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Qnasl

CLINICAL PHARMACOLOGY

Mechanism Of Action

Beclomethasone dipropionate is a prodrug that is extensively converted to the active metabolite, beclomethasone-17-monopropionate. The precise mechanism through which beclomethasone dipropionate affects rhinitis symptoms is unknown. Corticosteroids have been shown to have multiple anti-inflammatory effects, inhibiting both inflammatory cells (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, and neutrophils) and the release of inflammatory mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines).

Beclomethasone-17-monopropionate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor which is approximately 13 times that of dexamethasone, 6 times that of triamcinolone acetonide, 1.5 times that of budesonide and 25 times that of beclomethasone dipropionate. The clinical significance of these findings is unknown.

Pharmacodynamics

Adrenal Function

The effects of QNASL Nasal Aerosol on the HPA axis were evaluated in two 6-week, randomized, double-blind, parallel-group perennial allergic rhinitis trials – one in adult and adolescent patients 12 to 45 years of age and another in children 6 to 11 years of age. In the first study with adolescent and adult patients aged 12 to 45, QNASL Nasal Aerosol 320 mcg, once daily, was compared with both placebo nasal aerosol and a positive control (a placebo/prednisone group that received prednisone 10 mg orally once daily for the final 7 days of the treatment period). In the second study with pediatric patients aged 6 to 11, QNASL Nasal Aerosol 80 mcg once daily was compared to placebo nasal aerosol. HPA-axis function was assessed by 24-hour serial serum cortisol levels prior to the first dose and after 6 weeks of treatment. Patients were domiciled for the 24-hour serum cortisol assessments. The change from baseline in the 24-hour serum cortisol weighted mean for QNASL Nasal Aerosol and placebo after 6 weeks of treatment were compared.

In the HPA –axis study in patients 12 to 45 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the QNASL Nasal Aerosol 320 mcg/day and placebo treatment groups (9.04 and 8.45 mcg/dL, respectively). After 6 weeks of treatment, the geometric mean values were 8.18 and 8.01 mcg/dL, respectively, with a change from baseline in 24-hour serum cortisol weighted mean for the QNASL Nasal Aerosol and placebo groups of 0.86 and 0.44, resulting in a difference of 0.42. The geometric mean ratio for QNASL Nasal Aerosol 320 mcg/day to placebo was 0.96 (95% CI: 0.87, 1.06). For comparison, in the positive-control (prednisone) treatment group, the geometric mean ratio for placebo to placebo/prednisone 10 mg/day was 3.17 (95% CI: 2.68, 3.74).

In the HPA-axis study in patients 6 to 11 years of age, baseline geometric mean serum cortisol weighted mean values were similar in the QNASL Nasal Aerosol 80 mcg/day and placebo treatment groups (5.97 and 6.47 mcg/dL, respectively). After 6 weeks of treatment the geometric mean values were 6.19 and 7.13 mcg/dL, respectively with no decrease from baseline values in both treatment groups. The geometric mean ratio for QNASL Nasal Aerosol 80 mcg/day to placebo was 0.91 (95% CI; 0.81, 1.03).

Pharmacokinetics

Absorption

Following intranasal administration, most of the beclomethasone dipropionate undergoes extensive conversion to its active metabolite, beclomethasone-17-monopropionate, during absorption. Plasma concentrations of beclomethasone dipropionate and beclomethasone-17monopropionate have been measured with QNASL Nasal Aerosol in 2 adult and/or adolescent clinical trials and 1 pediatric clinical trial.

