DRUG INTERACTIONS
7 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.
( 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 ) 7.1 Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including mometasone furoate, a component of DULERA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4).
After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased.
Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate and potentially increase the risk for systemic corticosteroid side effects.
Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ] .
Consider the benefit of coadministration versus the potential risk of systemic corticosteroid effects, in which case patients should be monitored for systemic corticosteroid side effects.
7.2 Adrenergic Agents If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol, a component of DULERA, may be potentiated.
7.3 Xanthine Derivatives Concomitant treatment with xanthine derivatives may potentiate any hypokalemic effect of formoterol, a component of DULERA.
7.4 Diuretics Concomitant treatment with diuretics may potentiate the possible hypokalemic effect of adrenergic agonists.
The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded.
Although the clinical significance of these effects is not known, caution is advised in the coadministration of DULERA with non-potassium-sparing diuretics.
7.5 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and Drugs Known to Prolong the QTc Interval DULERA should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of DULERA, on the cardiovascular system may be potentiated by these agents.
Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.
7.6 Beta-Adrenergic Receptor Antagonists Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently.
Beta-blockers not only block the therapeutic effects of 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.
7.7 Halogenated Hydrocarbons There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.
OVERDOSAGE
10 10.1 Signs 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 adult subjects 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 a mcg/m 2 basis).
The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the MRHD.
10.2 Treatment DULERA: Treatment of overdosage consists of discontinuation of DULERA together with institution of appropriate symptomatic and/or supportive therapy.
The judicious use of a 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.
DESCRIPTION
11 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 [see How Supplied/Storage and Handling (16) ] .
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
CLINICAL STUDIES
14 14.1 Asthma Adult and Adolescent Patients Aged 12 Years of Age and Older The safety and efficacy of DULERA were demonstrated in two randomized, double-blind, parallel group, multicenter clinical trials of 12 to 26 weeks in duration involving 1509 patients 12 years of age and older with persistent asthma uncontrolled on medium or high dose inhaled corticosteroids (baseline FEV 1 means of 66% to 73% of predicted normal).
These studies included a 2 to 3-week run-in period with mometasone furoate to establish a certain level of asthma control.
One clinical trial compared DULERA to placebo and the individual components, mometasone furoate and formoterol (Trial 1) and one clinical trial compared two different strengths of DULERA to mometasone furoate alone (Trial 2) .
Trial 1: Clinical Trial with DULERA 100 mcg/5 mcg This 26-week, placebo-controlled trial (NCT00383240) evaluated 781 patients 12 years of age and older comparing DULERA 100 mcg/5 mcg (n=191 patients), mometasone furoate 100 mcg (n=192 patients), formoterol fumarate 5 mcg (n=202 patients) and placebo (n=196 patients); each administered as 2 inhalations twice daily by metered dose inhalation aerosols.
All other maintenance therapies were discontinued.
This study included a 2 to 3-week run-in period with mometasone furoate 100 mcg, 2 inhalations twice daily.
This trial included patients ranging from 12 to 76 years of age, 41% male and 59% female, and 72% Caucasian and 28% non-Caucasian.
Patients had persistent asthma and were not well controlled on medium dose of inhaled corticosteroids prior to randomization.
All treatment groups were balanced with regard to baseline characteristics.
Mean FEV 1 and mean percent predicted FEV 1 were similar among all treatment groups (2.33 L, 73%).
Eight (4%) patients receiving DULERA 100 mcg/5 mcg, 13 (7%) patients receiving mometasone furoate 100 mcg, 47 (23%) patients receiving formoterol fumarate 5 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure.
FEV 1 AUC (0-12 hr) was assessed as a co-primary efficacy endpoint to evaluate the contribution of the formoterol component to DULERA.
Patients receiving DULERA 100 mcg/5 mcg had significantly higher increases from baseline at Week 12 in mean FEV 1 AUC (0-12 hr) compared to mometasone furoate 100 mcg (the primary treatment comparison) and vs.
placebo (both p<0.001) ( Figure 1 ).
These differences were maintained through Week 26.
Figure 1 shows the change from baseline post-dose serial FEV 1 evaluations in Trial 1.
