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Asmanex (Mometasone Furoate Inhalation) - Description and Clinical Pharmacology

 
 



ASMANEX TWISTHALER 220 mcg
(mometasone furoate inhalation powder)

PRODUCT INFORMATION

FOR ORAL INHALATION ONLY

DESCRIPTION

Mometasone furoate, the active component of the ASMANEX TWISTHALER product, is a corticosteroid with the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16 (alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) and the following chemical structure:

Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6, and molecular weight 521.44 Daltons.

The ASMANEX TWISTHALER 220 mcg product is a cap-activated inhalation-driven multi-dose dry powder inhaler containing mometasone furoate and anhydrous lactose (which contains milk proteins). Each actuation of the ASMANEX TWISTHALER 220 mcg inhaler provides a measured dose of 1.5 mg mometasone furoate inhalation powder, containing 220 mcg of mometasone furoate. This results in delivery of 200 mcg mometasone furoate from the mouthpiece, based on in vitro testing at flow rates of 30 L/min and 60 L/min with constant volume (2 L). The amount of mometasone furoate emitted from the inhaler in vitro did not differ significantly for flow rates ranging from 28.3 L/min to 70 L/min for fixed intervals of 2 seconds. However, the amount of drug delivered to the lung will depend on patient factors such as inspiratory flow and peak inspiratory flow through the device. In adult and adolescent patients with varied asthma severity, mean peak inspiratory flow rate through the device was 69 L/min (range 5477 L/min).

CLINICAL PHARMACOLOGY

Mechanism of Action

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 (eg, mast cells, eosinophils, neutrophils, macrophages and lymphocytes) and mediators (eg, 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.

In a three-way cross over study in 15 asthmatic patients receiving 50 or 100 mcg of mometasone furoate inhalation powder to placebo twice daily for two weeks, mometasone furoate inhalation powder reduced airway reactivity to adenosine monophosphate. In another study, pretreatment with mometasone furoate inhalation powder for 5 days attenuated the early and late phase reactions following inhaled allergen challenge and also reduced allergen-induced hyperresponsiveness to methacholine. Mometasone furoate inhalation powder was also shown to attenuate the increase in inflammatory cells (total and activated eosinophils) in induced sputum following allergen and methacholine challenge. The clinical significance of these findings is unknown.

Studies in asthmatic patients have demonstrated that ASMANEX TWISTHALER provides a favorable ratio of topical to systemic activity due to its primary local effect along with the extensive hepatic metabolism and the lack of active metabolites (see below).

Though effective for the treatment of asthma, glucocorticoids do not affect asthma symptoms immediately. Maximum improvement in symptoms following inhaled administration of mometasone furoate may not be achieved for 1 to 2 weeks or longer after starting treatment. When glucocorticoids are discontinued, asthma stability may persist for several days or longer.

Pharmacokinetics

Absorption

Following a 1000 mcg inhaled dose of tritiated mometasone furoate inhalation powder to 6 healthy human subjects, plasma concentrations of unchanged mometasone furoate were shown to be very low compared to the total radioactivity in plasma. Following an inhaled single 400 mcg dose of ASMANEX TWISTHALER treatment to 24 healthy subjects, plasma concentrations for most subjects were near or below the lower limit of quantitation for the assay (50 pcg/mL). The mean absolute systemic bioavailability of the above single inhaled 400 mcg dose, compared to an intravenous 400 mcg dose of mometasone furoate, was determined to be less than 1%. Following administration of the recommended highest inhaled dose (400 mcg twice daily) to 64 patients for 28 days, concentration-time profiles were discernible, but with large inter-subject variability. The coefficient of variation for Cmax and AUC ranged from approximately 50100%. The mean peak plasma concentrations at steady state ranged from approximately 94 to 114 pcg/mL and the mean time to peak levels ranged from approximately 1.0 to 2.5 hours.

Distribution

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 terminal half-life of about 5 hours and the 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).

Metabolism

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 CYP 3A4 in the metabolism of this compound, however, no major metabolites were identified.

Excretion

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.

Special Populations

Administration of a single inhaled dose of 400 mcg mometasone furoate 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 to 105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment, however, the numbers of detectable levels were few. The effects of renal impairment, age or gender on mometasone furoate pharmacokinetics have not been adequately investigated.