The single-dose pharmacokinetics of QNASL Nasal Aerosol were evaluated in a randomized, open-label, 3-period, crossover trial in healthy adult volunteers. Systemic levels of beclomethasone-17-monopropionate and beclomethasone dipropionate after single-dose intranasal administration of beclomethasone dipropionate at doses of 80 and 320 mcg were compared with the systemic levels of beclomethasone-17-monopropionate and beclomethasone dipropionate after administration of orally inhaled beclomethasone dipropionate HFA at a dose of 320 mcg (QVAR® Inhalation Aerosol). The results of this trial demonstrated that the systemic bioavailability of QNASL Nasal Aerosol 320 mcg was approximately 27.5% (approximately 4fold lower) of that of orally inhaled beclomethasone dipropionate HFA 320 mcg/day based on the plasma concentrations of beclomethasone-17-monopropionate (AUClast: 1139.7 vs 4140.3 hr*pg/mL; GMR: 0.275; 90% CI for the GMR: 0.214, 0.354). The peak exposure to QNASL Nasal Aerosol 320 mcg/day was approximately 19.5% (approximately 5-fold lower) of that of orally inhaled beclomethasone dipropionate HFA 320 mcg/day as measured by beclomethasone17-monopropionate (Cmax: 262.7 vs 1343.7 pg/mL; GMR: 0.195; 90% CI for the GMR: 0.158, 0.241).

Following repeated once-daily administration of QNASL Nasal Aerosol, there was no accumulation or increase in plasma exposure to beclomethasone-17-monopropionate or beclomethasone dipropionate, most likely due to the short plasma half-life relative to the dosing frequency.

Distribution

The in vitro protein binding for beclomethasone-17-monopropionate was reported to be 94% to 96% over the concentration range of 1000 to 5000 pg/mL. The volume of distribution at steady state for beclomethasone dipropionate is moderate (20 L) but more extensive for beclomethasone-17-monopropionate (424 L).

Metabolism

Beclomethasone dipropionate undergoes extensive first-pass metabolism, forming three metabolites via CYP3A4, beclomethasone-17-monopropionate, beclomethasone-21monopropionate, and beclomethasone. Beclomethasone-17-monopropionate is the major and most active metabolite.

Elimination

The major route of elimination of inhaled beclomethasone dipropionate appears to be via metabolism. More than 90% of inhaled beclomethasone dipropionate is found as beclomethasone-17-monopropionate in the systemic circulation. The mean elimination half-life of beclomethasone-17-monopropionate is 2.8 hours. The terminal elimination half-lives of beclomethasone dipropionate and beclomethasone-17-monopropionate following intranasal dosing with QNASL Nasal Aerosol (320 mcg) were approximately 0.3 hours and 4.5 hours, respectively. Irrespective of the route of administration (injection, oral, or inhalation), beclomethasone dipropionate and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine. It is likely that intranasal beclomethasone dipropionate follows a similar elimination pathway.

Special Populations

Formal pharmacokinetic studies using QNASL Nasal Aerosol were not conducted in any special populations.

Clinical Studies

Seasonal And Perennial Allergic Rhinitis

Adult and Adolescent Patients Aged 12 Years and Older

The efficacy and safety of QNASL Nasal Aerosol have been evaluated in 3 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 6 weeks duration in adult and adolescent patients 12 years and older with symptoms of seasonal or perennial allergic rhinitis. The 3 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis, one 2-week efficacy trial in patients with seasonal allergic rhinitis, and one 6-week efficacy trial in patients with perennial allergic rhinitis. The trials included a total of 1049 patients (366 males and 683 females). About 81% of patients were Caucasian and 17% African American, the mean age was approximately 38 years. Of these patients 521 received QNASL Nasal Aerosol 320 mcg once daily administered as 2 actuations in each nostril.

Assessment of efficacy was based on the total nasal symptom score (TNSS). TNSS is calculated as the sum of the patients' scoring of the 4 individual nasal symptoms (rhinorrhea, sneezing, nasal congestion, and nasal itching) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective (rTNSS) or instantaneous (iTNSS). rTNSS required the patients to record symptom severity over the previous 12 hours; iTNSS required the patients to record symptom severity over the previous 10 minutes. Morning and evening TNSS scores were averaged over the treatment period and the difference from placebo in the change from baseline rTNSS was the primary efficacy endpoint. The morning iTNSS reflects the TNSS at the end of the 24-hour dosing interval and is an indication of whether the effect was maintained over the 24-hour dosing interval.

