-agonist (LABA) for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines.If you take more DULERA than your healthcare provider has prescribed, get medical help right away if you have any unusual symptoms, such as problems breathing, palpitations, chest pain, increased heart rate, nervousness or shakiness.Do not change or stop using DULERA or other asthma medicines used to control or treat your breathing problems unless told to do so by your healthcare provider. Your healthcare provider will change your medicines as needed.DULERA does not relieve sudden asthma symptoms. Always have rescue inhaler with you to treat sudden symptoms. Use your rescue inhaler if you have breathing problems between doses of DULERA. If you do not have rescue inhaler, call your healthcare provider to have one prescribed for you.Remove the cap from the mouthpiece of the actuator before using DULERA.DO NOT remove the canister from the actuator because: You may not receive the correct amount of medication.The dose counter may not function properly. Reinsertion may cause the dose counter to count down by and may discharge puff. Rinse your mouth with water after each dose (2 puffs) of DULERA. This will help to lessen the chance of getting yeast infection (thrush) in the mouth and throat.Do not spray DULERA in your eyes. If you accidentally get DULERA in your eyes, rinse your eyes with water and if redness or irritation continues, call your healthcare provider.Call your healthcare provider or get medical care right away if:your breathing problems worsen with DULERAyou need to use your rescue inhaler more often than usualyour rescue inhaler does not work as well for you at relieving symptomsyou need to use or more inhalations of your rescue inhaler for or more days in rowyou use whole canister of your rescue inhaler in weeks timeyour peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.you have asthma and your symptoms do not improve after using DULERA regularly for to weeksWhat are the possible side effects of DULERADULERA can cause serious side effects, including:See What is the most important information should know about DULERAThrush in the mouth and throat. You may develop yeast infection (Candida albicans) in your mouth or throat. Rinse your mouth with water after using DULERA to help prevent an infection in your mouth or throat.Immune system effects and higher chance for infections.Tell your healthcare provider about any signs of infection such as: fever feeling tired pain nausea body aches vomiting chills Adrenal insufficiency. Adrenal insufficiency is condition in which the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines and start inhaled corticosteroid medicines.Increased wheezing right after taking DULERA. Always have rescue inhaler with you to treat sudden wheezing.Serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of serious allergic reaction: rash hives swelling, including swelling of the face, mouth, and tongue breathing problemsUsing too much of LABA medicine may cause:chest pain increased or decreased blood pressure fast and irregular heartbeat headache tremor nervousness dizzinessweaknessseizureselectrocardiogram (ECG) changes Lower bone mineral density. This may be problem for people who already have higher chance for low bone density (osteoporosis).Slowed growth in children. childs growth should be checked often.Eye problems including glaucoma and cataracts. You should have regular eye exams while using DULERA.Decreases in blood potassium levels (hypokalemia)Increases in blood sugar levels (hyperglycemia)The most common side effects of DULERA include:inflammation of the nose and throat (nasopharyngitis)inflammation of the sinuses (sinusitis)headacheOther side effects:Worsening asthma or sudden asthma attacks have been reported with the use of inhaled mometasone furoate (one of the medicines in DULERA).Tell your healthcare provider about any side effect that bothers you or that does not go away.These are not all the side effects with DULERA. Ask your healthcare provider or pharmacist for more information.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.You may also report side effects to Merck Sharp Dohme Corp., subsidiary of Merck Co., Inc., at 1-877-888-4231.How do store DULERAStore DULERA at room temperature between 59F to 86F (15C to 30C).The 120-actuation inhaler can be stored in any position. For the 60-actuation inhaler, after priming, store the inhaler with the mouthpiece down or sideways. The contents of your DULERA are under pressure. Do not puncture. Do not use or store near heat or open flame. Storage above 120F may cause the canister to burst.Do not throw container into fire or incinerator.Keep DULERA and all medicines out of the reach of children.General Information about DULERAMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use DULERA for condition for which it was not prescribed. Do not give your DULERA to other people, even if they have the same condition. It may harm them.This Medication Guide summarizes the most important information about DULERA. