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Dulera

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Dulera

CLINICAL PHARMACOLOGY

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 beta2-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 beta2-adrenergic receptor agonist (beta2-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 beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

Pharmacodynamics

Cardiovascular Effects

DULERA

In a single-dose, double-blind placebo controlled crossover trial in 25 patients with asthma, single dose treatment of 10 mcg formoterol fumarate in combination with 400 mcg of mometasone furoate delivered via DULERA 200 mcg/5 mcg were compared to formoterol fumarate 10 mcg MDI, formoterol fumarate 12 mcg dry powder inhaler (DPI; nominal dose of formoterol fumarate delivered 10 mcg), or placebo. The degree of bronchodilation at 12 hours after dosing with DULERA was similar to formoterol fumarate delivered alone via MDI or DPI.

ECGs and blood samples for glucose and potassium were obtained prior to dosing and post dose. No downward trend in serum potassium was observed and values were within the normal range and appeared to be similar across all treatments over the 12 hour period. Mean blood glucose appeared similar across all groups for each time point. There was no evidence of significant hypokalemia or hyperglycemia in response to formoterol treatment.

No relevant changes in heart rate or changes in ECG data were observed with DULERA in the trial. No patients had a QTcB (QTc corrected by Bazett's formula) ≥ 500 msec during treatment.

In a single-dose crossover trial involving 24 healthy subjects, single dose of formoterol fumarate 10, 20, or 40 mcg in combination with 400 mcg of mometasone furoate delivered via DULERA were evaluated for safety (ECG, blood potassium and glucose changes). ECGs and blood samples for glucose and potassium were obtained at baseline and post dose. Decrease in mean serum potassium was similar across all three treatment groups (approximately 0.3 mmol/L) and values were within the normal range. No clinically significant increases in mean blood glucose values or heart rate were observed. No subjects had a QTcB > 500 msec during treatment.

Three active- and placebo-controlled trials (study duration ranging from 12, 26, and 52 weeks) evaluated 1913 patients 12 years of age and older with asthma. No clinically meaningful changes were observed in potassium and glucose values, vital signs, or ECG parameters in patients receiving DULERA.

HPA Axis Effects

The effects of inhaled mometasone furoate administered via DULERA on adrenal function were evaluated in two clinical trials in patients with asthma. HPA-axis function was assessed by 24-hour plasma cortisol AUC. Although both these trials have open-label design and contain small number of subjects per treatment arm, results from these trials taken together demonstrated suppression of 24-hour plasma cortisol AUC for DULERA 200 mcg/5 mcg compared to placebo consistent with the known systemic effects of inhaled corticosteroid.

In a 42-day, open-label, placebo and active-controlled study 60 patients with asthma 18 years of age and older were randomized to receive two inhalations twice daily of 1 of the following treatments: DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg, or placebo. At Day 42, the mean change from baseline plasma cortisol AUC(0-24 hr) was 8%, 22% and 34% lower compared to placebo for the DULERA 100 mcg/5 mcg (n=13), DULERA 200 mcg/5 mcg (n=15) and fluticasone propionate/salmeterol xinafoate 230 mcg/21 mcg (n=16) treatment groups, respectively.

In a 52-week, open-label safety study, primary analysis of the plasma cortisol 24-hour AUC was performed on 57 patients with asthma who received 2 inhalations twice daily of DULERA 100 mcg/5 mcg, DULERA 200 mcg/5 mcg, fluticasone propionate/salmeterol xinafoate 125/25 mcg, or fluticasone propionate/salmeterol xinafoate 250/25 mcg. At Week 52, the mean plasma cortisol AUC(0-24 hr) was 2.2%, 29.6%, 16.7%, and 32.2% lower from baseline for the DULERA 100 mcg/5 mcg (n=18), DULERA 200 mcg/5 mcg (n=20), fluticasone propionate/salmeterol xinafoate 125/25 mcg (n=8), and fluticasone propionate/salmeterol xinafoate 250/25 mcg (n=11) treatment groups, respectively.

