Albuterol

ALBUTEROL- albuterol aerosol, metered
Armstrong Pharmaceuticals, Inc.

Bronchodilator Aerosol For Oral Inhalation Only

Rx only

DESCRIPTION

The active component of Albuterol Inhalation Aerosol is albuterol (α1 -[(tert-butylamino)methyl]-4-hydroxy-m -xylene-α,α’-diol), a relatively selective beta2 -adrenergic bronchodilator, having the following structural formula:

Image from Drug Label Content

Albuterol is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol. The molecular weight of albuterol is 239.2, and the molecular formula is C13 H21 NO3 . Albuterol is a white to off-white crystalline solid. It is soluble in ethanol, sparingly soluble in water, and very soluble in chloroform.

Albuterol Inhalation Aerosol is a pressurized metered-dose aerosol unit for oral inhalation. It contains a microcrystalline (95% ≤ 10 µm) suspension of albuterol in propellants (trichloromonofluoromethane and dichlorodifluoromethane) with oleic acid. Each actuation delivers 100 mcg of albuterol from the valve and 90 mcg of albuterol from the mouthpiece. Each canister provides 200 inhalations.

CLINICAL PHARMACOLOGY

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 in 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%. The precise function of these receptors has not been established.

The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′, 5′- adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Albuterol has been shown in most controlled 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.

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O -methyl transferase.

The effects of rising doses of albuterol and isoproterenol aerosols were studied in volunteers and asthmatic patients. Results in normal volunteers indicated that albuterol is one half to one quarter as active as isoproterenol in producing increases in heart rate. In asthmatic patients similar cardiovascular differentiation between the two drugs was also seen.

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 are administered concurrently. The clinical significance of these findings is unknown.

Pharmacokinetics

Because of its gradual absorption from the bronchi, systemic levels of albuterol are low after inhalation of recommended doses. Studies undertaken with four subjects administered tritiated albuterol resulted in maximum plasma concentrations occurring within two to four hours. Due to the sensitivity of the assay method, the metabolic rate and half-life of elimination of albuterol in plasma could not be determined. However, urinary excretion provided data indicating that albuterol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted within 24 hours in the urine, and consists of 28% as unchanged drug and 44% as metabolite.

Clinical Trials

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 flow rate) and FEV1 (forced expiratory volume in one 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 three to four 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 (≥15%) improvement in FEV1 was observed as soon as five 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 two hours and in 33% to 47% for four 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 one hour and in 23% to 40% for four hours. In addition, at least 50% of the patients in both studies achieved an improvement in FEF25%–75% (forced expiratory flow 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 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 a majority of the patients and at 6 hours in approximately one third of the patients.

Albuterol Indications and Usage

Albuterol Inhalation Aerosol is indicated for the prevention and relief of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease, and for the prevention of exercise induced bronchospasm in patients 4 years of age and older.

Albuterol Inhalation Aerosol can be used with or without concomitant steroid therapy.

CONTRAINDICATIONS

Albuterol Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.

WARNINGS

Paradoxical Bronchospasm

Albuterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Albuterol Inhalation Aerosol should be discontinued immediately and alternative therapy instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial.

Cardiovascular Effects

Albuterol, like all other beta-adrenergic agonists, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of Albuterol Inhalation Aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, albuterol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Deterioration of Asthma

Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of Albuterol Inhalation Aerosol than usual, this may be a marker of destabilization of asthma and requires reevaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.

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