Dose-Ranging Trial

The dose-ranging trial was a 2-week trial that evaluated the efficacy of 3 doses of beclomethasone dipropionate nasal aerosol (80, 160, and 320 mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, only treatment with beclomethasone dipropionate nasal aerosol at the dose of 320 mcg/day resulted in statistically significant improvements compared with placebo in the primary efficacy endpoint, rTNSS (Table 3).

Table 3: Mean Changes from Baseline in Reflective Total Nasal Symptom Score Over 2 Weeks in Adult and Adolescent Patients with Seasonal Allergic Rhinitis (ITT Population)

Treatment N Baseline (SD) LS Mean (SE) Change from Baseline Difference From Placebo
LS Mean 95% CI
Beclomethasone dipropionate 320 mcg/day 122 9.17 (1.66) -2.22 (0.18) -0.63 -1.13, 0.13
Beclomethasone dipropionate 160 mcg/day 123 9.24 (1.57) -1.87 (0.18) -0.29 -0.78, 0.21
Beclomethasone dipropionate 80 mcg/day 118 9.33 (1.72) -1.88 (0.18) -0.29 -0.80, 0.21
Placebo 123 8.98 (1.47) -1.59 (0.18)

The 320 mcg dose also demonstrated a statistically significant decrease in morning iTNSS than placebo, indicating that the effect was maintained over the 24-hour dosing interval.

Seasonal and Perennial Allergic Rhinitis Trials

In 2 randomized, double-blind, parallel-group, multicenter, placebo-controlled efficacy trials, once-daily treatment with QNASL Nasal Aerosol for 2 weeks in patients with seasonal allergic rhinitis and for 6 weeks in patients with perennial allergic rhinitis resulted in statistically significant greater decreases from baseline in the rTNSS and morning iTNSS than placebo (Table 4).

Table 4: Mean Changes From Baseline in Reflective and Instantaneous Total Nasal Symptom Scores in Adult and Adolescent Patients with Seasonal or Perennial Allergic Rhinitis (ITT Population)

Treatment N Baseline (SD) LS Mean (SE) Change from Baseline Difference From Placebo
LS Mean 95% CI
Seasonal Allergic Rhinitis
Reflective Total Nasal Symptom Scores (rTNSS)
Beclomethasone dipropionate 320 mcg/day 167 9.6 (1.51) -2.0 (0.16) -0.91 -1.3, -0.5
Placebo 171 9.5 (1.54) -1.0 (0.15)    
Instantaneous Total Nasal Symptom Scores (iTNSS)
Beclomethasone dipropionate 320 mcg/day 167 9.0 (1.74) -1.7 (0.15) -0.92 -1.3, -0.5
Placebo 171 8.7 (1.81) -0.8 (0.15)    
Perennial Allergic Rhinitis
Reflective Total Nasal Symptom Scores (rTNSS)
Beclomethasone dipropionate 320 mcg/day 232 8.9 (1.70) -2.5 (0.14) -0.84 -1.2, -0.5
Placebo 234 9.0 (1.73) -1.6 (0.14)    
Instantaneous Total Nasal Symptom Scores (iTNSS)
Beclomethasone dipropionate 320 mcg/day 232 8.1 (1.98) -2.1 (0.13) -0.78 -1.1, -0.4
Placebo 234 8.3 (1.96) -1.4 (0.13)

Pediatric Patients 4 to 11 Years of Age

The efficacy and safety of QNASL Nasal Aerosol have been evaluated in 2 randomized, double-blind, parallel-group, multicenter, placebo-controlled clinical trials of 2 to 12 weeks duration in pediatric patients 4 to 11 years of age with symptoms of seasonal or perennial allergic rhinitis. The 2 clinical trials included one 2-week dose-ranging trial in patients with seasonal allergic rhinitis (6 -11 years of age), and one 12-week efficacy trial in patients with perennial allergic rhinitis (4 -11 years of age). The trials included a total of 1255 patients (680 males and 575 females). About 73% of patients were Caucasian and 20% African American, the mean age was approximately 8 years for one study and 9 years for the second study. Of these patients 596 received QNASL Nasal Aerosol 80 mcg once daily administered as 1 actuation of QNASL 40 mcg Nasal Aerosol in each nostril.