Other Mometasone Products

HPA Axis Effects

The potential effect of mometasone furoate via a dry powder inhaler (DPI) on the HPA axis was assessed in a 29-day study. A total of 64 adult patients with mild to moderate asthma were randomized to one of 4 treatment groups: mometasone furoate DPI 440 mcg twice daily, mometasone furoate DPI 880 mcg twice daily, oral prednisone 10 mg once daily, or placebo. The 30-minute post-Cosyntropin stimulation serum cortisol concentration on Day 29 was 23.2 mcg/dl for the mometasone furoate DPI 440 mcg twice daily group and 20.8 mcg/dl for the mometasone furoate DPI 880 mcg twice daily group, compared to 14.5 mcg/dl for the oral prednisone 10 mg group and 25 mcg/dl for the placebo group. The difference between mometasone furoate DPI 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.

Pharmacokinetics

Absorption

Mometasone furoate

Healthy Subjects: The systemic exposures to mometasone furoate from DULERA versus mometasone furoate delivered via DPI were compared. Following oral inhalation of single and multiple doses of the DULERA, mometasone furoate was absorbed in healthy subjects with median Tmax values ranging from 0.50 to 4 hours. Following single-dose administration of higher than recommended dose of DULERA (4 inhalations of DULERA 200 mcg/5 mcg) in healthy subjects, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for MF were 67.8 (49) pg/mL and 650 (51) pg•hr/mL, respectively while the corresponding estimates following 5 days of BID dosing of DULERA 800 mcg/20 mcg were 241 (36) pg/mL and 2200 (35) pg•hr/mL. Exposure to mometasone furoate increased with increasing inhaled dose of DULERA 100 mcg/5 mcg to 200 mcg/5 mcg. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of mometasone furoate is negligible ( < 1%).

The above study demonstrated that the systemic exposure to mometasone furoate (based on AUC) was approximately 52% and 25% lower on Day 1 and Day 5, respectively, following DULERA administration compared to mometasone furoate via a DPI.

Asthma Patients: Following oral inhalation of single and multiple doses of the DULERA, mometasone furoate was absorbed in asthma patients with median Tmax values ranging from 1 to 2 hours. Following single-dose administration of DULERA 400 mcg/10 mcg, the arithmetic mean (CV%) Cmax and AUC(0-12 hr) values for MF were 20 (88) pg/mL and 170 (94) pg•hr/mL, respectively while the corresponding estimates following BID dosing of DULERA 400 mcg/10 mcg at steady-state were 60 (36) pg/mL and 577 (40) pg•hr/mL.

Formoterol fumarate

Healthy Subjects: When DULERA was administered to healthy subjects, formoterol was absorbed with median Tmax values ranging from 0.167 to 0.5 hour. In a single-dose study with DULERA 400 mcg/10 mcg in healthy subjects, arithmetic mean (CV%) Cmax and AUC for formoterol were 15 (50) pmol/L and 81 (51) pmol*h/L, respectively. Over the dose range of 10 to 40 mcg for formoterol from DULERA, the exposure to formoterol was dose proportional.

Asthma Patients: When DULERA was administered to patients with asthma, formoterol was absorbed with median Tmax values ranging from 0.58 to 1.97 hours. In a single-dose study with DULERA 400 mcg/10 mcg in patients with asthma, arithmetic mean (CV%) Cmax and AUC(0-12 hr) for formoterol were 22 (29) pmol/L and 125 (42) pmol*h/L, respectively. Following multiple-dose administration of DULERA 400 mcg/10 mcg, the steady-state arithmetic mean (CV%) Cmax and AUC(0-12 hr) for formoterol were 41 (59) pmol/L and 226 (54) pmol*hr/L.

Distribution

Mometasone furoate: Based on the study employing a 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder in humans, no appreciable accumulation of mometasone furoate in the red blood cells was found. Following an intravenous 400 mcg dose of mometasone furoate, the plasma concentrations showed a biphasic decline, with a mean steady-state volume of distribution of 152 liters. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% (in a concentration range of 5 to 500 ng/mL).

