DULERA 50 mcg/5 mcg, 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, a 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 a white powder with an empirical formula of C 27 H 30 Cl 2 O 6 , 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, a racemate. Formoterol fumarate dihydrate is a selective beta 2 -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 a molecular weight of 840.9, and its empirical formula is (C 19 H 24 N 2 O 4 ) 2 •C 4 H 4 O 4 •2H 2 O. Formoterol fumarate dihydrate is a 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. DULERA 50 mcg/5 mcg, 100 mcg/5 mcg, and 200 mcg/5 mcg are each formulated as a hydrofluoroalkane (HFA-227; 1, 1, 1, 2, 3, 3, 3-heptafluoropropane) propelled pressurized metered dose inhaler containing sufficient amount of drug for 60 or 120 inhalations . After priming, each actuation of the inhaler delivers 60, 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 50, 100, or 200 mcg of mometasone furoate and 5 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 a cosolvent and oleic acid as a surfactant. DULERA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray. Image of Mometasone Furoate Chemical Structure Image of Formoterol Fumarate Dihydrate Chemical Structure

DULERA is a combination product containing a corticosteroid and a long-acting beta 2 -adrenergic agonist (LABA) indicated for: Treatment of asthma in patients 5 years of age and older. Important Limitation of Use: Not indicated for the relief of acute bronchospasm

Treatment of Asthma DULERA is indicated for the twice-daily treatment of asthma in patients 5 years of age and older. DULERA should be used for patients not adequately controlled on a long-term asthma-control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an ICS and long-acting beta 2 -adrenergic agonist (LABA). Important Limitation of Use: DULERA is NOT indicated for the relief of acute bronchospasm.

DULERA is a pressurized metered dose inhaler (MDI) that is available in 2 strengths (100 mcg/5 mcg or 200 mcg/5 mcg) for adult and adolescent patients aged 12 and older and 1 strength (50 mcg/5 mcg) for pediatric patients aged 5 to less than 12 years. DULERA 50 mcg/5 mcg delivers 50 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation. DULERA 100 mcg/5 mcg delivers 100 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation. DULERA 200 mcg/5 mcg delivers 200 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation. Each strength of DULERA is supplied with a blue colored actuator and green dust cap . Inhalation aerosol containing a combination of mometasone furoate (50 mcg, 100 mcg, or 200 mcg) and formoterol fumarate dihydrate (5 mcg) per actuation.

For oral inhalation only. Treatment of asthma in patients 12 years of age and older: 2 inhalations twice daily of DULERA 100 mcg/5 mcg or 200 mcg/5 mcg. Starting dosage is based on disease severity. Treatment of asthma in patients aged 5 to less than 12 years: 2 inhalations twice daily of DULERA 50 mcg/5 mcg

Administration Information Administer DULERA as two inhalations twice daily every day (morning and evening) by the orally inhaled route . 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 beta 2 -agonist should be taken for immediate relief. Shake well prior to each inhalation. After each dose, advise patients to rinse their mouth with water and, without swallowing, spit out the contents to help reduce the risk of oropharyngeal candidiasis. Remove the cap from the mouthpiece of the actuator before using DULERA. Prime DULERA before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray. Only use the DULERA canister with the DULERA actuator. Do not use the DULERA actuator with any other inhalation drug product. Do not use actuators from other products with the DULERA canister

Recommended Dosage Administer DULERA as two inhalations twice daily every day (morning and evening) by the orally inhaled route. Shake well prior to each inhalation. Individual patients may experience a variable time to onset and degree of symptom relief. If symptoms arise between doses, use an inhaled short-acting beta 2 -agonist for immediate relief. Improvement in lung function following administration of DULERA can occur within 5 minutes of treatment, although the maximum benefit may not be achieved for 1 week or longer after beginning treatment. Adult and Adolescent Patients Aged 12 Years and Older For patients 12 years and older, the dosage is either 2 inhalations twice daily of DULERA 100 mcg/5 mcg or DULERA 200 mcg/5 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. For patients who do not respond adequately after 2 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. The maximum recommended dosage is two inhalations of DULERA 200 mcg/5 mcg twice daily (maximum daily dosage 800 mcg/20 mcg). After asthma stability has been achieved, it may be desirable to titrate to the lowest effective dosage to reduce the possibility of side effects. If a previously effective dosage regimen of DULERA fails to provide adequate control of asthma, re-evaluate the therapeutic regimen and consider additional therapeutic options, e.g., replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids. Pediatric Patients Aged 5 to Less Than 12 Years For patients aged 5 to less than 12 years, the dosage is 2 inhalations of DULERA 50 mcg/5 mcg twice daily. The maximum daily dosage is 200 mcg/20 mcg.

