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Albuterol Sulfate Inhalation Solution, 0.021%, 0.042%, 0.083%

0.63 mg/3 mL* (0.021%), 1.25 mg/3 mL* (0.042%), and 2.5 mg/3 mL* (0.083%)

*(Potency expressed as albuterol, equivalent to 0.75 mg (0.021%), 1.5 mg (0.042%), and 3 mg (0.083%) albuterol sulfate)

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Albuterol sulfate is a relatively selective beta2-adrenergic agonist. Albuterol sulfate has the chemical name α1-[(tert-butylamino) methyl]-4-hydroxy-m-xylene-α,α’-diol sulfate (2:1) (salt). It has the following chemical structure:

Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official generic name in the United States, and salbutamol sulfate is the World Health Organization recommended generic name. Albuterol 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) and ethanol.

Albuterol sulfate inhalation solution is a sterile, clear, colorless solution of the sulfate salt of racemic albuterol, albuterol sulfate.

Albuterol sulfate inhalation solution is supplied in two strengths in unit dose vials. Each unit dose vial contains either 0.75 mg of albuterol sulfate (equivalent to 0.63 mg of albuterol) or 1.50 mg of albuterol sulfate (equivalent to 1.25 mg of albuterol) with sodium chloride and sulfuric acid in a 3-mL isotonic, sterile, aqueous solution. Sodium chloride is added to adjust isotonicity of the solution and sulfuric acid is added to adjust pH of the solution to 3.5 (see HOW SUPPLIED).

Albuterol sulfate inhalation solution does not require dilution prior to administration by nebulization. For albuterol sulfate inhalation solution, like all other nebulized treatments, the amount delivered to the lungs will depend on patient factors, the jet nebulizer utilized, and compressor performance. Using the Pari LC Plus™ nebulizer (with face mask or mouthpiece) connected to a Pari PRONEB™ compressor, under in vitro conditions, the mean delivered dose from the mouth piece (% nominal dose) was approximately 43% of albuterol (1.25 mg strength) and 39% of albuterol (0.63 mg strength) at a mean flow rate of 3.6 L/min. The mean nebulization time was 15 minutes or less. Albuterol sulfate inhalation solution should be administered from a jet nebulizer at an adequate flow rate, via a mouthpiece or face mask (see DOSAGE AND ADMINISTRATION).

2. INDICATIONS AND USAGE

Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma (reversible obstructive airway disease).

3. DOSAGE AND ADMINISTRATION

The usual starting dosage for patients 2 to 12 years of age is 1.25 mg or 0.63 mg of albuterol sulfate inhalation solution administered 3 or 4 times daily, as needed, by nebulization. More frequent administration is not recommended.

To administer 1.25 mg or 0.63 mg of albuterol, use the entire contents of one unit-dose vial (3 mL of 1.25 mg or 0.63 mg inhalation solution) by nebulization. Adjust nebulizer flow rate to deliver albuterol sulfate inhalation solution over 5 to 15 minutes.

The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During this time most patients gain optimum benefit from regular use of the inhalation solution.

Patients 6 to 12 years of age with more severe asthma (baseline FEV1 less than 60% predicted), weight >40 kg, or patients 11 to 12 years of age may achieve a better initial response with the 1.25 mg dose.

Albuterol sulfate inhalation solution has not been studied in the setting of acute attacks of bronchospasm. A 2.5 mg dose of albuterol provided by a higher concentration product (2.5 mg albuterol per 3 mL) may be more appropriate for treating acute exacerbations, particularly in children 6 years old and above.

If a previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often a sign of seriously worsening asthma which would require reassessment of therapy.

The drug compatibility (physical and chemical), clinical efficacy and safety of albuterol sulfate inhalation solution, when mixed with other drugs in a nebulizer have not been established.