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about DULERA that was written for healthcare professionals. For more information about DULERA, go to www.DULERA.com or call 1-800-622-4477.What are the ingredients in DULERAActive ingredients: mometasone furoate and formoterol fumarate dihydrateInactive ingredients: hydrofluoroalkane (HFA-227), anhydrous alcohol and oleic acid. 1.People with asthma who take long-acting beta2-adrenergic agonist (LABA) medicines such as formoterol (one of the medicines in DULERA), have an increased risk of death from asthma problems. It is not known whether mometasone furoate, the other medicine in DULERA, reduces the risk of death from asthma problems seen with formoterol. Call your healthcare provider if breathing problems worsen over time while using DULERA. You may need different treatment.Get emergency medical care if:breathing problems worsen quickly, andyou use your rescue inhaler medicine, but it does not relieve your breathing problems. Call your healthcare provider if breathing problems worsen over time while using DULERA. You may need different treatment.. Get emergency medical care if:breathing problems worsen quickly, andyou use your rescue inhaler medicine, but it does not relieve your breathing problems. breathing problems worsen quickly, and. you use your rescue inhaler medicine, but it does not relieve your breathing problems. 2.DULERA should be used only if your healthcare provider decides that your asthma is not well controlled with long-term asthma control medicine, such as an inhaled corticosteroid.. 3.When your asthma is well controlled, your healthcare provider may tell you to stop taking DULERA. Your healthcare provider will decide if you can stop DULERA without loss of asthma control. Your healthcare provider may prescribe different long-term asthma-control medicine for you, such as an inhaled corticosteroid.. 4.Children and adolescents who take LABA medicines may have an increased risk of being hospitalized for asthma problems.. Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to asthma symptoms.. LABA medicines are used in people with asthma. LABA medicines help the muscles around the airways in your lungs stay relaxed to prevent asthma symptoms, such as wheezing and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. In severe cases, wheezing can stop your breathing and may lead to death if not treated right away.. are well controlled with an asthma-control medicine, such as low to medium dose of an inhaled corticosteroid medicine. only need rescue inhaler once in awhile. to treat sudden severe symptoms of asthma. if you are allergic to any of the ingredients in DULERA. See the end of the Medication Guide for list of ingredients in DULERA.. have heart problems have high blood pressure have seizures have thyroid problems have diabetes have liver problems have osteoporosis have an immune system problem have eye problems such as increased pressure in the eye, glaucoma, or cataracts. are allergic to any medicines. are exposed to chickenpox or measles. have an aneurysm (swelling of an artery). have pheochromocytoma (a tumor of the adrenal gland that can affect your blood pressure). are scheduled to have surgery. have any other medical problems. are pregnant or planning to become pregnant. It is not known if DULERA may harm your unborn baby.. are breastfeeding. It is not known if DULERA passes into your milk and if it can harm your baby. You and your healthcare provider should decide if you will take DULERA while breastfeeding.. Use DULERA exactly as prescribed. Do not use DULERA more often than prescribed. DULERA comes in strengths. Your healthcare provider has prescribed the strength that is best for you. Note the differences between DULERA and your other inhaled medications, including the differences in prescribed use and physical appearance.. DULERA should be taken every day as puffs in the morning and puffs in the evening.. If you miss dose of DULERA, skip your missed dose and take your next dose at your regular time. Do not take DULERA more often or use more puffs than you have been prescribed.. While you are using DULERA times each day, do not use other medicines that contain long-acting beta2-agonist (LABA) for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines.. If you take more DULERA than your healthcare provider has prescribed, get medical help right away if you have any unusual symptoms, such as problems breathing, palpitations, chest pain, increased heart rate, nervousness or shakiness.. Do not change or stop using DULERA or other asthma medicines used to control or treat your breathing problems unless told to do so by your healthcare provider. Your healthcare provider will change your medicines as needed.. DULERA does not relieve sudden asthma symptoms. Always have rescue inhaler