Prescription Drugs

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%.

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.

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

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).

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

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.