Formoterol fumarate: The binding of formoterol to human plasma proteins in vitro was 61% to 64% at concentrations from 0.1 to 100 ng/mL. Binding to human serum albumin in vitro was 31% to 38% over a range of 5 to 500 ng/mL. The concentrations of formoterol used to assess the plasma protein binding were higher than those achieved in plasma following inhalation of a single 120 mcg dose.

Metabolism

Mometasone furoate: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites. In-vitro studies have confirmed the primary role of human liver cytochrome P-450 3A4 (CYP3A4) in the metabolism of this compound, however, no major metabolites were identified. Human liver CYP3A4 metabolizes mometasone furoate to 6-beta hydroxy mometasone furoate.

Formoterol fumarate: Formoterol is metabolized primarily by direct glucuronidation at either the phenolic or aliphatic hydroxyl group and O-demethylation followed by glucuronide conjugation at either phenolic hydroxyl groups. Minor pathways involve sulfate conjugation of formoterol and deformylation followed by sulfate conjugation. The most prominent pathway involves direct conjugation at the phenolic hydroxyl group. The second major pathway involves O-demethylation followed by conjugation at the phenolic 2'-hydroxyl group. Four cytochrome P450 isozymes (CYP2D6, CYP2C19, CYP2C9 and CYP2A6) are involved in the O-demethylation of formoterol. Formoterol did not inhibit CYP450 enzymes at therapeutically relevant concentrations. Some patients may be deficient in CYP2D6 or 2C19 or both. Whether a deficiency in one or both of these isozymes results in elevated systemic exposure to formoterol or systemic adverse effects has not been adequately explored.

Excretion

Mometasone furoate: Following an intravenous dosing, the terminal half-life was reported to be about 5 hours. Following the inhaled dose of tritiated 1000 mcg mometasone furoate, the radioactivity is excreted mainly in the feces (a mean of 74%), and to a small extent in the urine (a mean of 8%) up to 7 days. No radioactivity was associated with unchanged mometasone furoate in the urine. Absorbed mometasone furoate is cleared from plasma at a rate of approximately 12.5 mL/min/kg, independent of dose. The effective t½ for mometasone furoate following inhalation with DULERA was 25 hours in healthy subjects and in patients with asthma.

Formoterol fumarate: Following oral administration of 80 mcg of radiolabeled formoterol fumarate to 2 healthy subjects, 59% to 62% of the radioactivity was eliminated in the urine and 32% to 34% in the feces over a period of 104 hours. In an oral inhalation study with DULERA, renal clearance of formoterol from the blood was 217 mL/min. In single-dose studies, the mean t½ values for formoterol in plasma were 9.1 hours and 10.8 hours from the urinary excretion data. The accumulation of formoterol in plasma after multiple dose administration was consistent with the increase expected with a drug having a terminal t½ of 9 to 11 hour.

Following single inhaled doses ranging from 10 to 40 mcg to healthy subjects from the MFF MDI, 6.2% to 6.8% of the formoterol dose was excreted in urine unchanged. The (R,R) and (S,S)-enantiomers accounted, respectively, for 37% and 63% of the formoterol recovered in urine. From urinary excretion rates measured in healthy subjects, the mean terminal elimination half-lives for the (R,R)- and (S,S)-enantiomers were determined to be 13 and 9.5 hours, respectively. The relative proportion of the two enantiomers remained constant over the dose range studied.

Special Populations

Hepatic/Renal Impairment: There are no data regarding the specific use of DULERA in patients with hepatic or renal impairment.

A study evaluating the administration of a single inhaled dose of 400 mcg mometasone furoate by a dry powder inhaler to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50-105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.

Gender and Race: Specific studies to examine the effects of gender and race on the pharmacokinetics of DULERA have not been specifically studied.

Geriatrics: The pharmacokinetics of DULERA have not been specifically studied in the elderly population.