Drug-Drug Interaction

An inhaled dose of mometasone furoate 400 mcg 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 co-administration 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 to 324 pcg/mL). Since mometasone furoate plasma levels appear to increase and plasma cortisol levels appear to decrease upon concomitant administration of ketoconazole, caution should be exercised in the co-administration of these drugs.

Pharmacodynamics

The potential effect of mometasone furoate on the hypothalamic-pituitary-adrenal 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: ASMANEX TWISTHALER 440 mcg twice daily, ASMANEX TWISTHALER 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 ASMANEX 440 mcg twice daily group and 20.8 mcg/dL for the ASMANEX 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 ASMANEX 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.

Clinical Trials

The efficacy of ASMANEX TWISTHALER has been studied across a wide range of doses in double-blind placebo-controlled 12-week treatment clinical trials involving 1941 patients 12 years of age and older with asthma of varying severity.

Patients Previously Maintained on Bronchodilators Alone

ASMANEX TWISTHALER was studied in three 12-week double-blind trials in 737 patients with mild to moderate asthma (mean baseline FEV1

2.6 L, 72% of predicted normal) who were maintained on short-acting beta-2 agonists alone. The first two trials evaluated doses of 440 mcg administered as 2 inhalations once daily in the morning and one of these studies also evaluated 200 mcg twice daily. In both trials, AM pre-dose FEV1 was significantly improved at Endpoint (last observation) following treatment with 440 mcg ASMANEX TWISTHALER once daily in the morning as compared to placebo (14% vs. 2.5%, respectively, in one trial and 16% vs. 5.5% in the other). There was also a significant improvement in AM pre-dose FEV1 at Endpoint following treatment with ASMANEX TWISTHALER 220 mcg twice daily. Other measures of lung function (AM and PM PEFR) also showed improvement compared to placebo. Patients receiving ASMANEX TWISTHALER treatment had reduced frequency of beta-2 agonist rescue medication use compared to those on placebo (mean reductions at Endpoint 2.2 and 0.5 puffs per day, respectively, from a baseline of 4.1 puffs/day). Additionally, fewer patients receiving ASMANEX TWISTHALER 440 mcg once daily experienced asthma worsenings than did patients receiving placebo.

In the third trial, 195 asthmatic patients were treated with ASMANEX TWISTHALER 220 mcg once daily in the evening or placebo. The AM FEV1 at Endpoint was significantly improved compared to placebo (mean change at Endpoint 0.43 L or 16.8% vs. 0.16 L or 6%, respectively, see Figure 1). Evening PEF increased 24.96 L/min (7%) from baseline in the ASMANEX TWISTHALER group compared to 8.67 L/min (4%) in placebo.

Patients Previously Maintained on Inhaled Corticosteroids

The efficacy and safety of ASMANEX TWISTHALER in doses ranging from 110 mcg twice daily to 440 mcg twice daily was evaluated in three trials in 1072 patients previously maintained on inhaled corticosteroids. In the first two trials, asthmatic patients (mean baseline FEV1~ 2.6 L, 76% predicted) were previously on either beclomethasone dipropionate [841200 mcg/day], flunisolide [1002000 mcg/day], fluticasone propionate [110880 mcg/day], or triamcinolone acetonide [3002400 mcg/day]. The first trial included 307 patients who were treated in an open-label fashion with ASMANEX TWISTHALER 220 mcg (110 mcg 2 inhalations) twice daily for 2 weeks followed by 12 weeks of double-blind treatment with ASMANEX TWISTHALER 440 mcg once daily in the morning or placebo. The second trial involved 365 patients who continued on their previous dose of inhaled corticosteroids during a 2-week screening period before being switched to ASMANEX TWISTHALER 440 mcg twice daily, 220 mcg twice daily, 110 mcg twice daily, beclomethasone dipropionate 168 mcg twice daily or placebo for 12 weeks.

In the first trial, AM pre-dose FEV1 was effectively maintained (-1.4% change from baseline to Endpoint) over the 12 weeks in the patients who were randomized to ASMANEX TWISTHALER 440 mcg once daily in the morning while decreasing 10% at Endpoint in those switched to placebo. In addition, fewer patients treated with ASMANEX TWISTHALER experienced worsenings of asthma compared to placebo.

