Recommended Topic Related To:

Asmanex

"What are allergies?

Allergies occur when the body's immune system responds to a substance it considers an "invader." Substances that provoke the immune system into an allergic response are known as allergens. There is no such thing as a"...

Asmanex Twisthaler

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 (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.

Though effective for the treatment of asthma, corticosteroids 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 corticosteroids are discontinued, asthma stability may persist for several days or longer.

Pharmacodynamics

Adrenal Function

The effects of ASMANEX TWISTHALER (mometasone furoate) on adrenal function have been evaluated in 2 clinical studies: 1 in adults 18 years of age and older and 1 in pediatric patients 6 to 11 years of age. Both clinical studies were specifically designed to assess the effect of ASMANEX TWISTHALER (mometasone furoate) on adrenal function.

In a 29-day, randomized, double-blind, placebo-controlled, study in 64 adult and adolescent patients 18 years of age and older with asthma, ASMANEX TWISTHALER (mometasone furoate) 440 mcg twice daily and 880 mcg twice daily (twice the highest recommended daily dose) were compared to both placebo and prednisone 10 mg once daily as a positive control. 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 (n=16) and 20.8 mcg/dL for the ASMANEX 880 mcg twice daily group (n=16), compared to 14.5 mcg/dL for the oral prednisone 10 mg group (n=16) and 25 mcg/dL for the placebo group (n=16). The difference between ASMANEX 880 mcg twice daily (twice the maximum recommended dose) and placebo was statistically significant.

In a 29-day, randomized, double-blind, placebo-controlled, parallel-group clinical trial in 50 pediatric patients 6 to 11 years of age with asthma, ASMANEX TWISTHALER (mometasone furoate) 110 mcg twice daily, 220 mcg twice daily, and 440 mcg twice daily (2 - 8 times the highest pediatric daily recommended daily dose) were compared to placebo. HPA-axis function was assessed by 12-hour plasma cortisol AUC and 24-hour urinary-free cortisol concentrations. After 29 days of treatment, the mean changes in plasma cortisol AUC0-12h from baseline were -0.11, -19.5, -21.3, and -3.47 mcg.hr/dL for the treatment groups of ASMANEX TWISTHALER (mometasone furoate) 110 mcg twice daily (n=12), 220 mcg twice daily (n=12), 440 mcg twice daily (n=11), and placebo (n=7), respectively. The mean differences from placebo in the groups treated with ASMANEX TWISTHALER (mometasone furoate) 110 mcg twice daily, 220 mcg twice daily, and 440 mcg twice daily were 3.4 mcg.hr/dL (95% CI: 14.0, 20.7), -16.0 mcg.hr/dL (95% CI: -33.9, 1.9), and -17.9 mcg.hr/dL (95% CI: -35.8, 0.0), respectively. For 24-hour urinary-free cortisol, after 29 days of treatment, the mean changes from baseline were -1.53, -1.33, -6.70, and -4.68 mcg/day for the groups treated with ASMANEX TWISTHALER (mometasone furoate) 110 mcg twice daily (n=12), 220 mcg twice daily (n=12), 440 mcg twice daily (n=12), and placebo (n=10), respectively. The mean differences in urinary-free cortisol changes from baseline compared to placebo were 3.1 mcg/day (95% CI: -3.3, 9.6), 3.3 mcg/day (95% CI: -3.0, 9.7), and -2.0 mcg/day (95% CI: -8.6, 4.6) for the groups treated with 110 mcg twice daily, 220 mcg twice daily, and 440 mcg twice daily, respectively.

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 (mometasone furoate) 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 50% to 100%. 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 t he mean steady-state volume of distribution of 152 L. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% (in a concentration range of 5-500 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

Hepatic Impairment: 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 50-105 pcg/mL). The observed peak plasma concentrations appear to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.

Renal Impairment: The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated.

Pediatric: Mometasone furoate pharmacokinetics have not been investigated in the pediatric population [see Use In Specific Populations].

Gender: The effects of gender on mometasone furoate pharmacokinetics have not been adequately investigated.

Race: The effects of race on mometasone furoate pharmacokinetics have not been adequately investigated.

Drug-Drug Interaction

Inhibitors of Cytochrome P450 3A4: In a drug interaction study, 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 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).

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

In mice, mometasone furoate caused cleft palate at subcutaneous doses of 60 mcg/kg and above (less than the maximum recommended daily inhalation dose in adults on an mcg/m² basis). Fetal survival was reduced at 180 mcg/kg (approximately equal to the maximum recommended daily inhalation dose in adults on an mcg/m² basis). No toxicity was observed at 20 mcg/kg (less than the maximum recommended daily inhalation dose in adults on an mcg/m² basis).