Drug-Drug Interactions

A single-dose crossover study was conducted to compare the pharmacokinetics of 4 inhalations of the following: mometasone furoate MDI, formoterol MDI, DULERA (mometasone furoate/formoterol fumarate MDI), and mometasone furoate MDI plus formoterol fumarate MDI administered concurrently. The results of the study indicated that there was no evidence of a pharmacokinetic interaction between the two components of DULERA.

Inhibitors of Cytochrome P450 Enzymes: Ketoconazole: In a drug interaction study, an inhaled dose of mometasone furoate 400 mcg delivered by a dry powder inhaler was given to 24 healthy subjects twice daily for 9 days and ketoconazole 200 mg (as well as placebo) were given twice daily concomitantly on Days 4 to 9. Mometasone furoate plasma concentrations were < 150 pcg/mL on Day 3 prior to coadministration of ketoconazole or placebo. Following concomitant administration of ketoconazole, 4 out of 12 subjects in the ketoconazole treatment group (n=12) had peak plasma concentrations of mometasone furoate > 200 pcg/mL on Day 9 (211-324 pcg/mL). Mometasone furoate plasma levels appeared to increase and plasma cortisol levels appeared to decrease upon concomitant administration of ketoconazole.

Specific drug-drug interaction studies with formoterol have not been performed.

Animal Toxicology and/or Pharmacology

Animal Pharmacology

Formoterol fumarate: Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown.

Reproductive Toxicology Studies

Mometasone furoate: In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (approximately 1/3 of the maximum recommended human dose MRHD on a mcg/m² basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to the MRHD on a mcg/m² basis). No toxicity was observed at 20 mcg/kg (approximately one-tenth of the MRHD on a mcg/m² basis).

In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the MRHD on a mcg/m² basis). A dose of 300 mcg/kg (approximately 3 times the MRHD on a mcg/m² basis) produced delays in ossification, but no malformations.

When rats received subcutaneous doses of mometasone furoate throughout pregnancy or during the later stages of pregnancy, 15 mcg/kg (approximately 8 times the MRHD on an AUC basis) caused prolonged and difficult labor and reduced the number of live births, birth weight, and early pup survival. Similar effects were not observed at 7.5 mcg/kg (approximately 4 times the MRHD on an AUC basis).

In rabbits, mometasone furoate caused multiple malformations (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at topical dermal doses of 150 mcg/kg and above (approximately 3 times the MRHD on a mcg/m² basis). In an oral study, mometasone furoate increased resorptions and caused cleft palate and/or head malformations (hydrocephaly and domed head) at 700 mcg/kg (less than the MRHD on an area under the curve [AUC] basis). At 2800 mcg/kg (approximately 2 times the MRHD on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the MRHD on an AUC basis).

Formoterol fumarate: Formoterol fumarate administered throughout organogenesis did not cause malformations in rats or rabbits following oral administration. When given to rats throughout organogenesis, oral doses of 0.2 mg/kg (approximately 80 times the MRHD on a mcg/m² basis) and above delayed ossification of the fetus, and doses of 6 mg/kg (approximately 2400 times the MRHD on a mcg/m² basis) and above decreased fetal weight. Formoterol fumarate has been shown to cause stillbirth and neonatal mortality at oral doses of 6 mg/kg (approximately 2400 times the MRHD on a mcg/m² basis) and above in rats receiving the drug during the late stage of pregnancy. These effects, however, were not produced at a dose of 0.2 mg/kg (approximately 80 times the MRHD on a mcg/m² basis).

In another testing laboratory, formoterol fumarate was shown to be teratogenic in rats and rabbits. Umbilical hernia, a malformation, was observed in rat fetuses at oral doses of 3 mg/kg/day and above (approximately 1200 times greater than the MRHD on a mcg/m² basis). Brachygnathia, a skeletal malformation, was observed for rat fetuses at an oral dose of 15 mg/kg/day (approximately 6100 times the MRHD on a mcg/m² basis). In another study in rats, no teratogenic effects were seen at inhalation doses up to 1.2 mg/kg/day (approximately 500 times the MRHD on a mcg/m² basis). Subcapsular cysts on the liver were observed for rabbit fetuses at an oral dose of 60 mg/kg (approximately 49,000 times the MRHD on a mcg/m² basis). No teratogenic effects were observed at oral doses up to 3.5 mg/kg (approximately 3000 times the MRHD on a mcg/m² basis).