In the second trial, AM pre-dose FEV1 was significantly increased at Endpoint when patients were switched to ASMANEX TWISTHALER 220 mcg twice daily (7% increase) or 440 mcg twice daily (6.2% increase) as compared to a decrease of 7% when switched to placebo. Additionally, beta-2 agonist rescue medication use was decreased for patients who received ASMANEX TWISTHALER treatment relative to those on placebo (mean reduction from baseline to Endpoint 1.1 puffs/day vs. increase of 0.7 puffs/day). Fewer patients receiving ASMANEX TWISTHALER treatment experienced asthma worsenings than did patients receiving placebo.

The third trial evaluated the efficacy and safety of ASMANEX TWISTHALER compared to placebo in 400 asthmatic patients (mean FEV1 67% predicted at baseline) previously maintained on beclomethasone dipropionate (HFA or CFC) 168600 mcg/day, budesonide 2001200 mcg/day, flunisolide 5002000 mcg/day, fluticasone propionate 88880 mcg/day or triamcinolone acetonide 4001600 mcg/day. Following a 28-day inhaled corticosteroid dose-reduction phase, patients were randomized to ASMANEX TWISTHALER 440 mcg once daily in the evening (QD PM), 220 mcg QD PM, 220 mcg twice daily or placebo. At Endpoint, patients who received ASMANEX TWISTHALER 220 mcg QD PM, 440 mcg QD PM, or 220 mcg twice daily had a significant improvement in AM FEV1 [0.41 L (19%), 0.49 L (22%), and 0.51 L (24%) in the 220 mcg QD PM, 440 mcg QD PM, and 220 mcg twice daily treatment group, respectively] compared to placebo [0.16 L (8%)]. (See Figure 2). Evening PEF increased 15.65 L/min (4.1%) with the 220 mcg QD PM dose, 39.26 L/min (10.7%) with the 440 mcg QD PM dose and 36.7 L/min (10.8%) with the 220 mcg twice daily dose respectively compared to a 1.4 L/min (1%) increase with placebo. Patients receiving all doses of ASMANEX TWISTHALER treatment had reduced frequency of beta agonist rescue medication use compared to those on placebo (mean reductions at Endpoint of 1.4 to 1.8 puffs/day from a baseline of more than 3 puffs/day compared to an increase in use by 0.5 puffs/day for placebo). In addition, fewer patients receiving ASMANEX TWISTHALER experienced asthma worsenings than did those on placebo.

Patients Previously Maintained on Oral Corticosteroids

The efficacy of ASMANEX TWISTHALER 440 mcg and 880 mcg twice daily was evaluated in one 12-week double-blind trial in patients previously maintained on oral corticosteroids. A total of 132 patients requiring oral prednisone (baseline mean daily oral prednisone requirement approximately 12 mg; baseline FEV1 of 1.8 L, 59% of predicted normal), most of whom were also on inhaled corticosteroids (baseline inhaled steroid: beclomethasone dipropionate [168840 mcg/day], budesonide [8001600 mcg/day], flunisolide [10002000 mcg/day], fluticasone propionate [4401760 mcg/day], or triamcinolone acetonide [4002400 mcg/day]) were studied. Patients who received ASMANEX TWISTHALER 440 mcg twice daily had a significant reduction in their oral prednisone (46%) as compared to placebo (164% increase in oral prednisone dose). Additionally, 40% of patients on ASMANEX TWISTHALER 440 mcg twice daily were able to completely discontinue their use of prednisone, whereas 60% of patients on placebo had an increase in daily prednisone use. Patients on ASMANEX TWISTHALER had significant improvement in lung function (14% increase) compared to a 12% decrease in FEV1 in the placebo group. Additionally, mean rescue beta-2 agonist use was reduced to approximately 3 puffs/day from a baseline of 45 puffs/day with ASMANEX TWISTHALER treatment, compared to an increase of 0.3 puffs/day on placebo. Patients who received ASMANEX TWISTHALER 880 mcg twice daily experienced no additional benefit beyond that seen with 440 mcg twice daily.

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