The safety and efficacy of albuterol sulfate inhalation solution have been established in clinical trials when administered using the Pari LC Plus™ nebulizer and Pari PRONEB™ compressor. The safety and efficacy of albuterol sulfate inhalation solution when administered with other nebulizer systems have not been established.

Albuterol sulfate inhalation solution should be administered via jet nebulizer connected to an air compressor with adequate air flow, equipped with a mouthpiece or suitable face mask.

4. CONTRAINDICATIONS

Albuterol sulfate inhalation solution is contraindicated in patients with a history of hypersensitivity to albuterol and any other albuterol sulfate inhalation solution components.

5. MECHANISM OF ACTION

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 is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta2-adrenergic receptors. The precise function of these receptors has not been established. However, all 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women, this drug 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.

6.2 Labor and Delivery

Oral albuterol has been shown to delay pre-term labor in some reports. There are presently no well-controlled studies that demonstrate that it will stop pre-term labor or prevent labor at term. Because of the potential for beta agonist interference with uterine contractility, use of albuterol sulfate inhalation solution for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Albuterol has not been approved for the management of pre-term labor. The benefit:risk ratio when albuterol is administered for tocolysis has not been established. Serious adverse reactions, including pulmonary edema, have been reported following administration of albuterol to women in labor.

6.3 Nursing Mothers

Caution should be exercised when albuterol is administered to a nursing woman. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of albuterol by nursing mothers, 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.

6.4 Pediatric Use

Safety and effectiveness of albuterol sulfate inhalation solution 1.25 mg and 0.63 mg have been established in pediatric patients between the ages of 2 and 12 years. The use of albuterol sulfate inhalation solution in these age groups is supported by evidence from adequate and well-controlled studies of albuterol sulfate inhalation solution in children age 6 to 12 years and published reports of albuterol sulfate trials in pediatric patients 3 years of age and older. The safety and effectiveness of albuterol sulfate inhalation solution in children below 2 years of age have not been established.

7. WARNINGS AND PRECAUTIONS

7.1 Paradoxical Bronchospasm

Albuterol sulfate inhalation solution can produce paradoxical bronchospasm that 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.

7.2 Use of Anti-Inflammatory Agents

The use of beta-adrenergic 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).

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

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.

7.4 Cardiovascular Effects

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

7.5 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.

7.6 General

Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. As with other beta-agonists, inhaled and intravenous albuterol may produce a 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 potassium supplementation.

Information for Patients

The action of albuterol sulfate inhalation solution may last up to six hours, and therefore it should not be used more frequently than recommended. Do not increase the dose or frequency of medication without consulting your physician. If you find that treatment with albuterol sulfate inhalation solution 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. All asthma medication should only be used under the supervision and direction of a physician. Common effects with medications such as albuterol sulfate inhalation solution include palpitations, chest pain, rapid heart rate, tremor, or nervousness.

If you are pregnant or nursing, contact your physician about the use of albuterol sulfate inhalation solution. Effective and safe use of albuterol sulfate inhalation solution includes an understanding of the way it should be administered.

If the solution in the vial changes color or becomes cloudy, you should not use it.

The drug compatibility (physical and chemical), clinical efficacy, and safety of albuterol sulfate inhalation solution, when mixed with other drugs in a nebulizer, has not been established.

8. ADVERSE REACTIONS

8.1 Clinical Trials Experience

Adverse events reported in >1% of patients receiving AccuNeb and more frequently than in patients receiving placebo in a four-week double-blind study are listed in the following table.

Table 1: Adverse Events with an Incidence of >1% of Patients Receiving AccuNeb and Greater than Placebo (expressed as % of treatment group)

There was one case of ST segment depression in the 1.25 mg AccuNeb treatment group.

No clinically relevant laboratory abnormalities related to AccuNeb administration were seen in this study.

