Albuterol Sulfate Inhalation Solution

INDICATIONS AND USAGE Albuterol Inhalation Solution is indicated for the relief of bronchospasm in patients 2 to 12 years of age with asthma (reversible obstructive airway disease).

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 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 Inhalation Solution over 5 to 15 minutes. The use of Albuterol 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 FEV 1 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 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 Inhalation Solution, when mixed with other drugs in a nebulizer have not been established. The safety and efficacy of Albuterol 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 Inhalation Solution when administered with other nebulizer systems have not been established. Albuterol 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.

WARNINGS Paradoxical Bronchospasm As with other inhaled beta-adrenergic agonists, Albuterol Inhalation Solution can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, Albuterol Inhalation Solution should be discontinued immediately and alternative therapy instituted. It should be noted that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister or vial. 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). 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 Solution 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 of 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. Cardiovascular Effects Albuterol Inhalation Solution, like 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 for Albuterol Inhalation Solution 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 Inhalation Solution like all other 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, and oropharyngeal edema.

CONTRAINDICATIONS Albuterol Inhalation Solution is contraindicated in patients with a history of hypersensitivity to any of its components.

Drug Interactions Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with albuterol inhalation solution. Albuterol Inhalation Solution 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, since the action of albuterol on the vascular system may be potentiated. Beta-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as Albuterol Inhalation Solution, 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., 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 betablockers should be considered, although they should be administered with caution. The ECG changes and/or hypokalemia that 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 dose of the beta-agonist is exceeded. Although the clinical significance of these effects is unknown, caution is advised in the co-administration of beta-agonists with non-potassium sparing diuretics. 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.

Pregnancy Teratogenic Effects: Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol subcutaneously showed cleft palate formation in 5 of 111 (4.5%) fetuses at 0.25 mg/kg (less than the maximum recommended daily inhalation dose of Albuterol Inhalation Solution on a mg/m 2 basis) and cleft palate formation in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately equal to the maximum recommended daily inhalation dose of Albuterol Inhalation Solution on a mg/m 2 basis). The drug did not induce cleft palate formation when administered subcutaneously at a dose of 0.025 mg/kg (less than the maximum recommended daily inhalation dose of Albuterol Inhalation Solution on a mg/m 2 basis). Cleft palate formation also occurred in 23 of 72 (30.5%) fetuses from females treated subcutaneously with 2.5 mg/kg isoproterenol (positive control). A reproduction study in Stride rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at 50 mg/kg (approximately 60 times the maximum recommended daily inhalation dose of Albuterol Inhalation Solution on a mg/m 2 basis). A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material was transferred from the maternal circulation to the fetus. There are no adequate and well-controlled studies of the use of albuterol sulfate 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 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.

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.

ADVERSE REACTIONS Clinical Trial Experience Adverse events reported in >1% of patients receiving Albuterol Inhalation Solution 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 Albuterol Inhalation Solution and Greater than Placebo (expressed as % of treatment group) 1.25 mg Albuterol Inhalation Solution (N=115) 0.63 mg Albuterol Inhalation Solution (N=117) Placebo (N=117) Asthma Exacerbation 13 11.1 8.5 Otitis Media 4.3 0.9 0 Allergic Reaction 0.9 3.4 1.7 Gastroenteritis 0.9 3.4 0.9 Cold Symptoms 0 3.4 1.7 Flu Syndrome 2.6 2.6 1.7 Lymphadenopathy 2.6 0.9 1.7 Skin/Appendage Infection 1.7 0 0 Urticaria 1.7 0.9 0 Migraine 0.9 1.7 0 Chest Pain 0.9 1.7 0 Bronchitis 0.9 1.7 0.9 Nausea 1.7 0.9 0.9 There was one case of ST segment depression in the 1.25 mg Albuterol Inhalation Solution treatment group. No clinically relevant laboratory abnormalities related to Albuterol Inhalation Solution administration were seen in this study. Post-marketing Experience Metabolic acidosis has been reported after the use of albuterol 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.