with you to treat sudden symptoms. Use your rescue inhaler if you have breathing problems between doses of DULERA. If you do not have rescue inhaler, call your healthcare provider to have one prescribed for you.. Remove the cap from the mouthpiece of the actuator before using DULERA.. DO NOT remove the canister from the actuator because: You may not receive the correct amount of medication.The dose counter may not function properly. Reinsertion may cause the dose counter to count down by and may discharge puff. You may not receive the correct amount of medication.. The dose counter may not function properly. Reinsertion may cause the dose counter to count down by and may discharge puff. Rinse your mouth with water after each dose (2 puffs) of DULERA. This will help to lessen the chance of getting yeast infection (thrush) in the mouth and throat.. Do not spray DULERA in your eyes. If you accidentally get DULERA in your eyes, rinse your eyes with water and if redness or irritation continues, call your healthcare provider.. Call your healthcare provider or get medical care right away if:your breathing problems worsen with DULERAyou need to use your rescue inhaler more often than usualyour rescue inhaler does not work as well for you at relieving symptomsyou need to use or more inhalations of your rescue inhaler for or more days in rowyou use whole canister of your rescue inhaler in weeks timeyour peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.you have asthma and your symptoms do not improve after using DULERA regularly for to weeks. your breathing problems worsen with DULERA. you need to use your rescue inhaler more often than usual. your rescue inhaler does not work as well for you at relieving symptoms. you need to use or more inhalations of your rescue inhaler for or more days in row. you use whole canister of your rescue inhaler in weeks time. your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.. you have asthma and your symptoms do not improve after using DULERA regularly for to weeks. See What is the most important information should know about DULERA. Thrush in the mouth and throat. You may develop yeast infection (Candida albicans) in your mouth or throat. Rinse your mouth with water after using DULERA to help prevent an infection in your mouth or throat.. Immune system effects and higher chance for infections.. Tell your healthcare provider about any signs of infection such as: fever feeling tired pain nausea body aches vomiting chills fever. feeling tired. pain. nausea. body aches. vomiting. chills. Adrenal insufficiency. Adrenal insufficiency is condition in which the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines and start inhaled corticosteroid medicines.. Increased wheezing right after taking DULERA. Always have rescue inhaler with you to treat sudden wheezing.. Serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of serious allergic reaction: rash hives swelling, including swelling of the face, mouth, and tongue breathing problems. rash. hives. swelling, including swelling of the face, mouth, and tongue. breathing problems. Using too much of LABA medicine may cause:chest pain increased or decreased blood pressure fast and irregular heartbeat headache tremor nervousness dizzinessweaknessseizureselectrocardiogram (ECG) changes chest pain increased or decreased blood pressure a fast and irregular heartbeat headache tremor nervousness dizziness. weakness. seizures. electrocardiogram (ECG) changes Lower bone mineral density. This may be problem for people who already have higher chance for low bone density (osteoporosis).. Slowed growth in children. childs growth should be checked often.. Eye problems including glaucoma and cataracts. You should have regular eye exams while using DULERA.. Decreases in blood potassium levels (hypokalemia). Increases in blood sugar levels (hyperglycemia). inflammation of the nose and throat (nasopharyngitis). inflammation of the sinuses (sinusitis). headache. Worsening asthma or sudden asthma attacks have been reported with the use of inhaled mometasone furoate (one of the medicines in DULERA).. Store DULERA at room temperature between 59F to 86F (15C to 30C).. The 120-actuation inhaler can be stored in any position. For the 60-actuation inhaler, after priming, store the inhaler with the mouthpiece down or sideways. The contents of your DULERA are under pressure. Do not puncture. Do not use or store near heat or open flame. Storage above 120F may cause the canister to burst.. Do not throw container into fire or incinerator.. Keep DULERA and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

1.1Treatment of Asthma. DULERA is indicated for the treatment of asthma in patients 12 years of age and older.Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.. Important Limitation of UseDULERA is NOT indicated for the relief of acute bronchospasm.. DULERA is NOT indicated for the relief of acute bronchospasm.

