INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Albuterol sulfate inhalation solution is indicated for the relief of bronchospasm in patients 12 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. The results of clinical trials with albuterol sulfate inhalation solution in 135 patients showed the following side effects which were considered probably or possibly drug related: Percent Incidence of Adverse Reactions ReactionPercent Incidence = 135 Central Nervous SystemTremors20Dizziness7Nervousness4Headache3Sleeplessness1GastrointestinalNausea4Dyspepsia1Ear, nose and throatNasal congestion1Pharyngitis<1CardiovascularTachycardia1Hypertensions1RespiratoryBronchospasm8Cough4Bronchitis4Wheezing1No clinically relevant laboratory abnormalities related to albuterol sulfate inhalation solution were determined in these studies.Cases of urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) have been reported after the use of albuterol sulfate inhalation solution.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

ANIMAL PHARMACOLOGY OR TOXICOLOGY. 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 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 were administered concurrently. The significance of these findings is unknown.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2-year study in Sprague-Dawley rats, albuterol sulfate caused significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 2, 10, and 50 mg/kg (approximately 2, 8, and 40 times, respectively, the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 3/5, 3, and 15 times, respectively, the maximum recommended daily inhalation dose in children on mg/m basis). In another study this effect was blocked by the coadministration of propranolol, nonselective 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 200 times the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 75 times the maximum recommended daily inhalation dose for children on mg/m basis). In 22-month study in the Golden hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 10 times the maximum recommended daily inhalation dose for children on mg/m 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 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 albuterol sulfate up to 50 mg/kg (approximately 40 times the maximum recommended daily inhalation dose for adults on an mg/m basis).

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has preferential effect on beta 2-adrenergic receptors compared with isoproterenol. While it is recognized that beta 2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is population of beta 2-receptors in the human heart existing in concentration between 10% and 50%. The precise function of these receptors has not been established (see WARNINGS). The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3,5-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects.Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes.Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not substrate for the cellular uptake processes for catecholamines nor for catechol- O-methyl transferase. Pharmacokinetics. Studies in asthmatic patients have shown that less than 20% of 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 the urine 24 hours after drug administration. Following 3 mg dose of nebulized albuterol, the maximum albuterol plasma level at 0.5 hour was 2.1 ng/mL (range 1.4 to 3.2 ng/mL). There was significant dose-related response in FEV and peak flow rate. It has been demonstrated that following oral administration of mg of albuterol, the elimination half-life was to hours.

CLINICAL STUDIES SECTION.

CLINICAL STUDIES. In controlled clinical trials in adults, most patients exhibited an onset of improvement in pulmonary function within minutes as determined by FEV 1. FEV measurements also showed that the maximum average improvement in pulmonary function usually occurred at approximately hour following inhalation of 2.5 mg of albuterol by compressor-nebulizer and remained close to peak for hours. Clinically significant improvement in pulmonary function (defined as maintenance of 15% or more increase in FEV over baseline values) continued for to hours in most patients and in some patients continued up to hours. Published reports of trials in asthmatic children aged years or older have demonstrated significant improvement in either FEV or PEFR within to 20 minutes following single doses of albuterol inhalation solution. An increase of 15% or more in baseline FEV has been observed in children aged to 11 years up to hours after treatment with doses of 0.10 mg/kg or higher of albuterol inhalation solution. Single doses of 3, 4, or 10 mg resulted in improvement in baseline PEFR that was comparable in extent and duration to 2 mg dose, but doses above mg were associated with heart rate increases of more than 10%.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Albuterol sulfate inhalation solution is contraindicated in patients with history of hypersensitivity to albuterol or any of its components.

DESCRIPTION SECTION.