LABA monotherapy increases the risk of serious asthma-related events. Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms. Use with additional long-acting beta 2 -agonist: Do not use in combination because of risk of overdose. Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. After dosing, advise patients to rinse their mouth with water and spit out contents without swallowing. 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. 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. 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. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA. Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs. Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation. Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. Effects on growth: Monitor growth of pediatric patients. Glaucoma and cataracts: Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term. Coexisting conditions: Use with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia. 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, and Death Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone . Serious Asthma-Related Events with ICS/LABA Four large, 26-week, randomized, blinded, active-controlled clinical safety trials were conducted to evaluate the risk of serious asthma-related events when LABA were used in fixed-dose combination with ICS compared to ICS alone in patients with asthma. Three trials included adult and adolescent patients aged ≥12 years: one trial compared mometasone furoate/formoterol (DULERA) to mometasone furoate ; one trial compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder; and one trial compared budesonide/formoterol to budesonide. The fourth trial included pediatric patients 4 to 11 years of age and compared fluticasone propionate/salmeterol inhalation powder to fluticasone propionate inhalation powder. The primary safety endpoint for all four trials was serious asthma-related events (hospitalizations, intubations and death). A blinded adjudication committee determined whether events were asthma-related. The three adult and adolescent trials were designed to rule out a risk margin of 2.0, and the pediatric trial was designed to rule out a risk of 2.7. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of the three adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with ICS. Table 1: Meta-Analysis of Serious Asthma-Related Events in Patients with Asthma Aged 12 Years and Older ICS/LABA (N=17,537) Randomized patients who had taken at least 1 dose of study drug. Planned treatment used for analysis. ICS (N=17,552) ICS/LABA vs. ICS Hazard ratio (95% CI) Estimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials. ICS = Inhaled Corticosteroid, LABA = Long-acting Beta 2 -adrenergic Agonist. Serious asthma-related event Number of patients with events that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Patients can have one or more events, but only the first event was counted for analysis. A single, blinded, independent adjudication committee determined whether events were asthma-related. 116 105 1.10 (0.85, 1.44) Asthma-related death 2 0 Asthma-related intubation (endotracheal) 1 2 Asthma-related hospitalization (≥24 hour stay) 115 105 The pediatric safety trial included 6208 pediatric patients 4 to 11 years of age who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3107 (0.9%) patients randomized to ICS/LABA and 21/3101 (0.7%) patients randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significantly increased risk of a serious asthma-related event compared to ICS based on the pre-specified risk margin, with an estimated hazard ratio of time to first event of 1.29 (95% CI: 0.73, 2.27). Salmeterol Multicenter Asthma Research Trial (SMART) A 28-week, placebo-controlled U.S. trial that compared 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; relative risk: 4.37 [95% CI: 1.25, 15.34]). Use of background ICS was not required in SMART. The increased risk of asthma-related death is considered a class effect of LABA monotherapy. Formoterol Monotherapy Studies Clinical studies with formoterol used as monotherapy suggested a higher incidence of serious asthma exacerbation in patients who received formoterol than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the difference in serious asthma exacerbations between treatment groups

Deterioration of Disease and Acute Episodes DULERA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. DULERA has not been studied in patients with acutely deteriorating asthma. The initiation of DULERA in this setting is not appropriate. Increasing use of inhaled, short-acting beta 2 -agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of DULERA. DULERA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta 2 -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 beta 2 -agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs

Excessive Use of DULERA and Use with Other Long-Acting Beta 2 -Agonists As with other inhaled drugs containing beta 2 -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 beta 2 -agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using DULERA should not use an additional long-acting beta 2 -agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma

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

Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. 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

Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to DULERA because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although DULERA may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies. During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack. Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to DULERA. Lung function (FEV 1 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

Hypercorticism and Adrenal Suppression Mometasone furoate, a component of DULERA, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of DULERA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with DULERA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of DULERA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms

Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of DULERA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur

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

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

Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, DULERA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Formoterol fumarate, a component of DULERA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of DULERA at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs

Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, one of the components of DULERA. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care. In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV 1 85%–88% predicted), treatment with mometasone furoate dry powder inhaler (DPI) 200 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone furoate group compared to 0.002 (0.25%) for the placebo group. In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV 1 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

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

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

Coexisting Conditions DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis

Hypokalemia and Hyperglycemia Beta 2 -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.

In clinical trials, concurrent administration of DULERA and other drugs, such as short-acting beta 2 -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. Adrenergic agents: Use with caution. Additional adrenergic drugs may potentiate sympathetic effects. Xanthine derivatives and diuretics: Use with caution. May potentiate ECG changes and/or hypokalemia. MAO inhibitors, tricyclic antidepressants, macrolides, and drugs that prolong QTc interval: Use with extreme caution. May potentiate effect on the cardiovascular system. Beta-blockers: Use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm. Halogenated hydrocarbons: There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons

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

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

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

Diuretics Concomitant treatment with diuretics may potentiate the possible hypokalemic effect of adrenergic agonists. The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of DULERA with non-potassium-sparing diuretics

Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and Drugs Known to Prolong the QTc Interval DULERA should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of DULERA, on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias

Beta-Adrenergic Receptor Antagonists Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta 2 -agonists, such as formoterol, a component of DULERA, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution

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