ALBUTEROL SULFATE- albuterol sulfate aerosol, metered
Hikma Pharmaceuticals USA Inc.
FOR ORAL INHALATION ONLY
The active component of albuterol sulfate inhalation aerosol is albuterol sulfate, USP racemic α1 [(tert- Butylamino)methyl]-4-hydroxy-m -xylene-α,α’-diol sulfate (2:1)(salt), a relatively selective beta2 -adrenergic bronchodilator having the following chemical structure:
Albuterol sulfate is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol sulfate. The molecular weight of albuterol sulfate is 576.7, and the molecular formula is (C13 H21 NO3 )2 •H2 SO4 . Albuterol sulfate is a white to off-white crystalline solid. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate 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), ethanol, and oleic acid.
Each actuation delivers 120 mcg albuterol sulfate, USP from the valve and 108 mcg albuterol sulfate, USP from the 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 four “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 cardiac beta-adrenergic receptors. The precise function of these receptors has not been established. (See WARNINGS, Cardiovascular Effects section.)
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 muscles 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 beta2 -agonist 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 to 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 to 27 minutes in animals and 5 to 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.
In a single-dose bioavailability study which enrolled six healthy, male volunteers, transient low albuterol levels (close to the lower limit of quantitation) were observed after administration of two puffs from both albuterol sulfate inhalation aerosol and a CFC 11/12 propelled albuterol inhaler. No formal pharmacokinetic analyses were possible for either treatment, but systemic albuterol levels appeared similar.
In a 12-week, randomized, double-blind, double-dummy, active- and placebo-controlled trial, 565 patients with asthma were evaluated for the bronchodilator efficacy of albuterol sulfate inhalation aerosol (193 patients) in comparison to a CFC 11/12 propelled albuterol inhaler (186 patients) and an HFA-134a placebo inhaler (186 patients).
Serial FEV1 measurements (shown below as percent change from test-day baseline) demonstrated that two inhalations of albuterol sulfate inhalation aerosol produced significantly greater improvement in pulmonary function than placebo and produced outcomes which were clinically comparable to a CFC 11/12 propelled albuterol inhaler.
The mean time to onset of a 15% increase in FEV1 was 6 minutes and the mean time to peak effect was 50 to 55 minutes. The mean duration of effect as measured by a 15% increase in FEV1 was 3 hours. In some patients, duration of effect was as long as 6 hours.
In another clinical study in adults, two inhalations of albuterol sulfate inhalation aerosol taken 30 minutes before exercise prevented exercise-induced bronchospasm as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients.
In a 4-week, randomized, open-label trial, 63 children, 4 to 11 years of age, with asthma were evaluated for the bronchodilator efficacy of albuterol sulfate inhalation aerosol (33 pediatric patients) in comparison to a CFC 11/12 propelled albuterol inhaler (30 pediatric patients).
Serial FEV1 measurements as percent change from test-day baseline demonstrated that two inhalations of albuterol sulfate inhalation aerosol produced outcomes which were clinically comparable to a CFC 11/12 propelled albuterol inhaler.
The mean time to onset of a 12% increase in FEV1 for albuterol sulfate inhalation aerosol was 7 minutes and the mean time to peak effect was approximately 50 minutes. The mean duration of effect as measured by a 12% increase in FEV1 was 2.3 hours. In some pediatric patients, duration of effect was as long as 6 hours.
In another clinical study in pediatric patients, two inhalations of albuterol sulfate inhalation aerosol taken 30 minutes before exercise provided comparable protection against exercise-induced bronchospasm as a CFC 11/12 propelled albuterol inhaler.
Albuterol sulfate inhalation aerosol is indicated in adults and children 4 years of age and older for the treatment or prevention of bronchospasm with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm.
Albuterol sulfate inhalation aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any other albuterol sulfate inhalation aerosol component.
- Paradoxical Bronchospasm
- Inhaled albuterol sulfate can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, albuterol sulfate 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.
- 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 sulfate inhalation aerosol 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.
- Use of Anti-inflammatory Agents
- The use of beta-adrenergic-agonist bronchodilators alone may not be adequate to control asthma in many patients. Early consideration should be given to adding anti-inflammatory agents, e.g., corticosteroids, to the therapeutic regimen.
- Cardiovascular Effects
- Albuterol sulfate inhalation aerosol, like other beta-adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of albuterol sulfate inhalation aerosol at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce 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 aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.
- Do Not Exceed Recommended Dose:
- Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected.
- Immediate Hypersensitivity Reactions:
- Immediate hypersensitivity reactions may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.
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