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Hepatic impairment: Monitor patients for signs of increased drug exposure. (8.6). Hepatic impairment: Monitor patients for signs of increased drug exposure. (8.6). 8.1Pregnancy. Risk SummaryThere are no randomized clinical studies of DULERA, mometasone furoate, or formoterol fumarate in pregnant women. There are clinical considerations with the use of DULERA in pregnant women [see Clinical Considerations]. Animal reproduction studies with DULERA are not available; however, studies are available with its individual components, mometasone furoate and formoterol fumarate. In animal reproduction studies, subcutaneous administration of mometasone furoate to pregnant mice, rats, or rabbits caused increased fetal malformations and decreased fetal survival and growth following administration of doses that produced exposures approximately 1/3 to times the maximum recommended human dose (MRHD) on mcg/m2 or AUC basis [see Data]. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 1200 to 49,000 times the MRHD on mg/m2 or AUC basis [see Data]. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 500 times the MRHD.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskIn women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control.. Labor or deliveryThere are no adequate and well-controlled human studies that have studied the effects of DULERA during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of DULERA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.. Data. Animal Data. Mometasone FuroateIn an embryofetal development study with pregnant mice dosed throughout the period of organogenesis, mometasone furoate produced cleft palate at an exposure approximately one-third of the MRHD (on mcg/m2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at an exposure approximately equivalent to the MRHD (on mcg/m2 basis with maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with dose that produced an exposure approximately one-tenth of the MRHD (on mcg/m2 basis with maternal topical dermal doses of 20 mcg/kg and above).In an embryofetal development study with pregnant rats dosed throughout the period of organogenesis, mometasone furoate produced fetal umbilical hernia at exposures approximately times the MRHD (on mcg/m2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at exposures approximately times the MRHD (on mcg/m2 basis with maternal topical dermal doses of 300 mcg/kg and above).In another reproductive toxicity study, pregnant rats were dosed with mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at an exposure that was approximately times the MRHD (on an area under the curve (AUC) basis with maternal subcutaneous dose of 15 mcg/kg). There were no findings with an exposure approximately times the MRHD (on an AUC basis with maternal subcutaneous dose of 7.5 mcg/kg).Embryofetal development studies were conducted with pregnant rabbits dosed with mometasone furoate by either the topical dermal route or oral route throughout the period of organogenesis. In the study using the topical dermal route, mometasone furoate caused multiple malformations in fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at an exposure approximately times the MRHD (on mcg/m2 basis with maternal topical dermal doses of 150 mcg/kg and above). In the study using the oral route, mometasone furoate caused increased fetal resorptions and cleft palate and/or head malformations (hydrocephaly and domed head) at an exposure approximately 1/2 of the MRHD (on AUC basis with maternal oral dose of 700 mcg/kg). At an exposure approximately times the MRHD (on an AUC basis with maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No effects were observed at an exposure approximately 1/10 of the MRHD (on an AUC basis with maternal oral dose of 140 mcg/kg).. Formoterol FumarateIn embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species. However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 80 times the MRHD (on mcg/m2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 2400 times the MRHD (on mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). In pre- and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 2400 times the MRHD (on mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). However, no effects were observed in this study at an exposure approximately 80 times the MRHD (on mcg/m2 basis with maternal oral dose of 200 mcg/kg).In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species. Umbilical hernia, malformation, was observed in rat fetuses at exposures approximately 1200 times the MRHD (on mcg/m2 basis with maternal oral doses of 3000 mcg/kg/day and above). Brachygnathia, skeletal malformation, was observed in rat fetuses at an exposure approximately 6100 times the MRHD (on mcg/m2 basis with maternal oral dose of 15,000 mcg/kg/day). In another study with rats, no teratogenic effects were observed with exposures up to approximately 500 times the MRHD (on mcg/m2 basis with maternal inhalation dose of 1200 mcg/kg/day). Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 49,000 times the MRHD (on mcg/m2 basis with maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed with exposures up to approximately 3000 times the MRHD (on mcg/m2 basis with maternal oral dose of 3500 mcg/kg).. 8.2 Lactation. Risk SummaryThere are no available data on the presence of DULERA, mometasone furoate, or formoterol fumarate in human milk, the effects on the breastfed child, or the effects on milk production. Other inhaled corticosteroids, similar to mometasone furoate, are present in human milk. Formoterol fumarate is present in rat milk; however, due to species specific differences in lactation physiology, animal lactation data may not reliably predict levels in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for DULERA and any potential adverse effects on the breastfed infant from DULERA or from the underlying maternal condition.. 8.4Pediatric Use. The safety and effectiveness of DULERA have been established in patients 12 years of age and older in clinical trials up to 52 weeks in duration. In the 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 drug 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 efficacy of DULERA have not been established in children less than 12 years of age.Controlled clinical studies have shown that inhaled corticosteroids may cause reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 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 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 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)].. 