Prescription Drugs

CLINICAL PHARMACOLOGYThe primary action of beta-adrenergic drugs, including albuterol, is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3´,5´-adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in beta-adrenergic cells. The cyclic AMP thus formed mediates the cellular responses. 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. 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, 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. In controlled clinical trials, albuterol has been shown 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 ECG 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. Preclinical Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations that are amounting to approximately 5.0% of the plasma concentrations. In structures outside the 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 beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown. Pharmacokinetics Albuterol is rapidly and well absorbed following oral administration. After oral administration of 10 mL of VENTOLIN Syrup (albuterol sulfate syrup) (4 mg albuterol) in normal volunteers, maximum plasma albuterol concentrations of about 18 ng/mL are achieved within 2 hours, and the drug is eliminated with a half-life of about 5 to 6 hours. In other studies, the analysis of urine samples of patients given 8 mg of tritiated albuterol orally showed that 76% of the dose was excreted over 3 days, with the majority of the dose being excreted within the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite. Feces collected over this period contained 4% of the administered dose. Clinical Trials In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximal midexpiratory flow rate (MMEF) and forced expiratory volume in 1 second (FEV1), was within 30 minutes after a dose of VENTOLIN Syrup (albuterol sulfate syrup) . Peak improvement of pulmonary function occurred between 2 and 3 hours. In a controlled clinical trial involving 55 children, clinically significant improvement (defined as maintenance of mean values over baseline of 15% or 20% or more in the FEV1 and MMEF, respectively) continued to be recorded up to 6 hours. No decrease in the effectiveness was reported in one uncontrolled study of 32 children who took VENTOLIN Syrup (albuterol sulfate syrup) for a 3-month period.

DESCRIPTION VENTOLIN Syrup (albuterol sulfate syrup) contains albuterol sulfate, USP, the racemic form of albuterol, a relatively selective beta2-adrenergic bronchodilator. Albuterol sulfate has the chemical name a1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-a,a1-diol sulfate (2:1) (salt), and the following chemical structure: 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†s recommended name for albuterol base is salbutamol. VENTOLIN Syrup (albuterol sulfate syrup) for oral administration contains 2 mg of albuterol as 2.4 mg of albuterol sulfate in each teaspoonful (5 mL). The inactive ingredients for VENTOLIN Syrup (albuterol sulfate syrup) include: citric acid, USP anhydrous; FD&C Yellow No. 6; flavor strawberry artificial F-8636; hydroxypropyl methylcellulose 2906 or 2910, USP; saccharin, NF; sodium benzoate, NF; sodium citrate, USP dihydrate; and water purified, USP. The pH of the syrup is between 3.0 and 4.5.

INDICATIONS VENTOLIN Syrup (albuterol sulfate syrup) is indicated for the relief of bronchospasm in adults and children 2 years of age and older with reversible obstructive airway disease. DOSAGE AND ADMINISTRATION The following dosages of VENTOLIN Syrup (albuterol sulfate syrup) are expressed in terms of albuterol base: Usual Dose Adults and pediatric patients over 12 years of age: The usual starting dosage for adults and children over 12 years of age is 2 mg (1 teaspoonful) or 4 mg (2 teaspoonfuls) three or four times a day. Pediatric patients 6 to 12 years of age: The usual starting dosage for children 6 to 12 years of age is 2 mg (1 teaspoonful) three or four times a day. Pediatric patients 2 to 6 years of age: Dosing in children 2 to 6 years of age should be initiated at 0.1 mg/kg of body weight three times a day. The starting dosage should not exceed 2 mg (1 teaspoonful) three times a day. Dosage Adjustment Adults and pediatric patients over 12 years of age: For adults and children over 12 years of age, a dosage above 4 mg four times a day should be used only when the patient fails to respond to this dosage. If a favorable response does not occur with the 4 mg initial dosage, it may be cautiously increased stepwise as tolerated, but not to exceed 8 mg four times a day (total daily dose should not exceed 32 mg). Pediatric patients 6 to 12 years of age who fail to respond to the initial starting dosage of 2 mg four times a day: For children 6 to 12 years of age who fail to respond to the initial starting dosage of 2 mg four times a day, the dosage may be cautiously increased stepwise as tolerated but not to exceed 6 mg four times a day (total daily dose should not exceed 24 mg). Pediatric patients 2 to 6 years of age who do not respond satisfactorily to the initial dosage: For children 2 to 6 years of age who do not respond satisfactorily to the initial starting dosage, the dosage may be increased stepwise to 0.2 mg/kg of body weight three times a day as tolerated, but not to exceed a maximum of 4 mg (2 teaspoonfuls) given three times a day (total daily dose should not exceed 12 mg). Elderly patients and those sensitive to beta-adrenergic stimulators: The initial dosage should be restricted to 2 mg three or four times a day. If adequate bronchodilation is not obtained, dosage may be increased gradually as tolerated to as much as 8 mg three or four times per day (total daily dose should not exceed 32 mg). HOW SUPPLIED VENTOLIN Syrup (albuterol sulfate syrup) , a clear orange-yellow liquid with a strawberry flavor, contains 2 mg albuterol as the sulfate per 5 mL; amber glass bottles of 16 fluid ounces (NDC 0173-0351-54). Store between 2° and 30°C (36° and 86°F). Dispense in tight, light-resistant containers as defined in the USP/NF. Manufactured for Glaxo Wellcome Inc. Research Triangle Park, NC 27709 by Schering Corporation, Kenilworth, NJ 07033 USA., Rev. 6/97, RL-788