Figure 1 Trial 1 – DULERA 100 mcg/5 mcg – FEV 1 Serial Evaluations for Observed Cases at Week 12 Change from Baseline by Treatment Clinically judged deteriorations in asthma or reductions in lung function were assessed as another primary endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg (primary treatment comparison DULERA vs.
formoterol).
Deteriorations in asthma were defined as any of the following: a 20% decrease in FEV 1 ; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol.
Fewer patients who received DULERA 100 mcg/5 mcg reported an event compared to patients who received formoterol 5 mcg (p<0.001).
Table 3: Trial 1 – Clinically Judged Deterioration in Asthma or Reduction in Lung Function Includes only the first event day for each patient.
Patients could have experienced more than one event criterion.
DULERA 100 mcg/ 5 mcg Two inhalations, twice daily.
(n=191) Mometasone Furoate 100 mcg (n=192) Formoterol 5 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 FEV 1 Decrease in absolute FEV 1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV 1 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 PEF Decrease in AM or PM peak expiratory flow (PEF) on 2 or more consecutive days below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period).
37 (19%) 41 (21%) 62 (31%) 61 (31%) Emergency treatment 0 1 (<1%) 4 (2%) 1 (<1%) Hospitalization 1 (<1%) 0 0 0 Treatment with excluded asthma medication Thirty patients received glucocorticosteroids; 1 patient received formoterol via dry powder inhaler in the Formoterol 5 mcg group.
2 (1%) 4 (2%) 17 (8%) 8 (4%) The change in mean trough FEV 1 from baseline to Week 12 was assessed as another endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg.
A significantly greater increase in mean trough FEV 1 was observed for DULERA 100 mcg/5 mcg compared to formoterol 5 mcg (the primary treatment comparison) as well as to placebo ( Table 4 ).
Table 4: Trial 1 – Change in Trough FEV 1 from Baseline to Week 12 Treatment Arm N Baseline (L) Change From Baseline at Week 12 (L) Treatment Difference from Placebo (L) P-Value vs.
Placebo P-Value vs.
Formoterol LS means and p-values are from Week 12 estimates of a longitudinal analysis model.
DULERA 100 mcg/5 mcg 167 2.33 0.13 0.18 <0.001 <0.001 Mometasone furoate 100 mcg 175 2.36 0.07 0.12 <0.001 0.058 Formoterol fumarate 5 mcg 141 2.29 0.00 0.05 0.170 Placebo 145 2.30 -0.05 The effect of DULERA 100 mcg/5 mcg, two inhalations twice daily on selected secondary efficacy endpoints, including proportion of nights with nocturnal awakenings (-60% vs.
-15%), change in total rescue medication use (-0.6 vs.
+1.1 puffs/day), change in morning peak flow (+18.1 vs.
-28.4 L/min) and evening peak flow (+10.8 vs.
-32.1 L/min) further supports the efficacy of DULERA 100 mcg/5 mcg compared to placebo.
The subjective impact of asthma on patients’ health-related quality of life was evaluated by the Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment).
A change from baseline ≥0.5 points is considered a clinically meaningful improvement.
The mean difference in AQLQ between patients receiving DULERA 100 mcg/5 mcg and placebo was 0.5 [95% CI 0.32, 0.68].
Image of Figure 1 Trial 2: Clinical Trial With DULERA 200 mcg/5 mcg This 12-week double-blind trial (NCT00381485) evaluated 728 patients 12 years of age and older comparing DULERA 200 mcg/5 mcg (n=255 patients) with DULERA 100 mcg/5 mcg (n=233 patients) and mometasone furoate 200 mcg (n=240 patients), each administered as 2 inhalations twice daily by metered dose inhalation aerosols.
All other maintenance therapies were discontinued.
This trial included a 2 to 3-week run-in period with mometasone furoate 200 mcg, 2 inhalations twice daily.
Patients had persistent asthma and were uncontrolled on high dose inhaled corticosteroids prior to study entry.
All treatment groups were balanced with regard to baseline characteristics.
This trial included patients ranging from 12 to 84 years of age, 44% male and 56% female, and 89% Caucasian and 11% non-Caucasian.
Mean FEV 1 and mean percent predicted FEV 1 values were similar among all treatment groups (2.05 L, 66%).