Clinical Studies

Asthma

The safety and efficacy of DULERA were demonstrated in two randomized, double-blind, parallel group, multicenter clinical trials of 12 to 26 weeks in duration involving 1509 patients 12 years of age and older with persistent asthma uncontrolled on medium or high dose inhaled corticosteroids (baseline FEV1 means of 66% to 73% of predicted normal). These studies included 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 evaluated 781 patients 12 years of age and older comparing DULERA 100 mcg/5 mcg (n=191 patients), mometasone furoate 100 mcg (n=192 patients), formoterol fumarate 5 mcg (n=202 patients) and placebo (n=196 patients); each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This study included a 2 to 3-week run-in period with mometasone furoate 100 mcg, 2 inhalations twice daily. This trial included patients ranging from 12 to 76 years of age, 41% male and 59% female, and 72% Caucasian and 28% non-Caucasian. Patients had persistent asthma and were not well controlled on medium dose of inhaled corticosteroids prior to randomization. All treatment groups were balanced with regard to baseline characteristics. Mean FEV1 and mean percent predicted FEV1 were similar among all treatment groups (2.33 L, 73%). Eight (4%) patients receiving DULERA 100 mcg/5 mcg, 13 (7%) patients receiving mometasone furoate 100 mcg, 47 (23%) patients receiving formoterol fumarate 5 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure.

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

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

Change from Baseline by Treatment - Illustration

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

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

  DULERA100 mcg/ 5 mcg†
(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 FEV1 18 (9%) 19 (10%) 31 (15%) 41 (21%)
  Decrease in PEF§ 37 (19%) 41 (21%) 62 (31%) 61 (31%)
  Emergency treatment 0 1 (<1%) 4 (2%) 1 ( < 1%)
  Hospitalization 1 (<1%) 0 0 0
  Treatment with excluded asthma medication¶ 2 (1%) 4 (2%) 17 (8%) 8 (4%)
* Includes only the first event day for each patient. Patients could have experienced more than one event criterion.
† Two inhalations, twice daily.
‡ Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication).
§ Decrease in AM or PM peak expiratory flow (PEF) on 2 or more consecutive days below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period).
¶ Thirty patients received glucocorticosteroids; 1 patient received formoterol via dry powder inhaler in the Formoterol 5 mcg group.

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

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

Treatment Arm N Baseline (L) Change From Baseline at Week 12 (L) Treatment Difference from Placebo (L) P-Value vs. Placebo P-Value vs. Formoterol
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      
LS means and p-values are from Week 12 estimates of a longitudinal analysis model.

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

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

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

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

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

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

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

Treatment Arm N Baseline (L) Change from Baseline at Week 12 (L)
DULERA 100 mcg/5 mcg 232 2.1 0.14
DULERA 200 mcg/5 mcg 255 2.05 0.19
Mometasone furoate 200 mcg 239 2.07 0.1

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

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

  DULERA 100 mcg/ 5 mcg†
(n=233)
DULERA200 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 FEV1 23 (10%) 17 (7%) 33 (14%)
Decrease in PEF on two consecutive days§ 2 (1%) 4 (2%) 3 (1%)
Emergency treatment 2 (1%) 1 ( < 1%) 1 ( < 1%)
Hospitalization 0 1 ( < 1%) 0
Treatment with excluded asthma medication¶ 5 (2%) 8 (3%) 12 (5%)
* Includes only the first event day for each patient. Patients could have experienced more than one event criterion.
† Two inhalations, twice daily.
‡ Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication).
§ Decrease in AM or PM peak expiratory flow (PEF) below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period).
¶ Twenty four patients received glucocorticosteroids; 1 patient received albuterol in the DULERA 200 mcg / 5 mcg group. 20

Other Studies

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

Last reviewed on RxList: 2/1/2013
This monograph has been modified to include the generic and brand name in many instances.

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