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CLINICAL PHARMACOLOGYIn vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a 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 a 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 a 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 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 the urine within 24 hours after drug administration. Following a 3-mg dose of nebulized albuterol in adults, the maximum albuterol plasma levels at 0.5 hours were 2.1 ng/mL (range, 1.4 to 3.2 ng/mL). There was a significant dose-related response in FEV1 (forced expiratory volume in 1 second) and peak flow rate. It has been demonstrated that following oral administration of 4 mg of albuterol, the elimination half-life was 5 to 6 hours. Preclinical Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations 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 are administered concurrently. The clinical significance of these findings is unknown. Clinical Trials In controlled clinical trials in adults, most patients exhibited an onset of improvement in pulmonary function within 5 minutes as determined by FEV1. FEV1 measurements also showed that the maximum average improvement in pulmonary function usually occurred at approximately 1 hour following inhalation of 2.5 mg of albuterol by compressor-nebulizer and remained close to peak for 2 hours. Clinically significant improvement in pulmonary function (defined as maintenance of a 15% or more increase in FEV1 over baseline values) continued for 3 to 4 hours in most patients, with some patients continuing up to 6 hours. Published reports of trials in asthmatic children aged 3 years or older have demonstrated significant improvement in either FEV1 or PEFR within 2 to 20 minutes following single doses of albuterol inhalation solution. An increase of 15% or more in baseline FEV1 has been observed in children aged 5 to 11 years up to 6 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 a 2-mg dose, but doses above 3 mg were associated with heart rate increases of more than 10%.

CLINICAL PHARMACOLOGY Mechanism Of Action In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established. (See WARNINGS, Cardiovascular Effects section.) 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 leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Albuterol has been shown in most 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 betaadrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes. Preclinical Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% 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 beta2-agonist and methylxanthines were administered concurrently. The clinical significance of these findings is unknown. Propellant HFA-134a is devoid of pharmacological activity except at very high doses in animals (380-1300 times the maximum human exposure based on comparisons of AUC values), primarily producing ataxia, tremors, dyspnea, or salivation. These are similar to effects produced by the structurally related chlorofluorocarbons (CFCs), which have been used extensively in metered dose inhalers. In animals and humans, propellant HFA-134a was found to be rapidly absorbed and rapidly eliminated, with an elimination half-life of 3 to 27 minutes in animals and 5 to 7 minutes in humans. Time to maximum plasma concentration (Tmax) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation. Pharmacokinetics In a single-dose bioavailability study which enrolled six healthy, male volunteers, transient low albuterol levels (close to the lower limit of quantitation) were observed after administration of two puffs from both PROVENTIL® HFA Inhalation Aerosol and a CFC 11/12 propelled albuterol inhaler. No formal pharmacokinetic analyses were possible for either treatment, but systemic albuterol levels appeared similar. Clinical Trials In a 12-week, randomized, double-blind, double-dummy, active- and placebo-controlled trial, 565 patients with asthma were evaluated for the bronchodilator efficacy of PROVENTIL HFA Inhalation Aerosol (193 patients) in comparison to a CFC 11/12 propelled albuterol inhaler (186 patients) and an HFA-134a placebo inhaler (186 patients). Serial FEV1 measurements (shown below as percent change from test-day baseline) demonstrated that two inhalations of PROVENTIL HFA Inhalation Aerosol produced significantly greater improvement in pulmonary function than placebo and produced outcomes which were clinically comparable to a CFC 11/12 propelled albuterol inhaler. The mean time to onset of a 15% increase in FEV1 was 6 minutes and the mean time to peak effect was 50 to 55 minutes. The mean duration of effect as measured by a 15% increase in FEV1 was 3 hours. In some patients, duration of effect was as long as 6 hours. In another clinical study in adults, two inhalations of PROVENTIL HFA Inhalation Aerosol taken 30 minutes before exercise prevented exercise-induced bronchospasm as demonstrated by the maintenance of FEV1 within 80% of baseline values in the majority of patients. In a 4-week, randomized, open-label trial, 63 children, 4 to 11 years of age, with asthma were evaluated for the bronchodilator efficacy of PROVENTIL HFA Inhalation Aerosol (33 pediatric patients) in comparison to a CFC 11/12 propelled albuterol inhaler (30 pediatric patients). Serial FEV1 measurements as percent change from test-day baseline demonstrated that two inhalations of PROVENTIL HFA Inhalation Aerosol produced outcomes which were clinically comparable to a CFC 11/12 propelled albuterol inhaler. The mean time to onset of a 12% increase in FEV1 for PROVENTIL HFA Inhalation Aerosol was 7 minutes and the mean time to peak effect was approximately 50 minutes. The mean duration of effect as measured by a 12% increase in FEV1 was 2.3 hours. In some pediatric patients, duration of effect was as long as 6 hours. In another clinical study in pediatric patients, two inhalations of PROVENTIL HFA Inhalation Aerosol taken 30 minutes before exercise provided comparable protection against exercise-induced bronchospasm as a CFC 11/12 propelled albuterol inhaler.

