Label: ALBUTEROL aerosol, metered

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.

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.

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.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur after administration of Albuterol Inhalation Aerosol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema.

The contents of Albuterol Inhalation Aerosol are under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator. Avoid spraying in eyes. Keep out of reach of children.

General

Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen in individual patients and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator.

Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, albuterol may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease is usually transient, not requiring supplementation.

Although there have been no reports concerning the use of Albuterol Inhalation Aerosol during labor and delivery, it has been reported that high doses of albuterol administered intravenously inhibit uterine contractions. Although this effect is extremely unlikely as a consequence of aerosol use, it should be kept in mind.

Information for Patients

The action of Albuterol Inhalation Aerosol may last up to six hours or longer. Albuterol Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of Albuterol Inhalation Aerosol without consulting your physician. If you find that treatment with Albuterol Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, you should seek medical attention immediately. While you are using Albuterol Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of Albuterol Inhalation Aerosol. Effective and safe use of Albuterol Inhalation Aerosol includes an understanding of the way that it should be administered.

In general, the technique for administering Albuterol Inhalation Aerosol to children is similar to that for adults, since children's smaller ventilatory exchange capacity automatically provides proportionally smaller aerosol intake. Children should use Albuterol Inhalation Aerosol under adult supervision, as instructed by the patient's physician.

See illustrated Patient's Instructions for Use.

Drug Interactions

Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects.

Monoamine Oxidase Inhibitors or Tricyclic Antidepressants

Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within two weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated.

Beta-Blockers

Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol, but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers should be considered, although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics.

Digoxin

Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single-dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol.

Carcinogenesis, Mutagenesis, Impairment of Fertility

In a two-year study in Sprague-Dawley rats, albuterol sulfate caused a significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 2.0, 10, and 50 mg/kg (approximately 15, 70, and 340 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 6, 30, and 160 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m2 basis). In another study this effect was blocked by the coadministration of propranolol, a non-selective beta-adrenergic antagonist. In an 18-month study in CD-1 mice, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 500 mg/kg (approximately 1700 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m2 basis). In a 22-month study in the Golden hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 225 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis, or, approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m2 basis).

Albuterol sulfate was not mutagenic in the Ames test with or without metabolic activation using tester strains S. typhimurium TA1537, TA1538, and TA98 or E. Coli WP2, WP2uvrA, and WP67. No forward mutation was seen in yeast strain S. cerevisiae S9 nor any mitotic gene conversion in yeast strain S. cerevisiae JD1 with or without metabolic activation. Fluctuation assays in S. typhimurium TA98 and E.Coli WP2, both with metabolic activation, were negative. Albuterol sulfate was not clastogenic in a human peripheral lymphocyte assay or in an AH1 strain mouse micronucleus assay at intraperitoneal doses of up to 200 mg/kg.

Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of up to 50 mg/kg (approximately 340 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).

Pregnancy

Use in Labor and Delivery

Because of the potential for beta-agonist interference with uterine contractility, use of albuterol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Tocolysis

Albuterol has not been approved for the management of preterm labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including maternal pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in some animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below 4 years of age have not been established.

Exercise-Induced Bronchospasm Prevention

The usual dosage for adults and pediatric patients 4 years and older is two inhalations 15 minutes before exercise.

For treatment, see above.