Eleven (5%) patients receiving DULERA 100 mcg/5 mcg, 8 (3%) patients receiving DULERA 200 mcg/5 mcg and 13 (5%) patients receiving mometasone furoate 200 mcg discontinued the trial early due to treatment failure.
The primary efficacy endpoint was the mean change in FEV 1 AUC (0-12 hr) from baseline to Week 12.
Patients receiving DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg had significantly greater increases from baseline at Day 1 in mean FEV 1 AUC (0-12 hr) compared to mometasone furoate 200 mcg.
The difference was maintained over 12 weeks of therapy.
Mean change in trough FEV 1 from baseline to Week 12 was also assessed to evaluate the relative contribution of mometasone furoate to DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg ( Table 5 ).
A greater numerical increase in the mean trough FEV 1 was observed for DULERA 200 mcg/5 mcg compared to DULERA 100 mcg/5 mcg and mometasone furoate 200 mcg.
Table 5: Trial 2 – Change in Trough FEV 1 from Baseline to Week 12 Treatment Arm N Baseline (L) Change from Baseline at Week 12 (L) DULERA 100 mcg/5 mcg 232 2.10 0.14 DULERA 200 mcg/5 mcg 255 2.05 0.19 Mometasone furoate 200 mcg 239 2.07 0.10 Clinically judged deterioration in asthma or reduction in lung function was assessed as an additional endpoint.
Fewer patients who received DULERA 200 mcg/5 mcg or DULERA 100/5 mcg compared to mometasone furoate 200 mcg alone reported an event, defined as in Trial 1 by any of the following: a 20% decrease in FEV 1 ; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol.
Table 6: Trial 2 – Clinically Judged Deterioration in Asthma or Reduction in Lung Function Includes only the first event day for each patient.
Patients could have experienced more than one event criterion.
DULERA 100 mcg/ 5 mcg Two inhalations, twice daily.
(n=233) DULERA 200 mcg/ 5 mcg (n=255) Mometasone Furoate 200 mcg (n=240) Clinically judged deterioration in asthma or reduction in lung function 29 (12%) 31 (12%) 44 (18%) Decrease in FEV 1 Decrease in absolute FEV 1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV 1 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 days Decrease in AM or PM peak expiratory flow (PEF) below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period).
2 (1%) 4 (2%) 3 (1%) Emergency treatment 2 (1%) 1 (<1%) 1 (<1%) Hospitalization 0 1 (<1%) 0 Treatment with excluded asthma medication Twenty four patients received glucocorticosteroids; 1 patient received albuterol in the DULERA 200 mcg / 5 mcg group.
5 (2%) 8 (3%) 12 (5%) Other Studies in Adults In addition to Trial 1 and Trial 2, the safety and efficacy of the individual components, mometasone furoate MDI 100 mcg and 200 mcg (each administered as 2 inhalations by MDI), in comparison to placebo were demonstrated in two other, 12-week, placebo-controlled trials that evaluated the mean change in FEV 1 from baseline as a primary endpoint.
The safety and efficacy of formoterol MDI 5 mcg (administered as 2 inhalations twice daily) alone in comparison to placebo was replicated in another 26-week trial (NCT00383552) that also evaluated the same endpoint with a lower dose of mometasone furoate MDI in combination with formoterol.
Pediatric Patients Aged 5 to Less Than 12 Years The efficacy of DULERA 50 mcg/5 mcg in children aged 5 to less than 12 years was demonstrated in a randomized, active-controlled, multicenter clinical trial (NCT02741271) in which DULERA 50 mcg/5 mcg (administered as two inhalations, twice daily; n=91) was compared with mometasone furoate MDI 50 mcg (administered as two inhalations, twice daily; n=90), in 181 asthma patients aged 5 to less than 12 years.
These participants had been adequately controlled on an ICS/LABA for at least 4 weeks and had no symptoms of asthma worsening during a 2-week run-in on mometasone furoate MDI 50 mcg (administered as two inhalations twice daily).
Primary endpoint results showed that patients receiving DULERA 50 mcg/5 mcg had a statistically significant change from baseline to Week 12 in 60-min AM post-dose % predicted FEV 1 compared to mometasone furoate MDI 50 mcg (5.21, 95% CI: 3.22, 7.20) [Figure 2].