CLINICAL PHARMACOLOGY The prime action of beta-adrenergic drugs is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP). The cyclic AMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicate that 10% to 50% of the beta-receptors in the human heart may be beta2-receptors. The precise function of these receptors, however, is not yet established. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other 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. Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a 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 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. Animal Pharmacology/Toxicology Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in 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. Clinical Trials The safety and efficacy of AccuNeb (albuterol sulfate inhalation solution) was evaluated in a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study in 349 children 6 to 12 years of age with mild-to-moderate asthma (mean baseline FEV1 60% to 70% of predicted). Approximately half of the patients were also receiving inhaled corticosteroids. Patients were randomized to receive AccuNeb (albuterol sulfate inhalation solution) 0.63 mg, AccuNeb (albuterol sulfate inhalation solution) 1.25 mg, or placebo three times a day administered via a Pari LC Plus™ nebulizer and a Pari PRONEB™ compressor. Racemic albuterol, delivered by a chlorofluorocarbon (CFC) metered dose inhaler (MDI) or nebulized, was used on an as-needed basis as the rescue medication. Efficacy, as measured by the mean percent change from baseline in the area under the 6hour curve for FEV1, was demonstrated for both active treatment regimens (n=112 [1.25 mg group] and n=110 [0.63 mg group]) compared with placebo (n=110) on day 1 and day 28. Figures 1 and 2 illustrate the mean percentage change from pre-dose FEV1 on day 1 and day 28, respectively. The mean baseline FEV1 for all patients was 1.49 L. Figure 1 : % Change from Pre-Dose FEV1 Intent-to-Treat Population Day 1 Figure 2 : % Change from Pre-Dose FEV1 Intent-to-Treat Population Day 28 The onset of a 15% increase in FEV1 over baseline for both doses of AccuNeb (albuterol sulfate inhalation solution) was seen at 30 minutes (the first post-dose assessment). The mean time to peak effect was approximately 30 to 60 minutes for both doses on day 1 and after 4 weeks of treatment. The mean duration of effect, as measured by a > 15% increase from baseline in FEV1, was approximately 2.5 hours for both doses on day 1 and approximately 2 hours for both doses after 4 weeks of treatment. In some patients, the duration of effect was as long as 6 hours.

DESCRIPTIONThe active component of VENTOLIN Inhalation Solution is albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta2-adrenergic bronchodilator (see CLINICAL PHARMACOLOGY). It has the chemical name a1-[(tert-butylamino)methyl] -4-hydroxy-m-xylene-a, a'-diol sulfate (2:1)(salt) and the following chemical structure: Albuterol sulfate has a molecular weight of 576.7, and the empirical formula is (C13H21NO3)2·H2SO4. Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol base is salbutamol. VENTOLIN Inhalation Solution, 0.5% is in concentrated form. Dilute the appropriate volume of the solution (see DOSAGE AND ADMINISTRATION) with sterile normal saline solution to a total volume of 3 mL and administer by nebulization. Each milliliter of VENTOLIN Inhalation Solution contains 5 mg of albuterol (as 6 mg of albuterol sulfate) in an aqueous solution containing benzalkonium chloride; sulfuric acid is used to adjust the pH to between 3 and 5. VENTOLIN Inhalation Solution contains no sulfiting agents. It is supplied in a 20-mL amber glass bottle. VENTOLIN Inhalation Solution is a clear, colorless to light yellow solution.

Find Lowest Prices on PROVENTIL® HFA(albuterol sulfate) Inhalation Aerosol DESCRIPTION The active component of PROVENTIL® HFA (albuterol sulfate) Inhalation Aerosol is albuterol sulfate, USP racemic α1 [(tert-Butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1)(salt), a relatively selective beta2-adrenergic bronchodilator having the following chemical structure: Albuterol sulfate is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol sulfate. The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C13H21NO3)2•H2SO4. Albuterol sulfate is a white to off-white crystalline solid. It is soluble in water and slightly soluble in ethanol. PROVENTIL HFA 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), ethanol, and oleic acid. Each actuation delivers 120 mcg albuterol sulfate, USP from the valve and 108 mcg albuterol sulfate, USP from the mouthpiece (equivalent to 90 mcg of albuterol base from the mouthpiece). Each canister provides 200 inhalations. It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing four “test sprays” into the air, away from the face. This product does not contain chlorofluorocarbons (CFCs) as the propellant.

AccuNeb® (albuterol sulfate) 1.25 mg*/3 mL and 0.63 mg*/3 mL Inhalation Solution *(Potency expressed as albuterol, equivalent to 1.5 mg and 0.75 mg albuterol sulfate) DESCRIPTION AccuNeb® (albuterol sulfate) inhalation solution is a sterile, clear, colorless solution of the sulfate salt of racemic albuterol, albuterol sulfate. Albuterol sulfate is a relatively selective beta2-adrenergic bronchodilator (see CLINICAL PHARMACOLOGY). The chemical name for albuterol sulfate is α1 [(tert-butylamino) methyl]-4-hydroxy-mxylene-α, α'-diol sulfate (2:1) (salt), and its established chemical structure is as follows: The molecular weight of albuterol sulfate is 576.7 and the empirical formula is (C13H21NO3)2•H2SO4. Albuterol sulfate is a white crystalline powder, soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol is salbutamol. AccuNeb (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). AccuNeb (albuterol sulfate) Inhalation Solution does not require dilution prior to administration by nebulization. For AccuNeb (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. AccuNeb (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).

INDICATIONSVENTOLIN Inhalation Solution is indicated for the relief of bronchospasm in patients 2 years of age and older with reversible obstructive airway disease and acute attacks of bronchospasm. DOSAGE AND ADMINISTRATIONTo avoid microbial contamination, proper aseptic techniques 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. Children 2 to 12 Years of Age: For children 2 to 12 years of age, initial dosing should be based upon body weight (0.1 to 0.15 mg/kg per dose), with subsequent dosing titrated to achieve the desired clinical response. Dosing should not exceed 2.5 mg three to four times daily by nebulization. The following table outlines approximate dosing according to body weight. Approximate Weight Approximate Weight Dose Volume of (kg) (lb) (mg) Inhalation Solution 10-15 22-33 1.25 0.25 mL >15 >33 2.5 0.5 mL The appropriate volume of the 0.5% inhalation solution should be diluted in sterile normal saline solution to a total volume of 3 mL prior to administration via nebulization. Adults and Children Over 12 Years of Age: The usual dosage for adults and children over 12 years of age is 2.5 mg of albuterol administered three to four 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% inhalation solution with 2.5 mL of sterile normal saline solution. The flow rate is regulated to suit the particular nebulizer so that VENTOLIN Inhalation Solution will be delivered over approximately 5 to 15 minutes. The use of VENTOLIN Inhalation Solution 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 inhalation solution. 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 that would require reassessment of therapy. Drug compatibility (physical and chemical), efficacy, and safety of VENTOLIN Inhalation Solution when mixed with other drugs in a nebulizer have not been established. HOW SUPPLIEDVENTOLIN Inhalation Solution, 0.5% is supplied in amber glass bottles of 20 mL (NDC 0173-0385-58) with accompanying calibrated dropper in boxes of one. Store between 2° and 25°C (36° and 77°F). Glaxo Wellcome Inc, Research Triangle Park, NC 27709, September 1998 RL-634

