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Albuterol HFA (Albuterol Sulfate) - Description and Clinical Pharmacology


Albuterol Sulfate HFA
For Oral Inhalation Only


The active ingredient of Albuterol Sulfate HFA Inhalation Aerosol is albuterol sulfate, a racemic salt, which is a relatively selective beta2-adrenergic bronchodilator. Albuterol sulfate has the chemical name α1-[(tert -butylamino) methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1) (salt), and has the following chemical structure:

The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C13H21NO3)2•H2SO4. Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol Sulfate HFA Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1,1,1,2-tetrafluoroethane) and ethanol.

Each actuation delivers 120 mcg albuterol sulfate, from the canister valve and 108 mcg albuterol sulfate, from the actuator mouthpiece (equivalent to 90 mcg of albuterol base from the mouthpiece). Each canister provides 200 inhalations. It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing three “test sprays” into the air, away from the face.

This product does not contain chlorofluorocarbons (CFCs) as the propellant.


Mechanism of Action

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50% of total cardiac beta-adrenergic receptors. The precise function of these receptors has not been established (see WARNINGS for Cardiovascular Effects).

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3',5’-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Albuterol has been shown in most clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.


Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of the plasma concentrations. In structures outside the blood-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 β-agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (380-1300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These are similar to effects produced by the structurally related chlorofluorocarbons (CFCs), which have been used extensively in metered-dose inhalers.

In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3-27 minutes in animals and 5-7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.


The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of Albuterol Sulfate HFA Inhalation Aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (Cmax) and systemic exposure (AUCinf) of approximately 4,100 pg/mL and 28,426 pg.hr/mL, respectively compared to approximately 3,900 pg/mL and 28,395 pg.hr/mL, respectively following the same dose of an active HFA-134a albuterol inhaler comparator. The terminal plasma half-life of albuterol delivered by Albuterol Sulfate HFA Inhalation Aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products.

No pharmacokinetic studies for Albuterol Sulfate HFA Inhalation Aerosol have been conducted in neonates, children, or elderly subjects.

Clinical Trials

In a 6-week, randomized, evaluator-blind, placebo-controlled trial, Albuterol Sulfate HFA Inhalation Aerosol (58 patients) was compared to an HFA-134a placebo inhaler (58 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. An active comparator HFA-134a albuterol inhaler arm (56 patients) was included.

Serial FEV1 measurements, shown below as percent change from test-day baseline at Day 1 and at Day 43, demonstrated that two inhalations of Albuterol Sulfate HFA Inhalation Aerosol produced significantly greater improvement in FEV1 over the pre-treatment value than placebo, as well as a comparable bronchodilator effect to the active comparator HFA-134a albuterol inhaler.

The mean time of onset of a 15% increase in FEV1 at Day 1 was approximately 19 minutes and the mean time to peak effect was 70 minutes. The mean duration of effect as measured by a 15% increase in FEV1 over the pre-treatment value was approximately 3 hours. In some patients, the duration was as long as 6 hours.

In a placebo-controlled single-dose, crossover study in which Albuterol Sulfate HFA Inhalation Aerosol, administered at albuterol doses of 90, 180 and 270 mcg, produced bronchodilator responses significantly greater than those observed with an HFA-134a placebo inhaler and comparable to an active comparator HFA-134a albuterol inhaler.

Some patients who participated in these clinical trials were using concomitant steroid therapy.

FEV 1 as Mean Percent Change from Test-Day Pre-Dose in a 6-Week Clinical Trial

Day 1

Day 43

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