Preclinical

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

CLINICAL STUDIES

Inhalation Aerosol

In controlled clinical trials involving adults with asthma, the onset of improvement in pulmonary function was within 15 minutes, as determined by both MMEF (maximum midexpiratory wflow rate) and FEV₁ (forced expiratory volume in 1 second). MMEF measurements also showed that near maximum improvement in pulmonary function generally occurs within 60 to 90 minutes following two inhalations of albuterol and that clinically significant improvement generally continues for 3 to 4 hours in most patients. Some patients showed a therapeutic response (defined by maintaining FEV₁ values 15% or more above baseline) that was still apparent at 6 hours. Continued effectiveness of albuterol was demonstrated over a 13-week period in these same trials.

In controlled clinical trials involving children 4 to 12 years of age, FEV₁ measurements showed that maximum improvement in pulmonary function occurs within 30 to 60 minutes. The onset of clinically significant (³15%) improvement in FEV₁ was observed as soon as 5 minutes following 180 mcg of albuterol in 18 of 30 (60%) children in a controlled dose-ranging study. Clinically significant improvement in FEV₁ continued in the majority of patients for 2 hours and in 33% to 47% for 4 hours among 56 patients receiving inhalation aerosol in one pediatric study. In a second study among 48 patients receiving inhalation aerosol, clinically significant improvement continued in the majority for up to 1 hour and in 23% to 40% for 4 hours. In addition, at least 50% of the patients in both studies achieved an improvement in FEF_25%-75% (forced expiratory wflow rate between 25% and 75% of the forced vital capacity) of at least 20% for 2 to 5 hours. Continued effectiveness of albuterol was demonstrated over the 12-week study period.

In other clinical studies in adults and children, two inhalations of albuterol inhalation aerosol taken approximately 15 minutes before exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV₁ within 80% of baseline values in the majority of patients. One study in adults also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in the majority of patients and at 6 hours in approximately one third of the patients.

Inhalation Solution

In controlled clinical trials in adults, most patients exhibited an onset of improvement in pulmonary function within 5 minutes as determined by FEV₁. FEV₁ measurements also showed that the maximum average improvement in pulmonary function usually occurred at approximately 1 hour following inhalation of 2.5 mg of albuterol by compressor-nebulizer and remained close to peak for 2 hours. Clinically significant improvement in pulmonary function (defined as maintenance of a 15% or more increase in FEV₁ over baseline values) continued for 3 to 4 hours in most patients, with some patients continuing up to 6 hours.

Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant improvement in either FEV₁ or PEFR within 2 to 20 minutes following single doses of albuterol inhalation solution. An increase of 15% or more in baseline FEV₁ has been observed in children aged 5 to 11 years up to 6 hours after treatment with doses of 0.10 mg/kg or higher of albuterol inhalation solution. Single doses of 3, 4, or 10 mg resulted in improvement in baseline PEFR that was comparable in extent and duration to a 2-mg dose, but doses above 3 mg were associated with heart rate increases of more than 10%.

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