Airway inflammation is known to be an important component in the pathogenesis of asthma. Inflammation occurs in both large and small airways. Corticosteroids have multiple anti-inflammatory effects, inhibiting both inflammatory cells and release of inflammatory mediators. It is presumed that these anti-inflammatory actions play an important role in the efficacy of beclomethasone dipropionate in controlling symptoms and improving lung function in asthma. Inhaled beclomethasone dipropionate probably acts topically at the site of deposition in the bronchial tree after inhalation.

Bioavailability information on beclomethasone dipropionate (BDP) after inhaled administration is not available in adults. BDP undergoes rapid and extensive conversion to beclomethasone-17-monopropionate (17-BMP) during absorption. The pharmacokinetics of 17-BMP has been studied in asthmatics given single doses.

Absorption: The mean peak plasma concentration (C_max) of BDP was 88 pg/ml at 0. 5 hour after inhalation of 320 mcg using QVAR (four actuations of the 80 mcg/actuation strength). The mean peak plasma concentration of the major and most active metabolite, 17-BMP, was 1419 pg/ml at 0. 7 hour after inhalation of 320 mcg of QVAR. When the same nominal dose is provided by the two QVAR strengths (40 and 80 mcg/actuation), equivalent systemic pharmacokinetics can be expected. The C_max of 17-BMP increased dose proportionally in the dose range of 80 and 320 mcg.

Metabolism: Three major metabolites are formed via cytochrome P450 3A catalyzed biotransformation -beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP) and beclomethasone (BOH). Lung slices metabolize BDP rapidly to 17-BMP and more slowly to BOH. 17-BMP is the most active metabolite.

Distribution: There is no evidence of tissue storage of BDP or its metabolites.

Elimination: The major route of elimination of inhaled BDP appears to be via metabolism. More than 90% of inhaled BDP is found as 17-BMP in the systemic circulation. The mean elimination half-life of 17-BMP is 2. 8 hours. Irrespective of the route of administration (injection, oral or inhalation), BDP and its metabolites are mainly excreted in the feces. Less than 10% of the drug and its metabolites are excreted in the urine.

Special Populations: Formal pharmacokinetic studies using QVAR were not conducted in any special populations.

Pediatrics: The pharmacokinetics of 17-BMP, including dose and strength proportionalities, is similar in children and adults, although the exposure is highly variable. In 17 children (mean age 10 years), the Cmax of 17-BMP was 787 pg/ml at 0. 6 hour after inhalation of 160 mcg (four actuations of the 40 mcg/actuation strength of HFA beclomethasone dipropionate). The systemic exposure to 17-BMP from 160 mcg of HFA-BDP administered without a spacer was comparable to the systemic exposure to 17-BMP from 336 mcg CFC-BDP administered with a large volume spacer in 14 children (mean age 12 years). This implies that approximately twice the systemic exposure to 17-BMP would be expected for comparable mg doses of HFA-BDP without a spacer and CFC-BDP with a large volume spacer.

Improvement in asthma control following inhalation can occur within 24 hours of beginning treatment in some patients, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. The effects of QVAR on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 40 corticosteroid naive patients. QVAR, at doses of 80, 160 or 320 mcg twice daily was compared with placebo and 336 mcg twice daily of beclomethasone dipropionate in a CFC propellant based formulation (CFC-BDP). Active treatment groups showed an expected dose-related reduction in 24-hour urinary free cortisol (a sensitive marker of adrenal production of cortisol). Patients treated with the highest recommended dose of QVAR (320 mcg twice daily) had a 37. 3% reduction in 24-hour urinary free cortisol compared to a reduction of 47. 3% produced by treatment with 336 mcg twice daily of CFC-BDP. There was a 12. 2% reduction in 24 hour urinary free cortisol seen in the group of patients that received 80 mcg twice daily of QVAR and a 24. 6% reduction in the group of patients that received 160 mcg twice daily. An open label study of 354 asthma patients given QVAR at recommended doses for one year assessed the effect of QVAR treatment on the HPA axis (as measured by both morning and stimulated plasma cortisol). Less than 1% of patients treated for one year with QVAR had an abnormal response (peak less than 18 mcg/dL) to short-cosyntropin test.

