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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 a 6week, randomized, double-blind, parallel-group trial in adult and adolescent patients 12 to 45 years of age with perennial allergic rhinitis. 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). 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. 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).

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 in 2 clinical trials with QNASL Nasal Aerosol.

The single-dose pharmacokinetics of QNASL Nasal Aerosol were evaluated in a randomized, open-label, 3-period, crossover trial in healthy volunteers. Systemic levels of beclomethasone17-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% 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% of that of orally inhaled beclomethasone dipropionate HFA 320 mcg/day as measured by beclomethasone-17-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 sprays 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 2).

Table 2: 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 p Value
Beclomethasone dipropionate 320 mcg/day 122 9.17 (1.66) -2.22 (0.18) -0.63 -1.13, 0.13 0.013
Beclomethasone dipropionate 160 mcg/day 123 9.24 (1.57) -1.87 (0.18) -0.29 -0.78, 0.21 0.257
Beclomethasone dipropionate 80 mcg/day 118 9.33 (1.72) -1.88 (0.18) -0.29 -0.80, 0.21 0.255
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 3).

Table 3: 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 p Value
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 < 0.001
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 < 0.001
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 < 0.001
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 < 0.001
Placebo 234 8.3 (1.96) -1.4 (0.13)      

Last reviewed on RxList: 4/1/2014
This monograph has been modified to include the generic and brand name in many instances.

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