Bronchodilatory improvement with DULERA 50 mcg/5 mcg relative to mometasone furoate MDI 50 mcg was significant from the first assessment at 5 minutes and was sustained through 4 hours post-dose.
These improvements were evident as early as the first dose and were maintained through Week 12.
Figure 2: Change from Baseline AM Post-Dose in % Predicted FEV 1 Through Week 12 MF = mometasone furoate; MF/F = mometasone furoate/formoterol fumarate Population consists of all subjects who received at least one dose of blinded treatment and completed at least one efficacy evaluation.
Treatment Effects were estimated using the Primary Analysis Method [i.e., a cLDA model with control-based multiple imputation, including terms for treatment, time, age strata (5-7 yrs., 8-11 yrs.), treatment by time interaction, and region (US, ex-US)].
Figure 2 Postmarketing Safety and Efficacy Trial with DULERA This 26-week double-blind, randomized control trial evaluated 11,729 patients, 12 years of age and older, who received at least one dose of DULERA (100 mcg/5 mcg or 200 mcg/5 mcg, n=5868) or mometasone furoate monotherapy (100 mcg or 200 mcg, n=5861) each administered as 2 inhalations twice daily by metered dose inhalation aerosols (NCT01471340).
The primary safety objective was to evaluate whether the addition of formoterol to mometasone furoate (DULERA) was non-inferior to mometasone furoate in risk of serious asthma-related events (adjudicated hospitalization, intubation, and death).
A blinded adjudication committee determined whether events were asthma-related.
The study was designed to rule out a pre-defined risk margin of 2.0.
Enrolled patients had a diagnosis of persistent asthma, had been receiving a stable dose of asthma maintenance therapy for at least 4 weeks and had a history of one to four asthma exacerbations requiring hospitalization or systemic corticosteroid use in the previous year.
The assigned dose level of inhaled corticosteroid was based on the patients’ disease severity, considering their prior asthma medication and current level of asthma control.
The study included patients ranging in age from 12 to 88 years (median age 47 years), and were 66% female and 77% Caucasian.
DULERA was non-inferior to mometasone furoate in terms of time to first serious asthma-related event based on the pre-specified risk margin with an estimated hazard ratio of 1.22 [95% CI: 0.76, 1.94].
Table 7: Serious Asthma-Related Event (Postmarketing Trial) DULERA Actual treatment used for analysis.
n (%) Mometasone Furoate n (%) Total n (%) DULERA vs.
Mometasone Furoate Patients in population 5868 5861 11,729 Hazard Ratio The hazard ratio for time to first event was based on a Cox proportional hazard model with covariates of treatment (DULERA vs.
mometasone furoate) and inhaled corticosteroid dose level (100 mcg vs.
200 mcg), as treated.
(95% CI) Serious Asthma-related Event Results provided for all randomized patients who received at least one dose of DULERA (100 mcg/5 mcg and 200 mcg/5 mcg, two inhalations, prescribed twice daily) or mometasone furoate (100 mcg and 200 mcg, two inhalations, prescribed twice daily).
, Number of patients with an event 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 blinded adjudication committee determined whether events were asthma related.
39 (0.66) 32 (0.55) 71 (0.6) 1.22 (0.76, 1.94) Asthma-Related Hospitalization (≥24 hr stay) 39 (0.66) 32 (0.55) 71 (0.6) Asthma-Related Intubation (Endotracheal) 0 0 0 Asthma-Related Death 0 0 0 The key efficacy endpoint was time to first asthma exacerbation [defined as a clinical deterioration of asthma associated with systemic corticosteroid use for ≥3 consecutive days (or ≥1 depot injectable), emergency department visits <24 hours requiring systemic corticosteroid, or hospital stays of ≥24 hours].
The estimated hazard ratio for time to first exacerbation for DULERA relative to mometasone furoate was 0.89 [95% CI: 0.8, 0.98].
This outcome was primarily driven by a reduction in those events requiring systemic corticosteroid use, which accounted for 87% of the total number of first asthma exacerbations.