DESCRIPTION. Albuterol Sulfate Inhalation Solution, 0.5% contains albuterol sulfate, USP, the racemic form of albuterol and relatively selective beta 2-adrenergic bronchodilator (see CLINICAL PHARMACOLOGY section below). Albuterol sulfate has the chemical name 1-[( tert-Butylamino) methyl]-4-hydroxy- m-xylene-,-diol sulfate (2:1) (salt) and the following chemical structure: (C 13H 21NO 3) o 2SO Mol. Wt. 576.7Albuterol sulfate is white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organizations recommended name for albuterol base is salbutamol.Albuterol sulfate inhalation solution, 0.5%, is in concentrated form. Dilute 0.5 mL of the solution to mL with sterile normal saline solution prior to administration by nebulization (see DOSAGE AND ADMINISTRATION). Each 0.5 mL Unit-of-Use Vial Contains: ACTIVE: 2.5 mg of albuterol (equivalent to mg of albuterol sulfate, USP) in sterile, aqueous solution; sulfuric acid is used to adjust the pH to between and 5. Albuterol sulfate inhalation solution contains no sulfiting agents or preservatives. It is supplied in 0.5 mL sterile Unit-of-Use Vials. Albuterol sulfate inhalation solution is clear, colorless to light yellow solution.. b88244c6-figure-01.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. The usual dosage for adults and pediatric patients 12 years of age and older is 2.5 mg of albuterol (one unit-of-use vial) administered to times daily by nebulization. More frequent administration or higher doses are not recommended. To administer 2.5 mg of albuterol, dilute 0.5 mL of the 0.5% solution for inhalation to total volume of mL with sterile normal saline solution and administer by nebulization. The flow rate is regulated to suit the particular nebulizer so that albuterol sulfate inhalation solution will be delivered over approximately to 15 minutes.Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in nebulizer have not been established.The use of albuterol sulfate inhalation solution can be continued as medically indicated to control recurring bouts of bronchospasm. During treatment, most patients gain optimum benefit from regular use of the nebulizer solution.If previously effective dosage regimen fails to provide the usual relief, medical advice should be sought immediately, as this is often sign of seriously worsening asthma which would require reassessment of therapy.The nebulizer should be cleaned in accordance with the manufacturers instructions. Failure to do so could lead to bacterial contamination of the nebulizer and possible infection.

DRUG INTERACTIONS SECTION.

Drug Interactions. Other short-acting sympathomimetic aerosol bronchodilators or epinephrine 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 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 sulfate 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., 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 could 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 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.

GENERAL PRECAUTIONS SECTION.

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 pre-existing diabetes mellitus and ketoacidosis. As with other beta-agonist medications, 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 potassium supplementation.Repeated dosing with 0.15 mg/kg of albuterol inhalation solution in children aged to 17 years who were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum potassium levels.

HOW SUPPLIED SECTION.

HOW SUPPLIED Albuterol Sulfate Inhalation Solution, 0.5%, is clear, colorless to light yellow solution, and is supplied in plastic sterile unit-of-use vials of 0.5 mL each, supplied in individual foil pouches:NDC 0487-9901-30: 30 vials, each in an individual pouch.. Storage and Handling Store between 2C and 25C (36F 77F).Rx OnlyManufactured By: Nephron Pharmaceuticals Corporation West Columbia, SC 29172.

INFORMATION FOR PATIENTS SECTION.

Information for Patients. The action of albuterol sulfate inhalation solution may last up to hours or longer. Albuterol sulfate inhalation solution should not be used more frequently than recommended. Do not increase the dose or frequency of albuterol sulfate inhalation solution 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. While you are using albuterol sulfate inhalation solution, 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 use of albuterol sulfate inhalation solution. Effective and safe use of albuterol sulfate inhalation solution includes an understanding of the way that it should be administered.Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in nebulizer have not been established.See illustrated Patients Instructions for Use.

LABOR & DELIVERY SECTION.

Labor and Delivery. 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.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 beta 2-agonists, including albuterol.

NURSING MOTHERS SECTION.

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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.

OVERDOSAGE. The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under ADVERSE REACTIONS, e.g., 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, and sleeplessness. Hypokalemia may also occur. In isolated cases in children to 12 years of age, tachycardia with rates 200 beats/min has been observed. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of albuterol sulfate inhalation solution. Treatment consists of discontinuation of albuterol sulfate inhalation solution together with appropriate symptomatic therapy. The judicious use of 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 albuterol sulfate inhalation solution. The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 810 times the maximum recommended daily inhalation dose for adults on an mg/m basis or approximately 300 times the maximum recommended daily inhalation dose for children on mg/m basis). In mature rats, the subcutaneous (sc) median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 365 times the maximum recommended daily inhalation dose for adults on an mg/m basis or approximately 135 times the maximum recommended daily inhalation dose for children on mg/m basis). In small young rats, the sc median lethal dose is approximately 2000 mg/kg (approximately 1600 times the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 600 times the maximum recommended daily inhalation dose for children on mg/m basis). The inhalational median lethal dose has not been determined in animals.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Principal Display Panel Pouch Label (individually wrapped vials)NDC 0487-9901-30Principal Display Panel Carton (30 individually wrapped vials)NDC 0487-9901-30. Figure 06. Figure 07. Figure 08.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effectiveness of albuterol inhalation solution and solution for inhalation in children below the age of 12 years have not been established.

