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 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 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 at recommended doses.

Administration of tritiated albuterol by inhalation to four subjects resulted in maximum plasma concentrations within 2 to 4 hours. Due to the insensitivity of the assay method, the metabolic rate and half-life of elimination of albuterol in plasma could not be determined. However, data from urinary excretion studies indicated that albuterol has an elimination half-life of 3.8 hours. Approximately 72% of the inhaled dose is excreted in the urine within 24 hours, 28% as unchanged drug and 44% as metabolite.

Clinical Trials

In controlled clinical trials the onset of improvement in pulmonary function was within 15 minutes, as determined by both maximal midexpiratory flow rate (MMEF) and FEV1. MMEF measurements also showed that near maximum improvement in pulmonary function generally occurs within 60 to 90 minutes, following 2 inhalations of albuterol and that clinically significant improvement generally continues for 3 to 4 hours in most patients. In clinical trials, some patients with asthma showed a therapeutic response (defined by maintaining FEV1 values 15% or more above baseline) which was still apparent at 6 hours. Continued effectiveness of albuterol was demonstrated over a 13-week period in these same trials.

In clinical studies, 2 inhalations of albuterol taken approximately 15 minutes prior to exercise prevented exercise-induced bronchospasm, as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. One of these studies also evaluated the duration of the prophylactic effect to repeated exercise challenges, which was evident at 4 hours in the majority of patients, and at 6 hours in approximately one third of the patients.

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 re-evaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, eg, 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, eg, corticosteroids.

Paradoxical Bronchospasm

Albuterol Inhalation Aerosol 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 Inhalation Aerosol, 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 Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Immediate Hypersensitivity Reactions

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

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 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 pre-existing 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.

Information For Patients

The action of Albuterol Inhalation Aerosol may last up to 6 hours or longer. Albuterol Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of doses 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, tremor, or nervousness. If you are pregnant or nursing, contact your physician about the use of Albuterol Inhalation Aerosol. Effective and safe use of Albuterol Inhalation Aerosol includes an understanding of the way that it should be administered. See Illustrated Patient's Instructions For Use.

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. Avoid spraying in eyes.

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.

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 and above dietary doses of 2.0 mg/kg (approximately 15 times the maximum recommended daily inhalation dose for adults 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 up to 500 mg/kg (approximately 1700 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In a 22-month study in the Golden Hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 230 times the maximum recommended daily inhalation dose for adults 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.

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

Teratogenic Effects—Pregnancy Category C

Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses at and above 0.25 mg/kg (approximately equal to the maximum recommended daily inhalation dose for adults on a mg/m2 basis), induced cleft palate formation in 5 of 111 (4.5%) fetuses. At an sc dose of 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis) albuterol sulfate induced cleft palate formation in 10 of 108 (9.3%) fetuses. The drug did not induce cleft palate formation when administered at an sc dose of 0.025 mg/kg (significantly less than the maximum recommended daily inhalation dose for adults on a mg/m2 basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg isoproterenol (positive control) administered subcutaneously.

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

Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug is transferred to the fetus. Disposition in the fetal lungs is comparable to maternal lungs, but fetal liver disposition is 1% of the maternal liver levels.

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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 reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medications during their pregnancies. Because no consistent pattern of defects can be discerned, a relationship between albuterol use and congenital anomalies has not been established.

Use in Labor and Delivery—Use in Labor

Because of the potential for beta-agonist interference with uterine contractility, use of Albuterol Inhalation Aerosol 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 children below the age of 12 years have not been established.

Treatment of acute episodes of bronchospasm or prevention of asthmatic symptoms

The usual dosage for adults and children 12 years of age and older is 2 inhalations repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a larger number of inhalations is not recommended. For maintenance therapy or prevention of exacerbation of bronchospasm, 2 inhalations, 4 times a day should be sufficient.

The use of Albuterol Inhalation Aerosol can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimal benefit from regular use of the inhaler. Safe usage for periods extending over several years has been documented.