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 How Supplied DULERA is available in three strengths and supplied in the following package sizes ( Table 8 ): Table 8 Package NDC Strength Identifier (Color Band) Included on the outer carton, actuator, and canister labels DULERA 50 mcg/5 mcg 120 inhalations 0085-2223-01 Blue DULERA 100 mcg/5 mcg 120 inhalations 0085-7206-01 Yellow DULERA 100 mcg/5 mcg 60 inhalations (institutional pack) 0085-7206-07 Yellow DULERA 200 mcg/5 mcg 120 inhalations 0085-4610-01 Purple DULERA 200 mcg/5 mcg 60 inhalations (institutional pack) 0085-4610-05 Purple Each strength is supplied as a pressurized aluminum canister that has a blue plastic actuator integrated with a dose counter and a green dust cap.
Each 120-inhalation canister has a net fill weight of 13 grams and each 60-inhalation canister has a net fill weight of 8.8 grams.
Each canister is placed into a carton.
Each carton contains 1 canister and a Patient Information leaflet.
Initially the dose counter will display “64” or “124” actuations.
After the initial priming with 4 actuations, the dose counter will read “60” or “120” and the inhaler is now ready for use.
16.2 Storage and Handling Only use the DULERA canister with the DULERA actuator.
Do not use the DULERA actuator with any other inhalation drug product.
Do not use actuators from other products with the DULERA canister.
Do not remove the canister from the actuator because the correct amount of medication may not be discharged; the dose counter may not function properly; reinsertion may cause the dose counter to count down by 1 and discharge a puff.
The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate.
Discard the inhaler when the labeled number of actuations has been used (the dose counter will read “0”).
Store at controlled room temperature 20°C–25°C (68°F–77°F); excursions permitted to 15°C–30°C (59°F–86°F) [see USP Controlled Room Temperature].
The 120-inhalation inhaler does not require specific storage orientation.
For the 60-inhalation inhaler, after priming, store the inhaler with the mouthpiece down or in a horizontal position.
For best results, keep the canister at room temperature before use.
Shake well and remove the cap from the mouthpiece of the actuator before using.
Keep out of reach of children.
Avoid spraying in eyes.
Contents Under Pressure: Do not puncture.
Do not use or store near heat or open flame.
Exposure to temperatures above 120°F may cause bursting.
Never throw container into fire or incinerator.
GERIATRIC USE
8.5 Geriatric Use A total of 77 patients 65 years of age and older (11 of whom were 75 years and older) have been treated with DULERA in 3 clinical trials up to 52 weeks in duration.
Similar efficacy and safety results were observed in an additional 28 patients 65 years of age and older who were treated with DULERA in another clinical trial.
No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
As with other products containing beta 2 -agonists, special caution should be observed when using DULERA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta 2 -agonists.
Based on available data for DULERA or its active components, no adjustment of dosage of DULERA in geriatric patients is warranted.
MECHANISM OF ACTION
12.1 Mechanism 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 a selective long-acting beta 2 -adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma.
Mometasone furoate : Mometasone furoate is a 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 a 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 a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone.
The clinical significance of these findings is unknown.
Formoterol fumarate : Formoterol fumarate is a long-acting selective beta 2 -adrenergic receptor agonist (beta 2 -agonist).
Inhaled formoterol fumarate acts locally in the lung as a bronchodilator.
In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors.
Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors.
The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects.
The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′, 5′-adenosine monophosphate (cyclic AMP).
Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
In 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.
INDICATIONS AND USAGE
1 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.
( 1.1 ) Important Limitation of Use: Not indicated for the relief of acute bronchospasm.
( 1.1 ) 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 beta 2 -adrenergic agonist (LABA).
Important Limitation of Use: DULERA is NOT indicated for the relief of acute bronchospasm.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of DULERA have been established in patients 12 years of age and older in 3 clinical trials up to 52 weeks in duration.
In the 3 clinical trials, 101 patients 12 to 17 years of age were treated with DULERA.
Patients in this age-group demonstrated efficacy results similar to those observed in patients 18 years of age and older.
There were no obvious differences in the type or frequency of adverse reactions reported in this age group compared to patients 18 years of age and older.
Similar efficacy and safety results were observed in an additional 22 patients 12 to 17 years of age who were treated with DULERA in another clinical trial.
The safety and effectiveness of DULERA 50 mcg/5 mcg, two inhalations twice daily, have been established in patients with asthma aged 5 to less than 12 years in clinical trials up to 24 weeks of treatment duration.