PHARMACOKINETICS SECTION.

Pharmacokinetics. Studies in asthmatic patients have shown that less than 20% of 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 the urine 24 hours after drug administration. Following 3 mg dose of nebulized albuterol, the maximum albuterol plasma level at 0.5 hour was 2.1 ng/mL (range 1.4 to 3.2 ng/mL). There was significant dose-related response in FEV and peak flow rate. It has been demonstrated that following oral administration of mg of albuterol, the elimination half-life was to hours.

PRECAUTIONS SECTION.

PRECAUTIONS. 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 pre-existing diabetes mellitus and ketoacidosis. As with other beta-agonist medications, 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 potassium supplementation.Repeated dosing with 0.15 mg/kg of albuterol inhalation solution in children aged to 17 years who were initially normokalemic has been associated with an asymptomatic decline of 20% to 25% in serum potassium levels.. Information for Patients. The action of albuterol sulfate inhalation solution may last up to hours or longer. Albuterol sulfate inhalation solution should not be used more frequently than recommended. Do not increase the dose or frequency of albuterol sulfate inhalation solution 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. While you are using albuterol sulfate inhalation solution, 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 use of albuterol sulfate inhalation solution. Effective and safe use of albuterol sulfate inhalation solution includes an understanding of the way that it should be administered.Drug compatibility (physical and chemical), efficacy, and safety of albuterol sulfate inhalation solution when mixed with other drugs in nebulizer have not been established.See illustrated Patients Instructions for Use. Drug Interactions. Other short-acting sympathomimetic aerosol bronchodilators or epinephrine 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 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 sulfate 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., 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 could 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 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 2-year study in Sprague-Dawley rats, albuterol sulfate caused significant dose-related increase in the incidence of benign leiomyomas of the mesovarium at dietary doses of 2, 10, and 50 mg/kg (approximately 2, 8, and 40 times, respectively, the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 3/5, 3, and 15 times, respectively, the maximum recommended daily inhalation dose in children on mg/m basis). In another study this effect was blocked by the coadministration of propranolol, nonselective 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 200 times the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 75 times the maximum recommended daily inhalation dose for children on mg/m basis). In 22-month study in the Golden hamster, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 25 times the maximum recommended daily inhalation dose for adults on mg/m basis or approximately 10 times the maximum recommended daily inhalation dose for children on mg/m 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 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 albuterol sulfate up to 50 mg/kg (approximately 40 times the maximum recommended daily inhalation dose for adults on an mg/m basis). Pregnancy. Teratogenic Effects. Pregnancy Category C. Albuterol has been shown to be teratogenic in mice. study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 1/100, 1/10, and 1.0 times, respectively, the maximum recommended daily inhalation dose for adults on mg/m basis), showed cleft palate formation in of 111 (4.5%) fetuses at 0.25 mg/kg nad 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 isoproterenol (positive control) subcutaneously (approximately 1.0 times the maximum recommended daily inhalation dose for adults on mg/m basis). reproduction study in Stride Dutch rabbits revealed cranioschisis in of 19 (37%) fetuses when albuterol was administered orally at 50 mg/kg dose (approximately 80 times the maximum recommended daily inhalation dose for adults on mg/m 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 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 sulfate inhalation solution 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 beta 2-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, 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 of albuterol inhalation solution and solution for inhalation in children below the age of 12 years have not been established.

PREGNANCY SECTION.