If a previously effective dosage regimen fails to provide the usual response, 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, eg, corticosteroids.

Exercise-Induced Bronchospasm Prevention

The usual dosage for adults and children 12 years and older is 2 inhalations, 15 minutes prior to exercise. For treatment, see above.

As with all other inhalation aerosol medications, patients should make sure that the canister is firmly seated in the plastic mouthpiece before each use and the product is primed at specific times. Patients should prime Albuterol Inhalation Aerosol by actuating into the air, away from the eyes and face, four times before using for the first time and two times when the aerosol has not been used for a period of at least four days.

Albuterol, USP
Inhalation Aerosol

Patient's Instructions For Use

          Figure 1                        Figure 2

                              Figure 3

Before using your Albuterol Inhalation Aerosol, read complete instructions carefully.

1.

SHAKE THE INHALER WELL immediately before each use. Then remove the cap from the mouthpiece. Check mouthpiece for foreign objects prior to use. Make sure the canister is fully and firmly inserted into the actuator. The Albuterol Inhalation Aerosol canister should only be used with the white Albuterol Inhalation Aerosol mouthpiece. This white mouthpiece should not be used with any other inhalation drug product. Similarly, the canister should not be used with other mouthpieces.

2.

As with all other inhalation aerosol medications, patients should make sure that the canister is firmly seated in the plastic mouthpiece adapter before each use and the product is primed at specific times. Patients should prime Albuterol Inhalation Aerosol by actuating into the air, away from the eyes and face, four times before using for the first time and two times when the aerosol has not been used for a period of at least four days.

3.

BREATHE OUT FULLY THROUGH THE MOUTH, expelling as much air from your lungs as possible. Place the mouthpiece fully into the mouth, holding the inhaler in its upright position (See Figure 1) and closing the lips around it.

4.

WHILE BREATHING IN DEEPLY AND SLOWLY THROUGH THE MOUTH, FULLY DEPRESS THE TOP OF THE METAL CANISTER with your index finger. (See Figure 2.)

5.

HOLD YOUR BREATH AS LONG AS POSSIBLE. Before breathing out, remove the inhaler from your mouth and release your finger from the canister.

6.

Wait one minute and SHAKE the inhaler again. Repeat steps 2 through 4 for each inhalation prescribed by your physician.

7.

CLEANSE THE INHALER THOROUGHLY AND FREQUENTLY. Remove the metal canister and cleanse the plastic case and cap by rinsing thoroughly in warm running water, at least once a day. After thoroughly drying the plastic case and cap, gently replace the canister downward into the case without using a twisting motion. (See Figure 3.) Replace the cap.

DOSAGE: Use only as directed by your physician.

The correct amount of medication in each inhalation cannot be assured after 200 actuations from the 17.0 g canister or 80 actuations from the 6.8 g canister even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. Before you reach the specified number of actuations, you should consult your physician to determine whether a refill is needed. Just as you should not take extra doses without consulting your physician, you also should not stop using Albuterol Inhalation Aerosol without consulting your physician.

WARNINGS: The action of Albuterol Inhalation Aerosol may last up to 6 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 immediate medical attention. While taking Albuterol Inhalation Aerosol, other asthma drugs and inhaled medicines should be used only as prescribed by your physician.

Contents Under Pressure. Do not puncture. Do not 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. Avoid spraying in eyes.

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Failure to use the product within this temperature range may result in improper dosing. Shake well before using. For optimal results, the canister should be at room temperature before use.

Note: The indented statement below is required by the Federal government's Clean Air Act for all products containing or manufactured with chlorofluorocarbons (CFCs).

 

This product contains dichlorodifluoromethane (CFC-12) and trichloromonofluoromethane (CFC-11), substances which harm the environment by destroying ozone in the upper atmosphere.

Your physician has determined that this product is likely to help your personal health. USE THIS PRODUCT AS DIRECTED, UNLESS INSTRUCTED TO DO OTHERWISE BY YOUR PHYSICIAN. If you have any questions about alternatives, consult with your physician.