PATIENT INFORMATION The action of VENTOLIN Syrup (albuterol sulfate syrup) may last up to 6 hours or longer. VENTOLIN Syrup (albuterol sulfate syrup) should not be taken more frequently than recommended. Do not increase the dose or frequency of doses of VENTOLIN Syrup (albuterol sulfate syrup) without consulting your physician. If you find that treatment with VENTOLIN Syrup (albuterol sulfate syrup) becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to take the product more frequently than usual, you should seek medical attention immediately. While you are taking VENTOLIN Syrup (albuterol sulfate syrup) , other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, tremor, or nervousness. If you are pregnant or nursing, contact your physician about the use of VENTOLIN Syrup (albuterol sulfate syrup) . Effective use of VENTOLIN Syrup (albuterol sulfate syrup) includes an understanding of the way that it should be administered.

SIDE EFFECTSThe adverse reactions to albuterol are similar in nature to those of other sympathomimetic agents. In clinical trials, the most frequent adverse reactions to VENTOLIN Syrup (albuterol sulfate syrup) in adults and older children were: Percent Incidence of Adverse Reactions in Adults and Children (6-12 Years of Age) Adverse Event Percent Incidence Central Nervous System Tremor 10 Nervousness 9 Shakiness 9 Headache 4 Dizziness 3 Excitement 2 Hyperactivity 2 Sleeplessness 1 Disturbed sleep Cases of urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, and extrasystoles) have been reported after the use of VENTOLIN Syrup (albuterol sulfate syrup) . In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as angina, central nervous system stimulation, drying or irritation of the oropharynx, hypertension, nausea, unusual taste, vertigo, and vomiting. The reactions are generally transient in nature, and it is usually not necessary to discontinue treatment with VENTOLIN Syrup (albuterol sulfate syrup) . In selected cases, however, dosage may be reduced temporarily; after the reaction has subsided, dosage should be increased in small increments to the optimal dosage. DRUG INTERACTIONSThe concomitant use of VENTOLIN Syrup (albuterol sulfate syrup) and other oral sympathomimetic agents is not recommended since such combined use may lead to deleterious cardiovascular effects. This recommendation does not preclude the judicious use of an aerosol bronchodilator of the adrenergic stimulant type in patients receiving VENTOLIN Syrup (albuterol sulfate syrup) . Such concomitant use, however, should be individualized and not given on a routine basis. If regular coadministration is required, then alternative therapy should be considered. Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as VENTOLIN Syrup (albuterol sulfate syrup) , but may produce severe bronchospasm in asthmatic patients. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, eg, as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. Diuretics The ECG changes and/or hypokalemia that may result from the administration of nonpotassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with nonpotassium-sparing diuretics. Digoxin Mean decreases of 16% to 22% in serum digoxin levels were demonstrated after single dose intravenous and oral administration of albuterol, respectively, to normal volunteers who had received digoxin for 10 days. The clinical significance of these findings for patients with obstructive airway disease who are receiving albuterol and digoxin on a chronic basis is unclear. Nevertheless, it would be prudent to carefully evaluate the serum digoxin levels in patients who are currently receiving digoxin and albuterol. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Albuterol should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of albuterol on the vascular system may be potentiated.