8.2 Postmarketing Experience

Metabolic acidosis has been reported after the use of albuterol sulfate inhalation solution. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

9. OVERDOSAGE

The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of symptoms such as seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats per minute, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, and exaggeration of the pharmacological effects listed in ADVERSE REACTIONS. Hypokalemia may also occur. As with all sympathomimetic aerosol medications, cardiac arrest and even death may be associated with abuse of AccuNeb. Treatment consists of discontinuation of AccuNeb together with appropriate symptomatic therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of AccuNeb.

The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 580 times the maximum recommended daily inhalation dose of AccuNeb on a mg/m2 basis). The subcutaneous median lethal dose of albuterol sulfate in mature rats and small young rats is approximately 450 mg/kg and 2000 mg/kg, respectively (approximately 260 and 1200 times the maximum recommended daily inhalation dose of AccuNeb on a mg/m2 basis). The inhalation median lethal dose has not been determined in animals.

10. 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.

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 which may result from the administration of non-potassium 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 non-potassium sparing diuretics.

Digoxin: Mean decreases of 16% and 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.

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 2 weeks of discontinuation of such agents, because the action of albuterol on the cardiovascular system may be potentiated.

11. PHARMACOKINETICS

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 urine collected during the 24 hours after drug administration. Following oral administration of 4 mg albuterol, the elimination half-life was five to six hours. Following a 3 mg dose of nebulized albuterol in adults, the mean maximum albuterol plasma level at 0.5 hours was 2.1 ng/mL (range, 1.4 to 3.2 ng/mL). The pharmacokinetics of albuterol following administration of 0.63 mg or 1.25 mg albuterol sulfate inhalation solution by nebulization have not been determined in children 2 to 12 years old.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names: ACCUNEB, by DEY.

PROVENTIL (discontinued), by SCHERING.

VENTOLIN (discontinued), by GLAXOSMITHKLINE.

b) Generic drugs: Albuterol sulfate, by various manufacturers.

2) How Supplied:

Albuterol sulfate inhalation solution (by WATSON LABS) is supplied as a 3 mL, clear, colorless, sterile, preservative-free, aqueous solution in two different strengths, 0.021% (0.63 mg) and 0.042% (1.25 mg) of albuterol (equivalent to 0.75 mg of albuterol sulfate or 1.5 mg of albuterol sulfate per 3 mL) in unit-dose low-density polyethylene (LDPE) vials. Each unit-dose LDPE vial is protected in a foil-pouch, and each foil pouch contains 5 unit-dose LDPE vials. Each strength of albuterol sulfate inhalation solution is available in a shelf carton containing multiple foil pouches.

Albuterol sulfate inhalation solution 0.021% (0.63 mg/3 mL) (potency expressed as albuterol) contains 0.75 mg albuterol sulfate per 3 mL in unit-dose vials and is available in the following packaging configuration.

NDC 0591-3467-53: 5 foil pouches, each containing 5 vials, total 25 vials per carton.

Albuterol Sulfate Inhalation Solution, 0.042% (1.25 mg/3 mL) (potency expressed as albuterol) contains 1.50 mg albuterol sulfate per 3 mL in unit-dose vials and is available in the following packaging configuration.

NDC 0591-3468-53: 5 foil pouches, each containing 5 vials, total 25 vials per carton.

Albuterol Sulfate Inhalation Solution 0.083%, 2.5 mg/3 mL* (*Potency expressed as albuterol, equivalent to 3 mg albuterol sulfate). Equivalent to 0.5 mL albuterol (as the sulfate) 0.5% (2.5 mg albuterol) diluted to 3 mL. Supplied in cartons as listed below.

NDC 0591-3797-83 carton of 25 vials.

NDC 0591-3797-30 carton of 30 vials.

NDC 0591-3797-60 carton of 60 vials.

3) Storage:

Store between 20°C and 25°C (68°F - 77°F). Protect from light and excessive heat.

Store unit-dose vials in protective foil pouch at all times. Once removed from the foil pouch, use vial(s) within one week. Discard the vial if the solution is not colorless.

Keep out of the reach of children.

Rx only

Rev 01/07