INDICATIONS PROVENTIL® HFA Inhalation Aerosol is indicated in adults and children 4 years of age and older for the treatment or prevention of bronchospasm with reversible obstructive airway disease and for the prevention of exercise-induced bronchospasm. DOSAGE AND ADMINISTRATION For treatment of acute episodes of bronchospasm or prevention of asthmatic symptoms, the usual dosage for adults and children 4 years of age and older is two inhalations repeated every 4 to 6 hours. More frequent administration or a larger number of inhalations is not recommended. In some patients, one inhalation every 4 hours may be sufficient. Each actuation of PROVENTIL® HFA Inhalation Aerosol delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouthpiece. It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing four “test sprays” into the air, away from the face. Exercise Induced Bronchospasm Prevention The usual dosage for adults and children 4 years of age and older is two inhalations 15 to 30 minutes before exercise. To maintain proper use of this product, it is important that the mouthpiece be washed and dried thoroughly at least once a week. The inhaler may cease to deliver medication if not properly cleaned and dried thoroughly (see PATIENT INFORMATION section). Keeping the plastic mouthpiece clean is very important to prevent medication buildup and blockage. The inhaler may cease to deliver medication if not properly cleaned and air dried thoroughly. If the mouthpiece becomes blocked, washing the mouthpiece will remove the blockage. If a previously effective dose regimen fails to provide the usual response, this may be a marker of destabilization of asthma and requires reevaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. HOW SUPPLIED PROVENTIL® HFA (albuterol sulfate) Inhalation Aerosol is supplied as a pressurized aluminum canister with a yellow plastic actuator and orange dust cap each in boxes of one. Each actuation delivers 120 mcg of albuterol sulfate from the valve and 108 mcg of albuterol sulfate from the mouthpiece (equivalent to 90 mcg of albuterol base). Canisters with a labeled net weight of 6.7 g contain 200 inhalations (NDC 0085-1132-01). Store between 15°-25°C (59°-77°F). For best results, canister should be at room temperature before use. SHAKE WELL BEFORE USING. The yellow actuator supplied with PROVENTIL HFA Inhalation Aerosol should not be used with any other product canisters, and actuator from other products should not be used with a PROVENTIL HFA Inhalation Aerosol canister. The correct amount of medication in each canister cannot be assured after 200 actuations, even though the canister is not completely empty. The canister should be discarded when the labeled number of actuations have been used. WARNING: Avoid spraying in eyes. Contents under pressure. Do not puncture or incinerate. Exposure to temperatures above 120°F may cause bursting. Keep out of reach of children. PROVENTIL® HFA Inhalation Aerosol does not contain chlorofluorocarbons (CFCs) as the propellant. Attention Health Care Professional Detach Patient's Instructions for Use from package insert and dispense with the product. Developed and Manufactured by: 3M Health Care Limited, Loughborough UK or 3M Drug Delivery Systems, Northridge, CA 91324, USA. Manufactured for: Merck Sharp & Dohme Corp., a subsidiary of MERCK & CO., INC., Whitehouse Station, NJ 08889, USA. Revised: June 2012.

INDICATIONS AccuNeb (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). DOSAGE AND ADMINISTRATION The usual starting dosage for patients 2 to 12 years of age is 1.25 mg or 0.63 mg of AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) over 5 to 15 minutes. The use of AccuNeb (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. AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) solution, when mixed with other drugs in a nebulizer have not been established. The safety and efficacy of AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) when administered with other nebulizer systems have not been established. AccuNeb (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. HOW SUPPLIED AccuNeb (albuterol sulfate) Inhalation Solution is supplied as a 3 mL, clear, colorless, sterile, preservative-free, aqueous solution in two different strengths, 0.63 mg and 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 AccuNeb (albuterol sulfate inhalation solution) (albuterol sulfate) Inhalation Solution is available in a shelf carton containing multiple foil pouches. AccuNeb® (albuterol sulfate) Inhalation Solution, 0.63 mg (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 49502-692-03 5 foil pouches, each containing 5 vials, total 25 vials per carton AccuNeb® (albuterol sulfate) Inhalation Solution, 1.25 mg (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 49502-693-03 5 foil pouches, each containing 5 vials, total 25 vials per carton Storage Store between 2°C and 25°C (36°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. DEY®, Napa, CA 94558.  JAN 07