8.5Geriatric Use. total of 77 patients 65 years of age and older (11 of whom were 75 years and older) have been treated with DULERA in 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.. 8.6Hepatic Impairment Concentrations of mometasone furoate appear to increase with severity of hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. Asthma-related death: Long-acting beta2-adrenergic agonists increase the risk. Prescribe only for recommended patient populations. (5.1)Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2)Use with additional long-acting beta2-agonist: Do not use in combination because of risk of overdose. (5.3)Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation. (5.4)Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Use with caution in patients with these infections because of the potential for worsening of these infections. (5.5)Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to DULERA. (5.6)Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DULERA slowly. (5.7)Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA. (5.8)Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs. (5.9)Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation. (5.11)Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. (5.12)Effects on growth: Monitor growth of pediatric patients. (5.13)Glaucoma and cataracts: Monitor patients with change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts closely. (5.14)Coexisting conditions: Use with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.15)Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia. (5.16). Asthma-related death: Long-acting beta2-adrenergic agonists increase the risk. Prescribe only for recommended patient populations. (5.1). Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2). Use with additional long-acting beta2-agonist: Do not use in combination because of risk of overdose. (5.3). Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation. (5.4). Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Use with caution in patients with these infections because of the potential for worsening of these infections. (5.5). Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to DULERA. (5.6). Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DULERA slowly. (5.7). Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA. (5.8). Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs. (5.9). Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation. (5.11). Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. (5.12). Effects on growth: Monitor growth of pediatric patients. (5.13). Glaucoma and cataracts: Monitor patients with change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts closely. (5.14). Coexisting conditions: Use with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.15). Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia. (5.16). 5.1Asthma-Related Death. Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe DULERA for patients with asthma not adequately controlled on long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids.A 28-week, placebo-controlled US study comparing the safety of 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). This finding with salmeterol is considered class effect of the LABAs, including formoterol, one of the active ingredients in DULERA. No study adequate to determine whether the rate of asthma-related death is increased with DULERA has been conducted.Clinical studies with formoterol suggested higher incidence of serious asthma exacerbations in patients who received formoterol fumarate 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.. 5.2Deterioration 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 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 higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 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 regular basis (e.g., times day) should be instructed to discontinue the regular use of these drugs.. 5.3Excessive 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.. 5.4Local 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, it should be treated 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. Advise patients to rinse the mouth after inhalation of DULERA.. 5.5Immunosuppression. 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 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 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.. 5.6Transferring 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, 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 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.. 5.7Hypercorticism and Adrenal Suppression. Mometasone furoate, 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 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.. 5.8Drug 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, 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)]. 5.9Paradoxical 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.. 5.10Immediate Hypersensitivity Reactions. Immediate hypersensitivity reactions may occur after administration of DULERA, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm.. 5.11Cardiovascular 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, component of DULERA, can produce 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 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.. 5.12Reduction 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 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 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.. 5.13Effect on Growth. Orally inhaled corticosteroids, including DULERA, may cause 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 patients dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)].. 5.14Glaucoma and Cataracts. Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term administration of inhaled corticosteroids, including mometasone furoate, component of DULERA. Therefore, close monitoring is warranted in patients with change in vision or with history of increased intraocular pressure, glaucoma, and/or cataracts [see Adverse Reactions (6)].. 5.15Coexisting 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.. 5.16Hypokalemia 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.