Albuterol

5 WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur. Discontinue albuterol sulfate inhalation aerosol immediately and institute alternative therapy. ( 5.1 ) Need for more doses of albuterol sulfate inhalation aerosol than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 ) Albuterol sulfate inhalation aerosol is not a substitute for corticosteroids. ( 5.3 ) Cardiovascular effects may occur. Use with caution in patients sensitive to sympathomimetic drugs and patients with cardiovascular or convulsive disorders. ( 5.4 , 5.7 ) Excessive use may be fatal. Do not exceed recommended dose. ( 5.5 ) Immediate hypersensitivity reactions may occur. Discontinue albuterol sulfate inhalation aerosol immediately. ( 5.6 ) Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm Albuterol sulfate inhalation aerosol can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with albuterol sulfate inhalation aerosol, it should be discontinued immediately and alternative therapy should be instituted. It should be recognized that paradoxical bronchospasm, when associated with inhaled formulations, frequently occurs with the first use of a new canister. 5.2 Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient needs more doses of albuterol sulfate inhalation aerosol 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. 5.3 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. 5.4 Cardiovascular Effects Albuterol sulfate inhalation aerosol, like all other beta 2 -adrenergic agonists, can produce clinically significant cardiovascular effects in some patients such as changes in pulse rate or blood pressure. If such effects occur, albuterol sulfate inhalation aerosol 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 relevance of these findings is unknown. Therefore, albuterol sulfate inhalation aerosol, like all other sympathomimetic amines, should be used with caution in patients with underlying cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.5 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. 5.6 Hypersensitivity Reactions, including Anaphylaxis Immediate hypersensitivity reactions (e.g., urticaria, angioedema, rash, bronchospasm, hypotension), including anaphylaxis, may occur after administration of albuterol sulfate inhalation aerosol [see Contraindications ( 4 )] . 5.7 Coexisting Conditions Albuterol sulfate inhalation aerosol, like other sympathomimetic amines, should be used with caution in patients with convulsive disorders, hyperthyroidism, or diabetes mellitus and in patients who are unusually responsive to sympathomimetic amines. Large doses of intravenous albuterol have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.8 Hypokalemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects [see Clinical Pharmacology ( 12.1 )] . The decrease in serum potassium is usually transient, not requiring supplementation.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Paradoxical bronchospasm [see Warnings and Precautions ( 5.1 )] Cardiovascular effects [see Warnings and Precautions ( 5.4 )] Hypersensitivity reactions, including anaphylaxis [see Warnings and Precautions ( 5.6 )] Hypokalemia [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥3%) are throat irritation, viral respiratory infections, upper respiratory inflammation, cough, and musculoskeletal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd. at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflects exposure to albuterol sulfate in 248 subjects treated with albuterol sulfate inhalation aerosol in 3 placebo-controlled clinical trials of 2 to 12 weeks’ duration. The data from adults and adolescents is based upon 2 clinical trials in which 202 subjects with asthma aged 12 years and older were treated with albuterol sulfate inhalation aerosol 2 inhalations 4 times daily for 12 weeks’ duration. The adult/adolescent population was 92 female, 110 male and 163 white, 19 black, 18 Hispanic, 2 other. The data from pediatric subjects are based upon 1 clinical trial in which 46 subjects with asthma aged 4 to 11 years were treated with albuterol sulfate inhalation aerosol 2 inhalations 4 times daily for 2 weeks’ duration. The population was 21 female, 25 male and 25 white, 17 black, 3 Hispanic, 1 other. Adult and Adolescent Subjects Aged 12 Years and Older The two 12-week, randomized, double-blind trials in 610 adult and adolescent subjects with asthma that compared albuterol sulfate inhalation aerosol, a CFC 11/12-propelled albuterol inhaler, and an HFA-134a placebo inhaler. Overall, the incidence and nature of the adverse reactions reported for albuterol sulfate inhalation aerosol and a CFC 11/12-propelled albuterol inhaler were comparable. Table 1 lists the incidence of all adverse reactions (whether considered by the investigator to be related or unrelated to drug) from these trials that occurred at a rate of ≥3% in the group treated with albuterol sulfate inhalation aerosol and more frequently in the group treated with albuterol sulfate inhalation aerosol than in the HFA-134a placebo inhaler group. Table 1. Adverse Reactions with Albuterol Sulfate Inhalation Aerosol with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects Adverse