Patients in this age group demonstrated efficacy and safety results similar to those observed in patients aged 12 years and older who were treated with DULERA [see Adverse Reactions (6.1) and Clinical Studies (14.1) ].
The safety and effectiveness of DULERA have not been established in children younger than 5 years of age.
Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients.
In these studies, the mean reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8 per year) and appears to depend upon dose and duration of exposure.
This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function.
The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown.
The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied.
The growth of children and adolescents receiving orally inhaled corticosteroids, including DULERA, should be monitored routinely (e.g., via stadiometry).
If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered.
The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies.
To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2.2) ] .
PREGNANCY
8.1 Pregnancy Risk Summary There 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 8 times the maximum recommended human dose (MRHD) on a mcg/m 2 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 a mg/m 2 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 a 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 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-associated maternal and/or embryo/fetal risk In 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 delivery There 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 Furoate In 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 a mcg/m 2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at an exposure approximately equivalent to the MRHD (on a mcg/m 2 basis with a maternal subcutaneous dose of 180 mcg/kg).
No toxicity was observed with a dose that produced an exposure approximately one-tenth of the MRHD (on a mcg/m 2 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 6 times the MRHD (on a mcg/m 2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at exposures approximately 3 times the MRHD (on a mcg/m 2 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 8 times the MRHD (on an area under the curve (AUC) basis with a maternal subcutaneous dose of 15 mcg/kg).
There were no findings with an exposure approximately 4 times the MRHD (on an AUC basis with a 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 3 times the MRHD (on a mcg/m 2 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 a maternal oral dose of 700 mcg/kg).
At an exposure approximately 2 times the MRHD (on an AUC basis with a 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 a maternal oral dose of 140 mcg/kg).
Formoterol Fumarate In 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 a mcg/m 2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 2400 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 6000 mcg/kg and above).
In a 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 a mcg/m 2 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 a mcg/m 2 basis with a 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, a malformation, was observed in rat fetuses at exposures approximately 1200 times the MRHD (on a mcg/m 2 basis with maternal oral doses of 3000 mcg/kg/day and above).
Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 6100 times the MRHD (on a mcg/m 2 basis with a 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 a mcg/m 2 basis with a 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 a mcg/m 2 basis with a maternal oral dose of 60,000 mcg/kg/day).
No teratogenic effects were observed with exposures up to approximately 3000 times the MRHD (on a mcg/m 2 basis with a maternal oral dose of 3500 mcg/kg).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS LABA monotherapy increases the risk of serious asthma-related events.
( 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 beta 2 -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.
After dosing, advise patients to rinse their mouth with water and spit out contents without swallowing.
( 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: Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term.
( 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 ) 5.1 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 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 (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.
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 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.
5.3 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.
5.4 Local Effects In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with DULERA.
If oropharyngeal candidiasis develops, treat with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with DULERA therapy, but at times therapy with DULERA may need to be interrupted.
To reduce the risk of oropharyngeal candidiasis, after dosing with DULERA, advise patients to rinse their mouth with water and spit out the contents without swallowing.
5.5 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals.
Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.
In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure.
How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known.
The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known.
If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated.
If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated.
(See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered.
DULERA should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.
5.6 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to DULERA because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids.
After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function.
Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn.
During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss.
Although DULERA may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies.
During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction.
These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack.
Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to DULERA.
Lung function (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.
5.7 Hypercorticism and Adrenal Suppression Mometasone furoate, a component of DULERA, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.
Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of DULERA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.
Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with DULERA should be observed carefully for any evidence of systemic corticosteroid effects.
Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response.
It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time.
If such effects occur, the dosage of DULERA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.
5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of DULERA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].
5.9 Paradoxical Bronchospasm and Upper Airway Symptoms DULERA may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening.
If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator.
DULERA should be discontinued immediately and alternative therapy instituted.
5.10 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of DULERA, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm.
5.11 Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia.
Therefore, DULERA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Formoterol fumarate, a component of DULERA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms.
Although such effects are uncommon after administration of DULERA at recommended doses, if they occur, the drug may need to be discontinued.
In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression.
The clinical significance of these findings is unknown.
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.
5.12 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, one of the components of DULERA.
The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown.
Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care.
In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline 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.
5.13 Effect on Growth Orally inhaled corticosteroids, including DULERA, may cause a reduction in growth velocity when administered to pediatric patients.
