lts on a mg/m2 basis).
13.2 Animal Toxicology and/or Pharmacology
Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brainbarrier and reaches brain concentrations amounting to approximately 5% of the plasma concentrations. In structuresoutside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those inthe whole brain.
Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias andsudden death (with histologic evidence of myocardial necrosis) when β-agonists and methylxanthines were administeredconcurrently. The clinical significance of these findings is unknown.
14 CLINICAL STUDIES
14.1 Overview of Clinical Studies
The safety and effectiveness of ProAir Digihaler has been established in the treatment or prevention of bronchospasm inpatients 4 years of age and older with reversible obstructive airway disease and in the prevention of exercise-inducedbronchospasm in patients 4 years of age and older. The use of ProAir Digihaler for these indications is supported by
adequate and well-controlled studies in adults and pediatric patients of albuterol sulfate inhalation powder (ProAirRespiClick hereafter referred to as albuterol sulfate MDPI) [see Use in Specific Populations (8.4), Clinical Studies (14.2,14.3)].
14.2 Bronchospasm Associated with Asthma
Adult and Adolescent Patients 12 Years of Age and Older
In two 12-week, randomized, double-blind, placebo-controlled studies of identical design (Study 1 and Study 2), albuterolsulfate MDPI (153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic patients12 to 76 years of age at a dose of 180 mcg albuterol four times daily. Patients were maintained on inhaled corticosteroidtreatment. Serial FEV1 measurements, shown below in Figure 1 as average of the mean changes from test-day baseline atDay 1 and Day 85, demonstrated that two inhalations of albuterol sulfate MDPI produced significantly greaterimprovement in FEV1 AUC0-6hr over the pre-treatment value than placebo in Study 1. Consistent results were observed inStudy 2
Figure 1: FEV1 as Mean Change from Test-Day, Pre-Dose Baseline in a 12-Week Clinical Trial (Study 1)In Study 1, 44 of 78 patients treated with albuterol sulfate MDPI achieved a 15% increase in FEV1 within 30 minutespost-dose on Day 1. The median time to onset was 5.7 minutes, and median duration of effect as measured by a 15%
increase was approximately 2 hours. Consistent results were observed in Study 2. In a double-blind, randomized, placebo–controlled, single-dose crossover study eva luating albuterol sulfate MDPI and ProAir HFA in 71 adult and adolescent
subjects ages 12 and older with persistent asthma, ProAir RespiClick had bronchodilator efficacy that was significantly
greater than placebo at administered doses of 90 and 180 mcg.
Pediatric Patients 4 to 11 Years of Age
In a 3-week, randomized, double-blind, placebo-controlled trial, albuterol sulfate MDPI (92 patients) was compared to amatched placebo (92 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily.
Serial FEV1 measurements, expressed as the baseline-adjusted percent-predicted FEV1 AUC0-6h over the 3-week
treatment period, demonstrated that 2 inhalations of albuterol sulfate MDPI produced significantly greater i |