In rats, mometasone furoate produced umbilical hernia at topical dermal doses of 600 mcg/kg and above (approximately 6 times the maximum recommended daily inhalation dose in adults on an mcg/m² basis). A dose of 300 mcg/kg (approximately 3 times the maximum recommended daily inhalation dose in adults on an 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 6 times the maximum recommended daily inhalation dose in adults 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 3 times the maximum recommended daily inhalation dose in adults 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 maximum recommended daily inhalation dose in adults on an 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 maximum recommended daily inhalation dose in adults on an area under the curve [AUC] basis). At 2800 mcg/kg (approximately 2 times the maximum recommended daily inhalation dose in adults on an AUC basis) most litters were aborted or resorbed. No toxicity was observed at 140 mcg/kg (less than the maximum recommended daily inhalation dose in adults on an AUC basis).

Clinical Studies

Asthma

Adults and Adolescents 12 Years of Age and Older

The efficacy of ASMANEX TWISTHALER (mometasone furoate) in patients with asthma 12 years and older was evaluated in ten 8- to 12-week, randomized, double-blind, placebo-controlled, parallel-group clinical trials. These trials included 1750 patients ranging from 12 to 83 years of age, 38% male and 62% female, and 83% Caucasian, 8% black, 6% Hispanic, and 3% other race/ethnicity. Patients received ASMANEX TWISTHALER (mometasone furoate) 110 mcg twice daily (n=133), 220 mcg once daily in the morning (n=209), 220 mcg once daily in the evening (n=232), 220 mcg twice daily (n=433), 440 mcg once daily in the morning (n=419), 440 mcg once daily in the evening (n=250), or 440 mcg twice daily (n=74). The results of the clinical trials are presented based upon previous asthma therapy.

Patients ≥ 12 Years of Age Previously Maintained on Bronchodilators Alone

ASMANEX TWISTHALER (mometasone furoate) was studied in three 12-week, double-blind trials in 737 patients with mild to moderate asthma (mean baseline FEV 1≅2.6 L, 72% of predicted normal) who were maintained on short-acting beta-2 agonists alone. The first 2 trials evaluated doses of 440 mcg administered as 2 inhalations once daily in the morning and 1 of these studies also evaluated 220 mcg twice daily. In both trials, AM predose FEV1 was significantly improved at endpoint (last observation) following treatment with 440 mcg ASMANEX TWISTHALER (mometasone furoate) once daily in the morning as compared to placebo (14% vs. 2.5%, respectively, in 1 trial and 16% vs. 5.5% in the other). There was also a significant improvement in AM predose FEV1 at endpoint following treatment with ASMANEX TWISTHALER (mometasone furoate) 220 mcg twice daily. Other measures of lung function (AM and PM PEFR) also showed improvement compared to placebo. Patients receiving ASMANEX TWISTHALER (mometasone furoate) 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 worsening than did patients receiving placebo.

In the third trial, 195 asthmatic patients were treated with ASMANEX TWISTHALER (mometasone furoate) 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 (mometasone furoate) group compared to 8.67 L/min (4%) in placebo.

Figure 1 : A 12-Week Trial in Patients Previously Maintained on Inhaled Beta-2 Agonists

The AM FEV1 at endpoint  - Illustration

Patients ≥ 12 Years of Age Previously Maintained on Inhaled Corticosteroids

The efficacy and safety of ASMANEX TWISTHALER (mometasone furoate) in doses ranging from 110 mcg twice daily to 440 mcg twice daily was evaluated in 3 trials in 1072 patients previously maintained on inhaled corticosteroids. In the first 2 trials, asthmatic patients (mean baseline FEV1 ~2.6 L, 76% predicted) were previously on either beclomethasone dipropionate [84-1200 mcg/day], flunisolide [100-2000 mcg/day], fluticasone propionate [110-880 mcg/day], or triamcinolone acetonide [300-2400 mcg/day]. The first trial included 307 patients who were treated in an open-label fashion with ASMANEX TWISTHALER (mometasone furoate) 220 mcg (110 mcg x 2 inhalations) twice daily for 2 weeks followed by 12 weeks of double-blind treatment with ASMANEX TWISTHALER (mometasone furoate) 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 predose FEV1 was effectively maintained (-1.4% change from baseline to endpoint) over the 12 weeks in the patients who were randomized to ASMANEX TWISTHALER (mometasone furoate) 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 (mometasone furoate) experienced worsening of asthma compared to placebo.

In the second trial, AM predose FEV1 was significantly increased at endpoint when patients were switched to ASMANEX TWISTHALER (mometasone furoate) 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 (mometasone furoate) 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 (mometasone furoate) treatment experienced asthma worsening than did patients receiving placebo.

