ALBUTEROL SULFATE- albuterol sulfate solution
Nephron Pharmaceuticals Corporation
*Potency expressed as albuterol
Albuterol Sulfate Inhalation Solution, 0.5% contains albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta 2 -adrenergic bronchodilator (see CLINICAL PHARMACOLOGY section below). Albuterol sulfate has the chemical name α 1 -[( tert -Butylamino) methyl]-4-hydroxy- m -xylene-α,α′-diol sulfate (2:1) (salt) and the following chemical structure:
(C 13 H 21 NO 3 ) 2 • H 2 SO 4
Mol. Wt. 576.7
Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organization’s recommended name for albuterol base is salbutamol.
Albuterol sulfate inhalation solution, 0.5%, is in concentrated form. Dilute 0.5 mL of the solution to 3 mL with sterile normal saline solution prior to administration by nebulization (see DOSAGE AND ADMINISTRATION).
Each 0.5 mL Unit-of-Use Vial Contains: ACTIVE: 2.5 mg of albuterol (equivalent to 3 mg of albuterol sulfate, USP) in a sterile, aqueous solution; sulfuric acid is used to adjust the pH to between 3 and 5. Albuterol sulfate inhalation solution contains no sulfiting agents or preservatives. It is supplied in 0.5 mL sterile Unit-of-Use Vials.
Albuterol sulfate inhalation solution is a clear, colorless to light yellow solution.
In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta 2 -receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established (see WARNINGS).
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.
Studies in asthmatic patients have shown that less than 20% of a single albuterol dose was absorbed following either intermittent positive-pressure breathing (IPPB) or nebulizer administration; the remaining amount was recovered from the nebulizer and apparatus and expired air. Most of the absorbed dose was recovered in the urine 24 hours after drug administration. Following a 3 mg dose of nebulized albuterol, the maximum albuterol plasma level at 0.5 hour was 2.1 ng/mL (range 1.4 to 3.2 ng/mL). There was a significant dose-related response in FEV 1 and peak flow rate. It has been demonstrated that following oral administration of 4 mg of albuterol, the elimination half-life was 5 to 6 hours.
Preclinical: Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations that are 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 significance of these findings is unknown.
In controlled clinical trials in adults, most patients exhibited an onset of improvement in pulmonary function within 5 minutes as determined by FEV 1 . FEV 1 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 FEV 1 over baseline values) continued for 3 to 4 hours in most patients and in some patients continued up to 6 hours.
Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant improvement in either FEV 1 or PEFR within 2 to 20 minutes following single doses of albuterol inhalation solution. An increase of 15% or more in baseline FEV 1 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%.
INDICATIONS AND USAGE
Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm.
Albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to albuterol or any of its components.
Albuterol sulfate inhalation solution can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, albuterol sulfate inhalation solution 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 vial.
Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs and with the home use of nebulizers. It is therefore essential that the physician instruct the patient in the need for further evaluation if his/her asthma becomes worse.
Albuterol sulfate inhalation solution, 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 sulfate inhalation solution 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 sulfate inhalation solution, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of albuterol sulfate inhalation solution than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids.
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