Blinded, randomized, parallel, placebo-controlled and active-controlled clinical studies were conducted in 940 adult asthma patients to assess the efficacy and safety of QVAR in the treatment of asthma. Fixed doses ranging from 40 mcg to 160 mcg twice daily were compared to placebo, and doses ranging from 40 mcg to 320 mcg twice daily were compared with doses of 42 mcg to 336 mcg twice daily of an active CFC-BDP comparator. These studies provided information about appropriate dosing through a range of asthma severity. In all adult efficacy trials, at the doses studied, measures of pulmonary function [forced expiratory volume in 1 second (FEV₁) and morning peak expiratory flow (AM PEF)] and asthma symptoms were significantly improved with QVAR treatment when compared to placebo. A blinded, randomized, parallel, placebo-controlled study was conducted in 353 pediatric patients (age 5-12 years) to assess the efficacy and safety of HFA beclomethasone dipropionate in the treatment of asthma. Fixed doses of 40 mcg and 80 mcg twice daily were compared with placebo in this study.

In controlled clinical trials with adult patients not adequately controlled with beta-agonist alone, QVAR was effective at improving asthma control at doses as low as 40 mcg twice daily (80 mcg/day). Comparable asthma control was achieved at lower daily doses of QVAR than with CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP generally resulted in increased improvement in FEV₁. In this trial the improvement in FEV₁ across doses was greater for QVAR than for CFC-BDP, indicating a shift in the dose response curve for QVAR. For this reason, when considering QVAR dosing selection for patients currently using CFC-BDP, it is important to consult the dosing recommendations specifically for QVAR (see DOSAGE AND ADMINISTRATION).

In a 6 week clinical trial, 270 steroid naive patients with symptomatic asthma being treated with as-needed beta-agonist bronchodilators, were randomized to receive either 40 mcg twice daily of QVAR, 80 mcg twice daily of QVAR, or placebo. Both doses of QVAR were effective in improving asthma control with significantly greater improvements in FEV₁, AM PEF, and asthma symptoms than with placebo. Shown below is the change from baseline in AM PEF during this trial.

In a 6-week clinical trial, 256 patients with symptomatic asthma being treated with as-needed beta-agonist bronchodilators, were randomized to receive either 160 mcg twice daily of QVAR (delivered as either 40 mcg/actuation or 80 mcg/actuation) or placebo. Treatment with QVAR significantly improved asthma control, as assessed by FEV₁, AM PEF, and asthma symptoms, when compared to treatment with placebo. Comparable improvement in AM PEF was seen for patients receiving 160 mcg twice daily QVAR from the 40 mcg and 80 mcg strength products.

In another clinical trial, 347 patients with symptomatic asthma, being treated with as-needed inhaled beta-agonist bronchodilators and, in some cases, inhaled corticosteroids, were given a 7-12 day course of oral corticosteroids and then randomized to receive either 320 mcg daily of QVAR, 672 mcg of CFC-BDP, or placebo. Patients treated with either QVAR or CFC-BDP had significantly better asthma control, as assessed by AM PEF, FEV₁ and asthma symptoms, and fewer study withdrawals due to asthma symptoms, than those treated with placebo over 12 weeks of treatment. A daily dose of 320 mcg QVAR administered in divided doses provided comparable control of AM PEF and FEV1 as 672 mcg of CFC-BDP. Shown below are the mean AM PEF results from this trial.

Patients Previously on Inhaled Corticosteroids

In a 6-week clinical trial, 323 patients, who exhibited a deterioration in asthma control during an inhaled corticosteroid washout period, were randomized to daily treatment with either 40, 160, or 320 mcg twice daily QVAR or 42, 168, or 336 mcg twice daily CFC-BDP. Treatment with increasing doses of both QVAR and CFC-BDP resulted in increased improvement in FEV₁, FEF25-75% (forced expiratory flow over 25-75% of the vital capacity), and asthma symptoms. Shown below is the change from baseline in FEV₁ as percent predicted after 6 weeks of treatment.

Patients Previously Maintained on Oral Corticosteroids

Clinical experience has shown that some patients with asthma who require oral corticosteroid therapy for control of symptoms can be partially or completely withdrawn from oral corticosteroids if therapy with beclomethasone dipropionate aerosol is substituted. Inhaled corticosteroids may not be effective for all patients with asthma or at all stages of the disease in a given patient.

Pediatric Experience:In one 12-week clinical trial, pediatric patients (age 5-12 years) with symptomatic asthma (N=353) being treated with as-needed beta-agonist bronchodilators were randomized to receive either 40 mcg or 80 mcg twice daily of HFA beclomethasone dipropionate or placebo. Both doses were effective in improving asthma control with significantly greater improvements in FEV₁ (9% and 10% predicted change from baseline at week 12 in FEV1 percent predicted, respectively) than with placebo (4% predicted change).

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