PATIENT INFORMATION Patient's Instructions for Use VENTOLIN® (albuterol sulfate, USP) Inhalation Solution, 0.5%* *Potency expressed as albuterol. Read complete instructions carefully before using. 1. Draw the appropriate volume of VENTOLIN Inhalation Solution into the specially marked dropper that comes with each multidose bottle (Figure 1). For children 12 years of age and under, the volume is based upon body weight. Use the dropper volume prescribed by your doctor. 2. Squeeze the solution into the nebulizer reservoir through the appropriate opening, taking care not to touch the tip of the dropper (Figure 2). 3. Add sterile normal saline solution, as your doctor has directed. A general guideline for the amount of saline to add is: For children using 0.25 mL or 1.25 mg of VENTOLIN Inhalation Solution, add 2.75 mL of sterile normal saline. For children or adults using 0.5 mL or 2.5 mg of VENTOLIN Inhalation Solution, add 2.5 mL of sterile normal saline. 4. Gently swirl the nebulizer to mix the contents and connect it with the mouthpiece or face mask (Figure 3). 5. Connect the nebulizer to the compressor. 6. Sit in a comfortable, upright position; place the mouthpiece in your mouth (Figure 4) (or put on the face mask); and turn on the compressor. 7. Breathe as calmly, deeply, and evenly as possible until no more mist is formed in the nebulizer chamber (about 5 to 15 minutes). At this point, the treatment is finished. 8. Clean the nebulizer (see manufacturer's instructions). Note: Use only as directed by your doctor. More frequent administration or higher doses are not recommended. To avoid microbial contamination, proper aseptic techniques 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. The safety and effectiveness of VENTOLIN Inhalation Solution have not been determined when one or more drugs are mixed with it in a nebulizer. Check with your doctor before mixing any medications in your nebulizer. Store between 2° and 25°C (36° and 77°F).

PATIENT INFORMATION PROVENTIL® HFA(albuterol sulfate) Inhalation Aerosol FOR ORAL INHALATION ONLY Patient's Instructions for Use Figure 1 Figure 2 Before using your PROVENTIL® HFA (albuterol sulfate) Inhalation Aerosol, read complete instructions carefully. Children should use PROVENTIL HFA Inhalation Aerosol under adult supervision, as instructed by the patient's doctor Please note thatindicates that this inhalation aerosol does not contain chlorofluorocarbons (CFCs) as the propellant. SHAKE THE INHALER WELL immediately before each use. Then remove the cap from the mouthpiece (see Figure 1). Check mouthpiece for foreign objects prior to use. Make sure the canister is fully inserted into the actuator. As with all aerosol medications, it is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks. Prime by releasing four “test sprays” into the air, away from your face. 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 2) and closing the lips around it. WHILE BREATHING IN DEEPLY AND SLOWLY THROUGH THE MOUTH, FULLY DEPRESS THE TOP OF THE METAL CANISTER with your index finger (see Figure 2). HOLD YOUR BREATH AS LONG AS POSSIBLE, up to 10 seconds. Before breathing out, remove the inhaler from your mouth and release your finger from the canister. If your physician has prescribed additional puffs, wait 1 minute, shake the inhaler again, and repeat steps 3 through 5. Replace the cap after use. KEEPING THE PLASTIC MOUTHPIECE CLEAN IS EXTREMELY IMPORTANT TO PREVENT MEDICATION BUILDUP AND BLOCKAGE. THE MOUTHPIECE SHOULD BE WASHED, SHAKEN TO REMOVE EXCESS WATER, AND AIR DRIED THOROUGHLY AT LEAST ONCE A WEEK. INHALER MAY STOP SPRAYING IF NOT PROPERLY CLEANED. Routine cleaning instructions: Step 1. To clean, remove the canister and mouthpiece cap. Wash the mouthpiece through the top and bottom with warm running water for 30 seconds at least once a week (see Figure A). Never immerse the metal canister in water. Figure A Wash mouthpiece under warm running water. Figure B Allow mouthpiece to air dry, such as overnight. Figure C When blocked, little or no medicine comes out. Step 2. To dry, shake off excess water and let the mouthpiece air dry thoroughly, such as overnight (see Figure B). When the mouthpiece is dry, replace the canister and the mouthpiece cap. Blockage from medication buildup is more likely to occur if the mouthpiece is not allowed to air dry thoroughly. IF YOUR INHALER HAS BECOME BLOCKED (little or no medication coming out of the mouthpiece, see Figure C), wash the mouthpiece as described in Step 1 and air dry thoroughly as described in Step 2. IF YOU NEED TO USE YOUR INHALER BEFORE IT IS COMPLETELY DRY, SHAKE OFF EXCESS WATER, replace the canister, and test spray twice into the air, away from your face, to remove most of the water remaining in the mouthpiece. Then take your dose as prescribed. After such use, rewash and air dry thoroughly as described in Steps 1 and 2. 8. The correct amount of medication in each inhalation cannot be assured after 200 actuations, 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 specific 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 PROVENTIL HFA Inhalation Aerosol without consulting your physician. You may notice a slightly different taste or spray force than you are used to with PROVENTIL HFA Inhalation Aerosol, compared to other albuterol inhalation aerosol products. DOSAGE: Use only as directed by your physician. WARNINGS: The action of PROVENTIL® HFA Inhalation Aerosol should last up to 4 to 6 hours. PROVENTIL HFA Inhalation Aerosol should not be used more frequently than recommended. Do not increase the number of puffs or frequency of doses of PROVENTIL HFA Inhalation Aerosol without consulting your physician. If you find that treatment with PROVENTIL HFA Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking PROVENTIL HFA Inhalation Aerosol, other inhaled drugs should be taken only as directed by your physician. If you are pregnant or nursing, contact your physician about the use of PROVENTIL HFA Inhalation Aerosol. Common adverse effects of treatment with PROVENTIL HFA Inhalation Aerosol include palpitations, chest pain, rapid heart rate, tremor, or nervousness. Effective and safe use of PROVENTIL HFA Inhalation Aerosol includes an understanding of the way that it should be administered. Use PROVENTIL HFA Inhalation Aerosol only with the yellow actuator supplied with the product. The PROVENTIL HFA Inhalation Aerosol actuator should not be used with other aerosol medications. For best results, use at room temperature. Avoid exposing product to extreme heat and cold. Shake well before use. 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. Store between 15° - 25°C (59° - 77°F). Avoid spraying in eyes. Keep out of reach of children. Further Information: Your PROVENTIL® HFA (albuterol sulfate) Inhalation Aerosol does not contain chlorofluorocarbons (CFCs) as the propellant. Instead, the inhaler contains a hydrofluoroalkane (HFA-134a) as the propellant.