Reaction Percent of Subjects Albuterol Sulfate Inhalation Aerosol (n = 202) % CFC 11/12-Propelled Albuterol Inhaler (n = 207) % Placebo HFA-134a (n = 201) % Ear, nose, and throat Throat irritation Upper respiratory inflammation 10 5 6 5 7 2 Lower respiratory Viral respiratory infections Cough 7 5 4 2 4 2 Musculoskeletal Musculoskeletal pain 5 5 4 Adverse reactions reported by <3% of the adult and adolescent subjects receiving albuterol sulfate inhalation aerosol and by a greater proportion of subjects receiving albuterol sulfate inhalation aerosol than receiving HFA-134a placebo inhaler and that have the potential to be related to albuterol sulfate inhalation aerosol include diarrhea, laryngitis, oropharyngeal edema, cough, lung disorders, tachycardia, and extrasystoles. Palpitations and dizziness have also been observed with albuterol sulfate inhalation aerosol. Pediatric Subjects Aged 4 to 11 Years Results from the 2-week clinical trial in pediatric subjects with asthma aged 4 to 11 years showed that this pediatric population had an adverse reaction profile similar to that of the adult and adolescent populations. Three trials have been conducted to evaluate the safety and efficacy of albuterol sulfate inhalation aerosol in subjects between birth and 4 years of age. The results of these trials did not establish the efficacy of albuterol sulfate inhalation aerosol in this age group [see Use in Specific Populations ( 8.4 )] . Since the efficacy of albuterol sulfate inhalation aerosol has not been demonstrated in children between birth and 48 months of age, the safety of albuterol sulfate inhalation aerosol in this age group cannot be established. However, the safety profile observed in the pediatric population younger than 4 years was comparable to that observed in the older pediatric subjects and in adults and adolescents. Where adverse reaction incidence rates were greater in subjects younger than 4 years compared with older subjects, the higher incidence rates were noted in all treatment arms, including placebo. These adverse reactions included upper respiratory tract infection, nasopharyngitis, pyrexia, and tachycardia. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of albuterol sulfate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to albuterol or a combination of these factors. Cases of paradoxical bronchospasm, hoarseness, arrhythmias (including atrial fibrillation, supraventricular tachycardia), and hypersensitivity reactions (including urticaria, angioedema, rash) have been reported after the use of albuterol sulfate inhalation aerosol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypokalemia, hypertension, peripheral vasodilatation, angina, tremor, central nervous system stimulation, hyperactivity, sleeplessness, headache, muscle cramps, drying or irritation of the oropharynx, and metabolic acidosis.

<table width="100%"><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><col width="25%" align="left" valign="middle"/><thead><tr><th rowspan="2" styleCode="Botrule Lrule Rrule Toprule" align="center"><content styleCode="bold">Adverse Reaction</content></th><th colspan="3" styleCode="Botrule Rrule Toprule" align="center"><content styleCode="bold">Percent of Subjects</content></th></tr><tr><th styleCode="Botrule Lrule Rrule Toprule" valign="top" align="center"><content styleCode="bold">Albuterol Sulfate Inhalation Aerosol </content><content styleCode="bold">(n = 202) </content><content styleCode="bold">% </content></th><th styleCode="Botrule Rrule Toprule" valign="top" align="center"><content styleCode="bold">CFC 11/12-Propelled Albuterol Inhaler</content><content styleCode="bold">(n = 207) </content><content styleCode="bold">% </content></th><th styleCode="Botrule Rrule Toprule" valign="top" align="center"><content styleCode="bold">Placebo </content><content styleCode="bold">HFA-134a </content><content styleCode="bold">(n = 201) </content><content styleCode="bold">% </content></th></tr></thead><tbody><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Ear, nose, and throat </paragraph><paragraph> Throat irritation </paragraph><paragraph> Upper respiratory inflammation</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>10 </paragraph><paragraph>5 </paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>6 </paragraph><paragraph>5 </paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>7 </paragraph><paragraph>2 </paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Lower respiratory </paragraph><paragraph> Viral respiratory infections </paragraph><paragraph> Cough</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>7 </paragraph><paragraph>5 </paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>4 </paragraph><paragraph>2 </paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>4 </paragraph><paragraph>2 </paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Musculoskeletal </paragraph><paragraph> Musculoskeletal pain</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>5</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>5</paragraph></td><td styleCode="Botrule Rrule" valign="top" align="center"><paragraph> </paragraph><paragraph>4</paragraph></td></tr></tbody></table>