WARNINGS 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 Syrup (albuterol sulfate syrup) than usual, this may be a marker of destabilization of asthma and requires re-evaluation of the patient and the treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, eg, 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, eg, corticosteroids. Cardiovascular Effects VENTOLIN Syrup (albuterol sulfate syrup) , 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 Syrup (albuterol sulfate syrup) 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 Syrup (albuterol sulfate syrup) , like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Paradoxical Bronchospasm VENTOLIN Syrup (albuterol sulfate syrup) can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, VENTOLIN Syrup (albuterol sulfate syrup) should be discontinued immediately and alternative therapy instituted. Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of albuterol, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema,. Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the administration of oral albuterol sulfate in children. PRECAUTIONSGeneral Albuterol, as with all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension; in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus; and in patients who are unusually responsive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been seen and could be expected to occur in some patients after use of any beta-adrenergic bronchodilator. Large doses of intravenous albuterol have been reported to aggravate pre-existing diabetes 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 The action of VENTOLIN Syrup (albuterol sulfate syrup) may last up to 6 hours or longer. VENTOLIN Syrup (albuterol sulfate syrup) should not be taken more frequently than recommended. Do not increase the dose or frequency of doses of VENTOLIN Syrup (albuterol sulfate syrup) without consulting your physician. If you find that treatment with VENTOLIN Syrup (albuterol sulfate syrup) becomes less effective for symptomatic relief, your symptoms become worse, and/or you need to take the product more frequently than usual, you should seek medical attention immediately. While you are taking VENTOLIN Syrup (albuterol sulfate syrup) , other inhaled drugs and asthma medications should be taken only as directed by your physician. Common adverse effects include palpitations, chest pain, rapid heart rate, tremor, or nervousness. If you are pregnant or nursing, contact your physician about the use of VENTOLIN Syrup (albuterol sulfate syrup) . Effective use of VENTOLIN Syrup (albuterol sulfate syrup) includes an understanding of the way that it should be administered. 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 at and above dietary doses of 2 mg/kg (corresponding to less than the maximum recommended daily oral dose for adults and children on a mg/m2 basis). In another study, this effect was blocked by the coadministration of propranolol, a nonselective 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 65 times the maximum recommended daily oral dose for adults on a mg/m2 basis and approximately 50 times the maximum recommended daily oral 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 up to 50 mg/kg (approximately 8 times the maximum recommended daily oral dose for adults and children on an 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. Reproduction studies in rats demonstrated no evidence of impaired fertility at oral doses of albuterol sulfate up to 50 mg/kg (approximately 15 times the maximum recommended daily oral dose for adults on a mg/m2 basis). Teratogenic Effects Pregnancy Category C: Albuterol sulfate has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses at and above 0.25 mg/kg (corresponding to less than the maximum recommended daily oral dose for adults on an mg/m2 basis), induced cleft palate formation in 5 of 111 (4.5%) fetuses. At an sc dose of 2.5 mg/kg (corresponding to less than the maximum recommended daily oral dose for adults on an mg/m2 basis), albuterol sulfate induced cleft palate formation in 10 of 108 (9.3%) fetuses. The drug did not induce cleft palate formation when administered at an sc dose of 0.025 mg/kg (significantly less than the maximum recommended daily oral dose for adults on an mg/m2 basis). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated with 2.5 mg/kg of isoproterenol (positive control) administered subcutaneously. A reproduction study in Stride Dutch rabbits revealed cranioschisis in 7 of 19 (37%) fetuses when albuterol was administered orally at a dose of 50 mg/kg (approximately 25 times the maximum recommended daily oral dose for adults on an mg/m2 basis). Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug is transferred to the fetus. Disposition in the fetal lungs is comparable to maternal lungs, but fetal liver disposition is 1% of the maternal liver levels. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, 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. Use in Labor and Delivery Use in Labor Because of the potential for beta-agonist interference with uterine contractility, use of VENTOLIN Syrup (albuterol sulfate syrup) 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 Safety and effectiveness in children below the age of 2 years have not been established.