PATIENT INFORMATION AccuNeb® (Ack-u-neb) (albuterol sulfate) Inhalation Solution 1.25 mg*/3 mL and 0.63 mg*/3 mL (*Potency expressed as albuterol, equivalent to 1.5 mg and 0.75 mg albuterol sulfate) Read the patient information that comes with AccuNeb® (albuterol sulfate inhalation solution) before using it and each time you get a refill for your child. There may be new information. This leaflet does not take the place of talking to your child's doctor about your child's medical condition or treatment. What is AccuNeb® (albuterol sulfate inhalation solution) ? AccuNeb® (albuterol sulfate inhalation solution) is a medicine that is used for the relief of bronchospasms caused by asthma in children ages 2 to 12 years. Bronchospasm is the tightening and swelling of the muscles around the airways. AccuNeb® (albuterol sulfate inhalation solution) can help relax these airway muscles for up to 6 hours so that your child may breathe more easily. Who should not use AccuNeb® (albuterol sulfate inhalation solution) ? Do not give your child AccuNeb® (albuterol sulfate inhalation solution) if he or she is allergic to any of its ingredients. The active ingredient is albuterol sulfate. See the end of this leaflet for a complete list of ingredients. What should I tell my child's doctor before giving AccuNeb® (albuterol sulfate inhalation solution) ? Tell your child's doctor about all of your child's medical conditions including if your child has: Heart problems High blood pressure Seizures A thyroid problem called hyperthyroidism Diabetes Tell your child's doctor about all the medicines your child takes, including prescription and non-prescription medicines, vitamins and herbal supplements. AccuNeb® (albuterol sulfate inhalation solution) and some other medicines can affect each other and may cause serious side effects. Especially tell your child's doctor if your child is taking or using: Any short-acting bronchodilator medicines (sometimes called rescue inhalers) Epinephrine Medicines called monoamine oxidase inhibitors (MAOIs) or tricyclic anti-depressants or has stopped taking them in the past 2 weeks. These medicines are usually used for mental problems. Medicines called beta-blockers (used for heart problems and high blood pressure) Certain diuretic medicines (water pills) Digoxin Know the medicines your child takes. Keep a list of them and show it to your child's doctor and pharmacist each time your child gets a new medicine. How should AccuNeb® (albuterol sulfate inhalation solution) be given? Read the Patient's Instructions for Use that comes with AccuNeb® (albuterol sulfate inhalation solution) . Ask your pharmacist for these instructions if they are not with your medicine. Keep the instructions with AccuNeb® (albuterol sulfate inhalation solution) because you may want to read them again. Give AccuNeb® (albuterol sulfate inhalation solution) exactly as prescribed for your child. Do not change your child's dose or how often it is used without talking to your child's doctor first. AccuNeb® (albuterol sulfate inhalation solution) is breathed into the lungs. AccuNeb® (albuterol sulfate inhalation solution) is used with a special breathing machine called a nebulizer. Do not mix other medicines with AccuNeb® (albuterol sulfate inhalation solution) in the nebulizer. Do not use AccuNeb® (albuterol sulfate inhalation solution) that is not clear and colorless. Call your child's doctor or get emergency help right away if your child's breathing is not helped or gets worse during treatment with AccuNeb® (albuterol sulfate inhalation solution) . Call your child's doctor right away if your child needs to use AccuNeb® (albuterol sulfate inhalation solution) more often than prescribed. AccuNeb® (albuterol sulfate inhalation solution) has not been studied for treating acute attacks of bronchospasm (rescue use). Your child may need a different medicine for rescue use. If you give your child too much AccuNeb® (albuterol sulfate inhalation solution) , call your child's doctor right away. What are the side effects with AccuNeb® (albuterol sulfate inhalation solution) ? AccuNeb® (albuterol sulfate inhalation solution) may cause the following serious side effects: Worsening of the tightening and swelling of the muscles around your child's airways (bronchospasm). This side effect can be life threatening. Call your child's doctor or get emergency help right away if your child's breathing is not helped or gets worse during treatment with AccuNeb® (albuterol sulfate inhalation solution) . Serious and life threatening allergic reactions. Symptoms of a serious allergic reaction include: Hives, rash Swelling of your child's face, eyelids, lips, tongue, or throat, and trouble swallowing Worsening of your child's breathing problems such as wheezing, chest tightness or shortness of breath Shock (loss of blood pressure and consciousness). The most common side effects with AccuNeb® (albuterol sulfate inhalation solution) include a fast or irregular heartbeat, chest pain, shakiness, or nervousness. How should AccuNeb® (albuterol sulfate inhalation solution) be stored? Store AccuNeb® (albuterol sulfate inhalation solution) at room temperature, 36° to 77°F (2° to 25°C) in its tightly closed container. Protect vials from light before use. Therefore, keep unused vials in the foil pouch or carton. Once removed from the foil pouch, use vial(s) within one week. Do not use AccuNeb® (albuterol sulfate inhalation solution) after the expiration (EXP) date printed on the vial. Do not use AccuNeb® (albuterol sulfate inhalation solution) that is not clear and colorless. Safely, discard AccuNeb® (albuterol sulfate inhalation solution) that is out-of-date or no longer needed. Keep AccuNeb® (albuterol sulfate inhalation solution) and all medicines out of the reach of children. General Information about AccuNeb® (albuterol sulfate inhalation solution) Medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflets. Do not use AccuNeb® (albuterol sulfate inhalation solution) for a condition for which it was not prescribed. Do not give AccuNeb® (albuterol sulfate inhalation solution) to other people, even if they have the same symptoms your child has. It may harm them. This leaflet summarizes the most important information about AccuNeb® (albuterol sulfate inhalation solution) . If you would like more information, talk with your child's doctor. You can ask your child's doctor or pharmacist for information about AccuNeb® (albuterol sulfate inhalation solution) that is written for health professionals. You can also call the company that makes AccuNeb® (albuterol sulfate inhalation solution) toll free at 1-800-755-5560, or visit their website at www.dey.com. What are the ingredients in AccuNeb®? Active Ingredient: albuterol sulfate Inactive Ingredients:sodium chloride and sulfuric acid PATIENT'S INSTRUCTIONS FOR USE Read this patient information completely every time your prescription is filled as information may have changed.Keep these instructions with your medication,as you may want to read them again. AccuNeb (albuterol sulfate inhalation solution) should only be used under the direction of a physician. Your physician and pharmacist have more information about AccuNeb (albuterol sulfate inhalation solution) and the condition for which it has been prescribed. Contact them if you have additional questions. Storing your Medicine Store AccuNeb (albuterol sulfate inhalation solution) between 2° and 25°C (36°and 77°F).Vials should be protected from light before use, therefore, keep unused vials in the foil pouch.Do not use after the expiration (EXP) date printed on the vial. Dose AccuNeb (albuterol sulfate inhalation solution) is supplied as a single-dose, ready-to-use vial containing 3 mL of solution.No mixing or dilution is needed.Use one new vial with each nebulizer treatment. Instructions for Use 1. Remove one vial from the foil pouch.Place remaining vials back into foil pouch for storage. 2. Twist the cap completely off the vial and squeeze the contents into the nebulizer reservoir (Figure 1). Figure 1 3. Connect the nebulizer to the mouthpiece or face mask (Figure 2). Figure 2 4. Connect the nebulizer to the compressor. 5. Sit in a comfortable, upright position;place the mouthpiece in your mouth (Figure 3) or put on the face mask (Figure 4);and turn on the compressor. Figure 3 Figure 4 6. Breathe as calmly, deeply and evenly as possible through your mouth until no more mist is formed in the nebulizer chamber (about 5-15 minutes).At this point, the treatment is finished. 7. Clean the nebulizer (see manufacturer's instructions).