Pregnancy. Teratogenic Effects. Pregnancy Category C. Albuterol has been shown to be teratogenic in mice. study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 1/100, 1/10, and 1.0 times, respectively, the maximum recommended daily inhalation dose for adults on mg/m basis), showed cleft palate formation in of 111 (4.5%) fetuses at 0.25 mg/kg nad 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 isoproterenol (positive control) subcutaneously (approximately 1.0 times the maximum recommended daily inhalation dose for adults on mg/m basis). reproduction study in Stride Dutch rabbits revealed cranioschisis in of 19 (37%) fetuses when albuterol was administered orally at 50 mg/kg dose (approximately 80 times the maximum recommended daily inhalation dose for adults on mg/m 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 relationship between albuterol use and congenital anomalies has not been established.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert. Note: The Albuterol Sulfate Inhalation Solution is concentrated and must be diluted.Read complete instructions carefully before using.Note: Use only as directed by your physician. More frequent administration or higher doses are not recommended.Mixing Compatibility: The safety and effectiveness of Albuterol sulfate solution for inhalation have not been determined when one or more drugs are mixed with it in nebulizer. Store Albuterol Sulfate Inhalation Solution, 0.5%, between and 25 (36 and 77 F).. INSTRUCTIONS FOR USE. Twist open the top of one Albuterol Sulfate Inhalation Solution unit-of-use container (Figure 1). Squeeze the solution into the nebulizer reservoir through the appropriate opening (Figure 2). Add 2.5 mL of diluting fluid sterile normal saline solution (as your doctor has directed).Gently swirl the nebulizer to mix the contents and connect it with the mouthpiece or face mask (Figure 3). Connect the nebulizer to the compressor.Sit in comfortable, upright position; place the mouthpiece in your mouth (Figure 4) (or put on the face mask); and turn the compressor on. Breathe as calmly, deeply and evenly as possible until no more mist is formed in the nebulizer chamber (about to 15 minutes). At this point, the treatment is finished.Clean the nebulizer (see manufacturers instructions). Failure to clean the nebulizer in accordance with the manufacturers instructions could lead to bacterial contamination of the nebulizer, and possible infection.. Twist open the top of one Albuterol Sulfate Inhalation Solution unit-of-use container (Figure 1). Squeeze the solution into the nebulizer reservoir through the appropriate opening (Figure 2). Add 2.5 mL of diluting fluid sterile normal saline solution (as your doctor has directed).. Gently swirl the nebulizer to mix the contents and connect it with the mouthpiece or face mask (Figure 3). Connect the nebulizer to the compressor.. Sit in comfortable, upright position; place the mouthpiece in your mouth (Figure 4) (or put on the face mask); and turn the compressor on. Breathe as calmly, deeply and evenly as possible until no more mist is formed in the nebulizer chamber (about to 15 minutes). At this point, the treatment is finished.. Clean the nebulizer (see manufacturers instructions). Failure to clean the nebulizer in accordance with the manufacturers instructions could lead to bacterial contamination of the nebulizer, and possible infection.. b88244c6-figure-02. b88244c6-figure-03. b88244c6-figure-04. b88244c6-figure-05.

SPL UNCLASSIFIED SECTION.

Potency expressed as albuterol.

STORAGE AND HANDLING SECTION.

Storage and Handling Store between 2C and 25C (36F 77F).Rx OnlyManufactured By: Nephron Pharmaceuticals Corporation West Columbia, SC 29172.

TERATOGENIC EFFECTS SECTION.

Teratogenic Effects. Pregnancy Category C. Albuterol has been shown to be teratogenic in mice. study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg (approximately 1/100, 1/10, and 1.0 times, respectively, the maximum recommended daily inhalation dose for adults on mg/m basis), showed cleft palate formation in of 111 (4.5%) fetuses at 0.25 mg/kg nad 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 isoproterenol (positive control) subcutaneously (approximately 1.0 times the maximum recommended daily inhalation dose for adults on mg/m basis). reproduction study in Stride Dutch rabbits revealed cranioschisis in of 19 (37%) fetuses when albuterol was administered orally at 50 mg/kg dose (approximately 80 times the maximum recommended daily inhalation dose for adults on mg/m 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 relationship between albuterol use and congenital anomalies has not been established.

WARNINGS SECTION.

WARNINGS. PARADOXICAL BRONCHOSPASM. Albuterol sulfate inhalation solution can produce paradoxical bronchospasm, which 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 new vial.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 sulfate inhalation solution, like all other beta-adrenergic agonists, can produce 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 sulfate inhalation solution 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 wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, albuterol sulfate inhalation solution, 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 period of hours or chronically over several days or longer. If the patient needs more doses of albuterol sulfate inhalation solution than usual, this may be 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.. 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.. 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.