Monitor the growth of pediatric patients receiving DULERA routinely (e.g., via stadiometry).
To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4) ] .
5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term administration of inhaled corticosteroids, including mometasone furoate, a component of DULERA.
Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term [see Adverse Reactions (6) ] .
5.15 Coexisting Conditions DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines.
Doses of the related beta 2 -agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.
5.16 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ).
Serious Asthma-Related Events Inform patients with asthma that LABA when used alone increases the risk of asthma-related hospitalization, or asthma-related death.
Available data show that when ICS and LABA are used together, such as with DULERA, there is not a significant increase in risk of these events.
Not for Acute Symptoms DULERA is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose.
Treat acute symptoms with an inhaled, short-acting, beta 2 -agonist (the health care provider should prescribe the patient with such medication and instruct the patient in how it should be used).
Instruct patients to seek medical attention immediately if they experience any of the following: If their symptoms worsen Significant decrease in lung function as outlined by the physician If they need more inhalations of a short-acting beta 2 -agonist than usual Advise patients not to increase the dose or frequency of DULERA.
Do not exceed the daily dosage of DULERA of two inhalations twice daily.
If they miss a dose, instruct patients to take their next dose at the same time they normally do.
DULERA provides bronchodilation for up to 12 hours.
Instruct patients not to stop or reduce DULERA therapy without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2) ] .
Do Not Use Additional Long-Acting Beta 2 -Agonists When patients are prescribed DULERA, other long-acting beta 2 -agonists should not be used [see Warnings and Precautions (5.3) ] .
Risks Associated With Corticosteroid Therapy Local Effects: Advise patients that localized infections with Candida albicans occurred in the mouth and pharynx in some patients.
If oropharyngeal candidiasis develops, treat 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: Warn patients who are on immunosuppressant doses of corticosteroids to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay.
Inform patients 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: Advise patients that DULERA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression.
Additionally, instruct patients that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.
Instruct patients to taper slowly from systemic corticosteroids if transferring to DULERA [see Warnings and Precautions (5.7) ].
Reduction in Bone Mineral Density: Advise patients who are at an increased risk for decreased BMD that the use of corticosteroids may pose an additional risk and that they should be monitored and, where appropriate, be treated for this condition [see Warnings and Precautions (5.12) ].
Reduced Growth Velocity: Inform patients that orally inhaled corticosteroids, a component of DULERA, may cause a 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); consider regular eye examinations [see Warnings and Precautions (5.14) ].
Risks Associated With Beta-Agonist Therapy Inform patients that treatment with beta 2 -agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness [see Warnings and Precautions (5.11) ].
Instructions for Use Instruct patients regarding the following: Read the Patient Information before use and follow the Instructions for Use carefully.
Remind patients to: Remove the cap from the mouthpiece of the actuator before use.
After dosing, rinse their mouth with water without swallowing and spit out after breathing in the medicine.
This will help reduce the risk of oropharyngeal candidiasis.
Not remove the canister from the actuator.
Not wash inhaler in water.
The mouthpiece should be cleaned using a dry wipe after every 7 days of use.
DOSAGE AND ADMINISTRATION
2 For oral inhalation only.
( 2.1 ) Treatment of asthma in patients ≥12 years: 2 inhalations twice daily of DULERA 100 mcg/5 mcg or 200 mcg/5 mcg.
Starting dosage is based on disease severity.
( 2.2 ) Treatment of asthma in patients aged 5 to less than 12 years: 2 inhalations twice daily of DULERA 50 mcg/5 mcg.
( 2.2 ) 2.1 Administration Information Administer DULERA as two inhalations twice daily every day (morning and evening) by the orally inhaled route (see Patient Instructions for Use in the Patient Information leaflet).
Do not use more than two inhalations twice daily of the prescribed strength of DULERA as some patients are more likely to experience adverse effects with higher doses of formoterol.
If symptoms arise between doses, an inhaled short-acting 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.
2.2 Recommended Dosage Administer DULERA as two inhalations twice daily every day (morning and evening) by the orally inhaled route.
Shake well prior to each inhalation.
Individual patients may experience a variable time to onset and degree of symptom relief.
If symptoms arise between doses, use an inhaled short-acting 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.