OVERDOSE 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 insomnia. Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of PROVENTIL® HFA Inhalation Aerosol. Treatment consists of discontinuation of PROVENTIL HFA Inhalation Aerosol 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 PROVENTIL HFA Inhalation Aerosol. The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 6800 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 1400 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 6400 times the maximum recommended daily inhalation dose for children on a mg/m² basis). The inhalation median lethal dose has not been determined in animals. CONTRAINDICATIONS PROVENTIL® HFA Inhalation Aerosol is contraindicated in patients with a history of hypersensitivity to albuterol or any other PROVENTIL HFA components.

OVERDOSE 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 (albuterol sulfate inhalation solution) . Treatment consists of discontinuation of AccuNeb (albuterol sulfate inhalation solution) 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 (albuterol sulfate inhalation solution) . 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 (albuterol sulfate inhalation solution) 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 (albuterol sulfate inhalation solution) on a mg/m² basis). The inhalation median lethal dose has not been determined in animals. CONTRAINDICATIONS AccuNeb (albuterol sulfate inhalation solution) is contraindicated in patients with a history of hypersensitivity to any of its components.

SIDE EFFECTSThe results of clinical trials with VENTOLIN Inhalation Solution in 135 patients showed the following side effects that were considered probably or possibly drug related: Percent Incidence of Adverse Reactions Percent Incidence Reaction n = 135 Central nervous system Tremors 20% Dizziness 7% Nervousness 4% Headache 3% Sleeplessness 1% Gastrointestinal Nausea 4% Dyspepsia 1% Ear, nose, and throat Nasal congestion 1% Pharyngitis

SIDE EFFECTS Adverse reaction information concerning PROVENTIL® HFA Inhalation Aerosol is derived from a 12-week, double-blind, double-dummy study which compared PROVENTIL HFA Inhalation Aerosol, a CFC 11/12 propelled albuterol inhaler, and an HFA-134a placebo inhaler in 565 asthmatic patients. The following table lists the incidence of all adverse events (whether considered by the investigator drug related or unrelated to drug) from this study which occurred at a rate of 3% or greater in the PROVENTIL HFA Inhalation Aerosol treatment group and more frequently in the PROVENTIL HFA Inhalation Aerosol treatment group than in the placebo group. Overall, the incidence and nature of the adverse reactions reported for PROVENTIL HFA Inhalation Aerosol and a CFC 11/12 propelled albuterol inhaler were comparable. Adverse Experience Incidences (% of patients) in a Large 12-week Clinical Trial* Body System/ Adverse Event (Preferred Term) PROVENTIL® HFA Inhalation Aerosol (N=193) CFC 11/12 Propelled Albuterol Inhaler (N=186) HFA-134a Placebo Inhaler (N=186) Application Site Disorders Inhalation Site Sensation 6 9 2 Inhalation Taste Sensation 4 3 3 Body as a Whole Allergic Reaction/Symptoms 6 4 < 1 Back Pain 4 2 3 Fever 6 2 5 Central and Peripheral Nervous System Tremor 7 8 2 Gastrointestinal System Nausea 10 9 5 Vomiting 7 2 3 Heart Rate and Rhythm Disorder Tachycardia 7 2 < 1 Psychiatric Disorders Nervousness 7 9 3 Respiratory System Disorders Respiratory Disorder (unspecified) 6 4 5 Rhinitis 16 22 14 Upper Resp Tract Infection 21 20 18 Urinary System Disorder Urinary Tract Infection 3 4 2 *This table includes all adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of at least 3.0% in the PROVENTIL HFA Inhalation Aerosol group and more frequently in the PROVENTIL HFA Inhalation Aerosol group than in the HFA-134a placebo inhaler group. Adverse events reported by less than 3% of the patients receiving PROVENTIL HFA Inhalation Aerosol, and by a greater proportion of PROVENTIL HFA Inhalation Aerosol patients than placebo patients, which have the potential to be related to PROVENTIL HFA Inhalation Aerosol include: dysphonia, increased sweating, dry mouth, chest pain, edema, rigors, ataxia, leg cramps, hyperkinesia, eructation, flatulence, tinnitus, diabetes mellitus, anxiety, depression, somnolence, rash. Palpitation and dizziness have also been observed with PROVENTIL HFA Inhalation Aerosol. Adverse events reported in a 4-week pediatric clinical trial comparing PROVENTIL HFA Inhalation Aerosol and a CFC 11/12 propelled albuterol inhaler occurred at a low incidence rate and were similar to those seen in the adult trials. In small, cumulative dose studies, tremor, nervousness, and headache appeared to be dose related. Rare cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema have been reported after the use of inhaled albuterol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vertigo, central nervous system stimulation, insomnia, headache, metabolic acidosis, and drying or irritation of the oropharynx. DRUG INTERACTIONS Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as PROVENTIL HFA Inhalation Aerosol, 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 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 nonpotassiumsparing diuretics. Albuterol-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 PROVENTIL HFA Inhalation Aerosol 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.