Assessment of efficacy was based on the total nasal symptom score (TNSS) as described in adult and adolescents efficacy studies.

Dose-Ranging Seasonal Allergic Rhinitis Trial

The dose-ranging trial was a 2-week trial that evaluated the efficacy of 2 doses of beclomethasone dipropionate nasal aerosol (80 and 160mcg, once daily) in patients with seasonal allergic rhinitis. In this trial, treatment with beclomethasone dipropionate nasal aerosol at the dose of 80 mcg/day resulted in statistically significant improvements compared with placebo in the primary efficacy endpoint, rTNSS (Table 5).

Table 5: Mean Changes from Baseline in Reflective and Instantaneous Total Nasal Symptom Scores Over 2 Weeks in Pediatric Patients with Seasonal Allergic Rhinitis (ITT Population)

Treatment N Baseline (SD) LS Mean (SE) Change from Baseline Difference From Placebo
LS Mean 95% CI
Reflective Total Nasal Symptom Scores (rTNSS)
Beclomethasone dipropionate 80 mcg/day 239 8.9 (1.62) -1.9 (0.14) -0.71 -1.1, -0.3
Beclomethasone dipropionate 160 mcg/day 241 9.0 (1.71) -2.0 (0.14) -0.76 -1.1, -0.4
Placebo 234 9.0 (1.70) -1.2 (0.14) - -
Instantaneous Total Nasal Symptom Scores (iTNSS)
Beclomethasone dipropionate 80 mcg/day 238 8.1 (1.99) -1.6 (0.13) -0.63 -1.0, -0.3
Beclomethasone dipropionate 160 mcg/day 241 8.1 (2.13) -1.7 (0.13) -0.73 -1.1, -0.4
Placebo 234 8.2 (2.10) -1.0 (0.13) - -

The 80 mcg daily dose also demonstrated a statistically significant decrease in morning iTNSS than placebo, indicating that the effect was maintained over the 24-hour dosing interval. Based on the results from the dose ranging trial, 80 mcg once daily was chosen as the dose for pediatric patients 4-11 years of age.

Perennial Allergic Rhinitis Trial

In a randomized, double-blind, parallel-group, multicenter, placebo-controlled efficacy trial, treatment with QNASL Nasal Aerosol 80 mcg once daily in patients with perennial allergic rhinitis resulted in statistically significant greater decreases from baseline in the rTNSS (the primary endpoint) and iTNSS than placebo over the first six weeks of treatment (Table 6).

Table 6: Mean Changes from Baseline in Reflective Total Nasal Symptom Score Over 6 Weeks in Pediatric Patients 6 to 11 Years of Age with Perennial Allergic Rhinitis (FAS)

Treatment N Baseline (SD) LS Mean (SE) Change from Baseline Difference From Placebo
LS Mean 95% CI
Reflective Total Nasal Symptom Scores (rTNSS)
Beclomethasone dipropionate 80 mcg/day 296 8.6 (1.56) -2.26 (0.12) -0.66 -1.08,-0.24
Placebo 153 8.6 (1.60) -1.60 (0.17) - -
Instantaneous Total Nasal Symptom Scores (iTNSS)
Beclomethasone dipropionate 80 mcg/day 296 7.9 (2.05) -1.98 (0.12) -0.58 -0.99, -0.18
Placebo 153 7.8 (2.12) -1.39 (0.17) - -
FAS=full analysis set

For pediatric patients 4-11 years of age, improvements in average patient-reported rTNSS and iTNSS were also significantly greater in QNASL Nasal Aerosol 80 mcg per day treated patients compared with placebo.

Last reviewed on RxList: 1/5/2015
This monograph has been modified to include the generic and brand name in many instances.

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