The third trial evaluated the efficacy and safety of ASMANEX TWISTHALER (mometasone furoate) compared to placebo in 400 asthmatic patients (mean FEV1 67% predicted at baseline) previously maintained on beclomethasone dipropionate (hydrofluoroalkane [HFA] or chlorofluorocarbon [CFC]) 168-600 mcg/day, budesonide 200-1200 mcg/day, flunisolide 500-2000 mcg/day, fluticasone propionate 88-880 mcg/day, or triamcinolone acetonide 400-1600 mcg/day. Following a 28-day inhaled corticosteroid dose-reduction phase, patients were randomized to ASMANEX TWISTHALER (mometasone furoate) 440 mcg once daily in the evening , 220 mcg once daily in the evening , 220 mcg twice daily, or placebo. At endpoint, patients who received ASMANEX TWISTHALER (mometasone furoate) 220 mcg once daily in the evening, 440 mcg once daily in the evening, 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 once daily in the evening, 440 mcg once daily in the evening, 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 once daily in the evening dose, 39.26 L/min (10.7%) with the 440 mcg once daily in the evening 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 (mometasone furoate) treatment had reduced frequency of beta-agonist rescue medication use compared to those on placebo (mean reductions at endpoint of 1.4-1.8 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 (mometasone furoate) experienced asthma worsening than did those on placebo.

Figure 2 : A 12-Week Trial in Patients Previously Maintained on Inhaled Corticosteroids

A 12-Week Trial in Patients Previously Maintained on Inhaled Corticosteroids - Illustration

Patients ≥ 12 Years of Age Previously Maintained on Oral Corticosteroids

The efficacy of ASMANEX TWISTHALER (mometasone furoate) 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 [168-840 mcg/day], budesonide [800-1600 mcg/day], flunisolide [1000-2000 mcg/day], fluticasone propionate [440-1760 mcg/day], or triamcinolone acetonide [400-2400 mcg/day]) were studied. Patients who received ASMANEX TWISTHALER (mometasone furoate) 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 (mometasone furoate) 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 (mometasone furoate) 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 4-5 puffs/day with ASMANEX TWISTHALER (mometasone furoate) 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.

Pediatric Patients 4 to 11 Years of Age

The efficacy of ASMANEX TWISTHALER (mometasone furoate) in patients with asthma 4 to 11 years of age was evaluated in three 12week, randomized, double- blind, placebo-controlled, parallel-group clinical trials. These trials included 630 patients receiving ASMANEX TWISTHALER (mometasone furoate) , ranging from 4 to 11 years of age, 63% male and 37% female, and 67% Caucasian, 13% black, 17% Hispanic, and 3% other race/ethnicity. Patients received ASMANEX TWISTHALER (mometasone furoate) 110 mcg once daily in the evening (n=98), 110 mcg once daily in the morning (n=181), 110 mcg twice daily (n=179), or 220 mcg once daily in the morning (n=172). The results for 1 clinical trial are described below. The other 2 clinical trials support the efficacy of ASMANEX TWISTHALER (mometasone furoate) .

A 12-week, placebo-controlled trial of 296 patients 4 to 11 years of age with asthma of at least 6 months duration (mean % predicted FEV1 at baseline ranging from 77.3%-79.7%) was conducted to demonstrate the efficacy of the ASMANEX TWISTHALER in the treatment of asthma. Patients were treated with ASMANEX TWISTHALER (mometasone furoate) 110 mcg once daily in the evening (n=98) or placebo (n=99) for 12 weeks. Assessment of efficacy was based upon morning predose FEV1. The primary endpoint was the mean change from baseline to endpoint in percent-predicted FEV1. For the primary endpoint, improvement in the ASMANEX TWISTHALER (mometasone furoate) 110 mcg once daily in the evening treatment group (4.73) was statistically significant compared to placebo (-1.77). Figure 3 displays the results for % predicted FEV1 change from baseline at endpoint.

In this study, secondary endpoints of morning and evening peak expiratory flow and rescue medication use were supportive of efficacy of ASMANEX TWISTHALER (mometasone furoate) .

Figure 3 : A 12 Week Trial in Children 4 to 11 Years of Age: % Predicted FEV1 Change from Baseline Over Time and at Endpoint by Treatment Group

% Predicted FEV1 Change from Baseline Over Time and at Endpoint - Illustration

Last reviewed on RxList: 10/14/2010
This monograph has been modified to include the generic and brand name in many instances.

A A A

Asmanex Twisthaler - User Reviews

Asmanex Twisthaler User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Asmanex Twisthaler sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Allergies & Asthma

Improve treatments & prevent attacks.


NIH talks about Ebola on WebMD