SIDE EFFECTS Clinical Trial Experience: Adverse events reported in > 1% of patients receiving AccuNeb (albuterol sulfate 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 AccuNeb (albuterol sulfate inhalation solution) and Greater than Placebo (expressed as % of treatment group) 1.25 mg AccuNeb (N=115) 0.63 mg AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) treatment group. No clinically relevant laboratory abnormalities related to AccuNeb (albuterol sulfate inhalation solution) administration were seen in this study. 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.. DRUG INTERACTIONS Other short-acting sympathomimetic aerosol bronchodilators or epinephrine should not be used concomitantly with AccuNeb (albuterol sulfate inhalation solution) . AccuNeb (albuterol sulfate 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 AccuNeb (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., 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. 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 coadministration 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.

WARNINGS Paradoxical Bronchospasm VENTOLIN Inhalation Solution can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, VENTOLIN 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 canister or 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 VENTOLIN Inhalation Solution, 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 VENTOLIN 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 T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Therefore, VENTOLIN 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 a period of hours or chronically over several days or longer. If the patient needs more doses of VENTOLIN Inhalation Solution 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 of urticaria, angioedema, rash, bronchospasm, 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. 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. PRECAUTIONSGeneral Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, hypertension, and cardiac arrhythmia; 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 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. 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 patients The action of VENTOLIN Inhalation Solution may last up to 6 hours or longer. VENTOLIN Inhalation Solution should not be used more frequently than recommended. Do not increase the dose or frequency of VENTOLIN Inhalation Solution without consulting your physician. If you find that treatment with VENTOLIN 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 VENTOLIN 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, and tremor or nervousness. If you are pregnant or nursing, contact your physician about use of VENTOLIN Inhalation Solution. Effective and safe use of VENTOLIN Inhalation Solution includes an understanding of the way that it should be administered. To avoid microbial contamination, proper aseptic techniques 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. Drug compatibility (physical and chemical), efficacy, and safety of VENTOLIN Inhalation Solution when mixed with other drugs in a nebulizer have not been established. See illustrated Patient's Instructions for Use. Carcinogenesis, Mutagenesis, 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 (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). 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 of up to 500 mg/kg (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). In a 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 a mg/m2 basis or approximately 10 times the maximum recommended daily inhalation dose for children 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 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 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 1/100, 1/10, and 1.0 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 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 80 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. Use in Labor and Delivery Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN 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 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 The safety and effectiveness of VENTOLIN Inhalation Solution have been established in children 2 years of age and older. Use of VENTOLIN Inhalation Solution in these age-groups is supported by evidence from adequate and well-controlled studies of VENTOLIN 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 VENTOLIN Inhalation Solution in children below 2 years of age have not been established.

