Dulera

DULERA is a combination product containing a corticosteroid and a long-acting beta₂-adrenergic agonist (LABA) indicated for:

• Treatment of asthma in patients 5 years of age and older. (
  1.1 Treatment of Asthma

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

  Important Limitation of Use:

  • DULERA is NOT indicated for the relief of acute bronchospasm.
  )

Important Limitation of Use:

• Not indicated for the relief of acute bronchospasm. (
  1.1 Treatment of Asthma

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

  Important Limitation of Use:

  • DULERA is NOT indicated for the relief of acute bronchospasm.
  )

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. (

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

• Hepatic impairment: Monitor patients for signs of increased drug exposure. (
  8.6 Hepatic Impairment

  Concentrations of mometasone furoate appear to increase with severity of hepatic impairment

  [see Clinical Pharmacology (12.3)]

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  )

• LABA monotherapy increases the risk of serious asthma-related events. (
  5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, and Death

  Use of LABA as monotherapy (without ICS) for asthma is associated with an increased risk of asthma-related death

  [see Salmeterol Multicenter Asthma Research Trial (SMART)]

  . Available data from controlled clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone

  [see Serious Asthma-Related Events with ICS/LABA]

  .

  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

  [see Clinical Studies (14.1)]

  ; 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 Beta2-adrenergic Agonist.
  Serious asthma-related eventNumber 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 (2.7), 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: Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (
  5.2 Deterioration of Disease and Acute Episodes

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

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

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

  When beginning treatment with DULERA, patients who have been taking oral or inhaled, short-acting beta₂-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs.
  )
• Use with additional long-acting beta₂-agonist: Do not use in combination because of risk of overdose. (
  5.3 Excessive Use of DULERA and Use with Other Long-Acting Beta₂-Agonists

  As with other inhaled drugs containing beta₂-adrenergic agents, DULERA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta₂-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using DULERA should not use an additional long-acting beta₂-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma.
  )
• 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. (
  5.4 Local Effects

  In clinical trials, the development of localized infections of the mouth and pharynx with

  Candida albicans

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

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

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

  DULERA should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
  )
• 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 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 (FEV₁or 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: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DULERA slowly. (
  5.7 Hypercorticism and Adrenal Suppression

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

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

  It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of DULERA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
  )
• Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA. (
  5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors

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

  [see Drug Interactions (7.1)and Clinical Pharmacology (12.3)].
  )
• Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs. (
  5.9 Paradoxical Bronchospasm and Upper Airway Symptoms

  DULERA may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening. If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator. DULERA should be discontinued immediately and alternative therapy instituted.
  )
• Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation. (
  5.11 Cardiovascular and Central Nervous System Effects

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

  Formoterol fumarate, a component of DULERA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of DULERA at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
  )
• Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. (
  5.12 Reduction in Bone Mineral Density

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

  In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV₁85%–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 FEV₁82%–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.
  )
• Effects on growth: Monitor growth of pediatric patients. (
  5.13 Effect on Growth

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

  [see Use in Specific Populations (8.4)]

  .
  )
• Glaucoma and cataracts: Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term. (
  5.14 Glaucoma and Cataracts

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

  [see Adverse Reactions (6)]

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  )
• Coexisting conditions: Use with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (
  5.15 Coexisting Conditions

  DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta₂-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
  )
• Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia. (
  5.16 Hypokalemia and Hyperglycemia

  Beta₂-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with DULERA at recommended doses.
  )