Paradoxical Bronchospasm: Albuterol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, albuterol 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. Solutions: 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.

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 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 QT_c 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 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).

Immediate Hypersensitivity Reactions: Immediate hypersensitivity reactions may occur after administration of albuterol, as demonstrated by rare cases or urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema and, for inhalation aerosol and capsules for inhalation, anaphylaxis.

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).

Additional Information for Inhalation Aerosol: 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. Keep out of reach of children.

Additional Information for Inhalation Solution 0.05%: Microbial Contamination: To avoid microbial contamination, proper aseptic technique should be used each time the bottle is opened. Precautions should be taken to prevent contact of the dropper tip of the bottle with any surface, including the nebulizer reservoir and associated ventilatory equipment. In addition, if the solution changes color or becomes cloudy, it should not be used.

Additional Information for Inhalation Capsules: Inhalation of capsule particles may result if damage to the capsule has occurred from handling by the patient.

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. 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. Inhalation Aerosol and Inhalation Solutions: 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.

Additional Information for Inhalation Aerosol: 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.

Additional Information for Inhalation Solution: Repeated dosing with 0.15 mg/kg of albuterol inhalation solution in children aged 5 to 17 years who were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum potassium levels.

Information for the Patient

See PATIENT INFORMATION section.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

In a 2-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. [Inhalation Solutions: Approximately 2, 8, and 40 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m² basis or approximately 3/5, 3, and 15 times, respectively, the maximum recommended daily inhalation dose in children on a mg/m² basis.] [Capsules for Inhalation: Approximately 7, 35 and 170 times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m² basis or approximately 3, 15 and 80 times, respectively, the maximum recommended daily dose in children on a mg/m² basis.] [Inhalation Aerosol: 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 for 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 tumorgenicity at dietary doses of up to 500 mg/kg. [Inhalation Solutions: Approximately 200 times the maximum recommended daily inhalation dose for adults on a mg/m² basis or approximately 75 times the maximum recommended daily inhalation dose for children on a mg/m² basis.] [Capsules for Inhalation: Approximately 850 times the maximum recommended daily inhalation dose for adults on a mg/m² basis or approximately 400 times the maximum recommended daily inhalation dose for children on a mg/m² basis.] [Inhalation Aerosol: 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 tumorgenicity at dietary doses of up to 50 mg/kg [approximately 25 times for adults, 10 times for children [inhalation solution], 120 times for adults, and 55 times for children [capsules for inhalation] and 225 times for adults and 110 times for children [inhalation aerosol] the maximum recommended daily inhalation dose 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 up to 50 mg/kg approximately 40 times [inhalation solution], 170 times [capsules for inhalation] and 340 times [inhalation aerosol] the maximum recommended daily inhalation dose for adults on a mg/m² basis.

Pregnancy, Teratogenic Effects, Pregnancy Category C

Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous doses of 0.025, 0.25, and 2.5 mg/kg (approximately 2/25, 1.0, and 8.0 [inhalation aerosol]; 1/100, 1/10, and 1.0 [inhalation solution]; 1/25, 2/5, and 4 [capsules for inhalation] times, respectively, the maximum recommended daily inhalation dose for adults on a mg/m² basis), showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg. The drug did not induce cleft palate formation at the lowest dose, 0.025 mg/kg. Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of isoproterenol (positive control) subcutaneously (approximately 1.0 time [solution], 4 times [capsules] and 8 times [inhalation aerosol] the maximum recommended daily inhalation dose for adults on a mg/m² basis).

A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a 50-mg/kg dose (approximately to 80 [inhalation solution] 340 [capsules for inhalation] 680 [inhalation aerosol] times the maximum recommended daily inhalation dose for adults on a mg/m² basis.

There are no adequate and well-controlled studies in pregnant women. Albuterol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been rarely reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established.

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 after inhalation of recommended doses. 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

Inhalation Aerosol and Capsules for Inhalation: Safety and effectiveness in children below 4 years of age have not been established.

Inhalation Solution: The safety and effectiveness of albuterol inhalation solution have been established in children 2 years of age and older. Use of albuterol inhalation solution in these age-groups is supported by evidence from adequate and well-controlled studies of inhalation solution in adults; the likelihood that the disease course, pathophysiology, and the drug's effect in pediatric and adult patients are substantially similar; and published reports of trials in pediatric patients 3 years of age or older. The recommended dose for the pediatric population is based upon three published dose comparison studies of efficacy and safety in children 5 to 17 years, and on the safety profile in both adults and pediatric patients at doses equal to or higher than the recommended doses. The safety and effectiveness of albuterol inhalation solution in children below 2 years of age have not been established.

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