WARNINGS Paradoxical Bronchospasm Inhaled albuterol sulfate can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROVENTIL® HFA 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. 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 PROVENTIL HFA Inhalation Aerosol 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. 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, to the therapeutic regimen. Cardiovascular Effects PROVENTIL HFA Inhalation Aerosol, like other betaadrenergic 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 after administration of PROVENTIL HFA Inhalation Aerosol 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, PROVENTIL HFA Inhalation Aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Do Not Exceed Recommended Dose Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs in patients with asthma. The exact cause of death is unknown, but cardiac arrest following an unexpected development of a severe acute asthmatic crisis and subsequent hypoxia is suspected. 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. PRECAUTIONS General Albuterol sulfate, 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 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. Information for Patients See illustrated Patient's Instructions for Use. SHAKE WELL BEFORE USING. Patients should be given the following information: It is recommended to prime the inhaler before using for the first time and in cases where the inhaler has not been used for more than 2 weeks by releasing four “test sprays” into the air, away from the face. KEEPING THE PLASTIC MOUTHPIECE CLEAN IS VERY IMPORTANT TO PREVENT MEDICATION BUILDUP AND BLOCKAGE. THE MOUTHPIECE SHOULD BE WASHED, SHAKEN TO REMOVE EXCESS WATER, AND AIR DRIED THOROUGHLY AT LEAST ONCE A WEEK. INHALER MAY CEASE TO DELIVER MEDICATION IF NOT PROPERLY CLEANED. The mouthpiece should be cleaned (with the canister removed) by running warm water through the top and bottom for 30 seconds at least once a week. The mouthpiece must be shaken to remove excess water, then air dried thoroughly (such as overnight). Blockage from medication buildup or improper medication delivery may result from failure to thoroughly air dry the mouthpiece. If the mouthpiece should become blocked (little or no medication coming out of the mouthpiece), the blockage may be removed by washing as described above. If it is necessary to use the inhaler before it is completely dry, shake off excess water, replace canister, test spray twice away from face, and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly. The action of PROVENTIL® HFA Inhalation Aerosol should last up to 4 to 6 hours. PROVENTIL HFA Inhalation Aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of doses of PROVENTIL HFA Inhalation Aerosol without consulting your physician. If you find that treatment with PROVENTIL HFA Inhalation Aerosol becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to use the product more frequently than usual, medical attention should be sought immediately. While you are taking PROVENTIL HFA Inhalation Aerosol, other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, or nervousness. If you are pregnant or nursing, contact your physician about use of PROVENTIL HFA Inhalation Aerosol. Effective and safe use of PROVENTIL HFA Inhalation Aerosol includes an understanding of the way that it should be administered. Use PROVENTIL HFA Inhalation Aerosol only with the actuator supplied with the product. Discard the canister after 200 sprays have been used. In general, the technique for administering PROVENTIL HFA Inhalation Aerosol to children is similar to that for adults. Children should use PROVENTIL HFA Inhalation Aerosol under adult supervision, as instructed by the patient's physician. (See Patient's Instructions for Use.) Carcinogenesis, Mutagenesis, And Impairment Of Fertility In a 2-year study in SPRAGUE-DAWLEY® rats, albuterol sulfate caused a dose-related increase in the incidence of benign leiomyomas of the mesovarium at the above dietary doses of 2 mg/kg (approximately 15 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 6 times 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 nonselective betaadrenergic 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 1700 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m² basis). In a 22-month study in Golden Hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses of up to 50 mg/kg (approximately 225 times the maximum recommended daily inhalation dose for adults on a mg/m² basis and approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m² basis). Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. 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 up to 50 mg/kg (approximately 340 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). Pregnancy Teratogenic Effects Pregnancy Category C Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice given albuterol sulfate 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 for adults on a mg/m² basis) and in 10 of 108 (9.3%) fetuses at 2.5 mg/kg (approximately 8 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). The drug did not induce cleft palate formation at a dose of 0.025 mg/kg (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 subcutaneously with 2.5 mg/kg of isoproterenol (positive control). A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol sulfate was administered orally at 50 mg/kg dose (approximately 680 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). In an inhalation reproduction study in SPRAGUE-DAWLEY rats, the albuterol sulfate/HFA-134a formulation did not exhibit any teratogenic effects at 10.5 mg/kg (approximately 70 times the maximum recommended daily inhalation dose for adults on a mg/m² basis). A study in which pregnant rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus. There are no adequate and well-controlled studies of PROVENTIL HFA Inhalation Aerosol or albuterol sulfate in pregnant women. PROVENTIL HFA Inhalation Aerosol 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 Because of the potential for beta-agonist interference with uterine contractility, use of PROVENTIL HFA 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 pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol. Nursing Mothers Plasma levels of albuterol sulfate and HFA-134a after inhaled therapeutic doses are very low in humans, but it is not known whether the components of PROVENTIL HFA Inhalation Aerosol are excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in animal studies and lack of experience with the use of PROVENTIL HFA Inhalation Aerosol 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. Caution should be exercised when albuterol sulfate is administered to a nursing woman. Pediatrics The safety and effectiveness of PROVENTIL HFA Inhalation Aerosol in pediatric patients below the age of 4 years have not been established. Geriatrics PROVENTIL HFA Inhalation Aerosol has not been studied in a geriatric population. As with other beta2-agonists, special caution should be observed when using PROVENTIL HFA Inhalation Aerosol in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug.

WARNINGS Paradoxical Bronchospasm As with other inhaled beta-adrenergic agonists, AccuNeb (albuterol sulfate inhalation solution) can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, AccuNeb (albuterol sulfate 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 AccuNeb (albuterol sulfate inhalation solution) than usual, this may be a marker of destabilization of asthma and requires reevaluation 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 AccuNeb (albuterol sulfate 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 AccuNeb (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 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, AccuNeb (albuterol sulfate 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. PRECAUTIONS 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 AccuNeb (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 AccuNeb (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 AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) . Effective and safe use of AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) solution, when mixed with other drugs in a nebulizer, has not been established. See illustrated Patient's Instructions for Use. 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 and above dietary doses of 2 mg/kg (approximately equivalent to the maximum recommended daily inhalation dose for AccuNeb (albuterol sulfate inhalation solution) 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 140 times the maximum recommended daily inhalation dose of AccuNeb on a mg/m² basis). In a 22-month study in Golden hamsters, albuterol sulfate showed no evidence of tumorigenicity at dietary doses up to 50 mg/kg (approximately 20 times the maximum recommended daily inhalation dose of AccuNeb on a mg/m² basis). Albuterol sulfate was not mutagenic in the Ames test or a mutation test in yeast. 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 30 times the maximum recommended daily inhalation dose of AccuNeb (albuterol sulfate inhalation solution) 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 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 AccuNeb (albuterol sulfate inhalation solution) on a mg/m² 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 AccuNeb (albuterol sulfate inhalation solution) on a mg/m² 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 AccuNeb (albuterol sulfate inhalation solution) on a mg/m² 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 AccuNeb (albuterol sulfate inhalation solution) on a mg/m² basis). A study in which pregnant rats were dosed with radiolabelled 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. 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 AccuNeb (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. 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 of AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) in these age groups is supported by evidence from adequate and well-controlled studies of AccuNeb (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 AccuNeb (albuterol sulfate inhalation solution) in children below 2 years of age have not been established.