Albuterol for Asthma

INDICATIONS AND USAGE ProAir Digihaler is a beta 2 -adrenergic agonist indicated for: Treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. ( 1.1 ) Prevention of exercise-induced bronchospasm in patients 4 years of age and older. ( 1.2 ) 1.1 Bronchospasm ProAir ® Digihaler ® is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. 1.2 Exercise-Induced Bronchospasm ProAir Digihaler is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older. 1.2 Exercise-Induced Bronchospasm ProAir Digihaler is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

DOSAGE AND ADMINISTRATION For oral inhalation only Treatment or prevention of bronchospasm in adults and children 4 years of age and older: 2 inhalations every 4 to 6 hours by oral inhalation. In some patients, 1 inhalation every 4 hours may be sufficient. ( 2.1 ) Prevention of exercise-induced bronchospasm in adults and children 4 years of age and older: 2 inhalations 15 to 30 minutes before exercise by oral inhalation. ( 2.2 ) ProAir Digihaler does not require priming. ( 2.3 ) Do not use with a spacer or volume holding chamber. ( 2.3 ) Keep the inhaler clean and dry at all times. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. Never wash or put any part of the inhaler in water. ( 2.3 ) Discard 13 months after opening the foil pouch, when the dose counter displays 0, or after the expiration date on the product, whichever comes first. ( 2.3 ) ProAir Digihaler contains a built-in electronic module which detects, records, and stores data on inhaler events for transmission to the mobile App. Use of the App is not required for administration of medication to the patient. ( 2.3 ) 2.1 Recommended Dosage for Bronchospasm The recommended dosage is 2 inhalations every 4 to 6 hours by oral inhalation. More frequent administration or a larger number of inhalations is not recommended. In some patients, 1 inhalation every 4 hours may be sufficient. 2.2 Recommended Dosage for Exercise-Induced Bronchospasm The recommended dosage is 2 inhalations 15 to 30 minutes before exercise by oral inhalation. 2.3 Administration and Maintenance Information Administer ProAir Digihaler by oral inhalation only. ProAir Digihaler inhaler does not require priming. Do not use ProAir Digihaler with a spacer or volume holding chamber. Keep the inhaler clean and dry at all times. Never wash or put any part of your inhaler in water. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. 2.4 Dose Counter ProAir Digihaler inhaler has a dose counter attached to the actuator. When the patient receives the inhaler: For the 200 dose canister, the number 200 will be displayed. For the 30 dose canister, the number 30 will be displayed. The dose counter will count down each time the inhaler is actuated. When the dose counter reaches 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Discard ProAir Digihaler 13 months after opening the foil pouch, when the dose counter displays 0 or after the expiration date on the product, whichever comes first [see Patient Counseling Information ( 17 )]. 2.5 Storage of Data on Inhaler Events ProAir Digihaler contains a built-in electronic module which detects, records, and stores data on inhaler events, including peak inspiratory flow rate (L/min), for transmission to the mobile App where inhaler events are categorized. Use of the App is not required for administration of albuterol sulfate to the patient. There is no evidence the use of the App leads to improved clinical outcomes, including safety and effectiveness [see How Supplied/Storage and Handling ( 16 )]. 2.1 Recommended Dosage for Bronchospasm The recommended dosage is 2 inhalations every 4 to 6 hours by oral inhalation. More frequent administration or a larger number of inhalations is not recommended. In some patients, 1 inhalation every 4 hours may be sufficient. 2.2 Recommended Dosage for Exercise-Induced Bronchospasm The recommended dosage is 2 inhalations 15 to 30 minutes before exercise by oral inhalation. 2.3 Administration and Maintenance Information Administer ProAir Digihaler by oral inhalation only. ProAir Digihaler inhaler does not require priming. Do not use ProAir Digihaler with a spacer or volume holding chamber. Keep the inhaler clean and dry at all times. Never wash or put any part of your inhaler in water. Routine maintenance is not required. If the mouthpiece needs cleaning, gently wipe the mouthpiece with a dry cloth or tissue as needed. 2.4 Dose Counter ProAir Digihaler inhaler has a dose counter attached to the actuator. When the patient receives the inhaler: For the 200 dose canister, the number 200 will be displayed. For the 30 dose canister, the number 30 will be displayed. The dose counter will count down each time the inhaler is actuated. When the dose counter reaches 20, the color of the numbers will change to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. When the dose counter reaches 0, the background will change to solid red. Discard ProAir Digihaler 13 months after opening the foil pouch, when the dose counter displays 0 or after the expiration date on the product, whichever comes first [see Patient Counseling Information ( 17 )]. 2.5 Storage of Data on Inhaler Events ProAir Digihaler contains a built-in electronic module which detects, records, and stores data on inhaler events, including peak inspiratory flow rate (L/min), for transmission to the mobile App where inhaler events are categorized. Use of the App is not required for administration of albuterol sulfate to the patient. There is no evidence the use of the App leads to improved clinical outcomes, including safety and effectiveness [see How Supplied/Storage and Handling ( 16 )].

WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur. Discontinue ProAir Digihaler immediately and treat with alternative therapy. ( 5.1 ) Need for more doses of ProAir Digihaler than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 ) ProAir Digihaler 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 ProAir Digihaler immediately. ( 5.6 ) Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm ProAir Digihaler can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, ProAir Digihaler should be discontinued immediately and alternative therapy instituted. 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 ProAir Digihaler, 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. 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 ProAir Digihaler, like other beta-adrenergic 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 ProAir Digihaler 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, ProAir Digihaler, like all sympathomimetic amines, should be used with caution in patients with 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 may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. ProAir Digihaler contains small amounts of lactose, which may contain trace levels of milk proteins. Hypersensitivity reactions including anaphylaxis, angioedema, pruritus, and rash have been reported with the use of therapies containing lactose (lactose is an inactive ingredient in ProAir Digihaler). The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving ProAir Digihaler. 5.7 Coexisting Conditions ProAir Digihaler, like 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. 5.8 Hypokalemia As with other beta-agonists, ProAir Digihaler 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. 5.1 Paradoxical Bronchospasm ProAir Digihaler can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, ProAir Digihaler should be discontinued immediately and alternative therapy instituted. 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 ProAir Digihaler, 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. 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 ProAir Digihaler, like other beta-adrenergic 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 ProAir Digihaler 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, ProAir Digihaler, like all sympathomimetic amines, should be used with caution in patients with 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 may occur after administration of albuterol sulfate, as demonstrated by rare cases of urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema. ProAir Digihaler contains small amounts of lactose, which may contain trace levels of milk proteins. Hypersensitivity reactions including anaphylaxis, angioedema, pruritus, and rash have been reported with the use of therapies containing lactose (lactose is an inactive ingredient in ProAir Digihaler). The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving ProAir Digihaler. 5.7 Coexisting Conditions ProAir Digihaler, like 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. 5.8 Hypokalemia A

DRUG INTERACTIONS Other short-acting sympathomimetic bronchodilators should not be used concomitantly with ProAir Digihaler. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect. ( 7 ) Beta-blockers: May decrease effectiveness of ProAir Digihaler and produce severe bronchospasm. Patients with asthma should not normally be treated with beta-blockers. ( 7.1) Diuretics, or non-potassium sparing diuretics: May potentiate hypokalemia or ECG changes. Consider monitoring potassium levels. ( 7.2 ) Digoxin: May decrease serum digoxin levels. Consider monitoring digoxin levels. ( 7.3 ) Monoamine oxidase (MAO) inhibitors and tricyclic antidepressants: May potentiate effect of albuterol on the cardiovascular system. Consider alternative therapy in patients taking MAOs or tricyclic antidepressants. ( 7.4 ) 7.1 Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as ProAir Digihaler, 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, consider cardioselective beta-blockers, although they should be administered with caution. 7.2 Diuretics The ECG changes and/or hypokalemia which 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 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 non-potassium sparing diuretics. Consider monitoring potassium levels. 7.3 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 ProAir Digihaler. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants ProAir Digihaler 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. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants. 7.1 Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as ProAir Digihaler, 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, consider cardioselective beta-blockers, although they should be administered with caution. 7.2 Diuretics The ECG changes and/or hypokalemia which 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 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 non-potassium sparing diuretics. Consider monitoring potassium levels. 7.3 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 ProAir Digihaler. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants ProAir Digihaler 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. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

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 Prasco Laboratories at 1-866-525-0688 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 HFA in 248 subjects treated with albuterol sulfate HFA 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 HFA 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 HFA 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 HFA, 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 HFA 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 HFA and more frequently in the group treated with albuterol sulfate HFA than in the HFA-134a placebo inhaler group. Table 1. Adverse Reactions with Albuterol Sulfate HFA with ≥3% Incidence and More Common than Placebo in Adult and Adolescent Subjects Adverse Reaction Percent of Subjects Albuterol Sulfate HFA (n = 202) % CFC 11/12-Propelled Albuterol Inhaler (n = 207) % Placebo HFA-134a (n = 201) % Ear, nose, and throat Throat irritation 10 6 7 Upper respiratory inflammation 5 5 2 Lower respiratory Viral respiratory infections 7 4 4 Cough 5 2 2 Musculoskeletal Musculoskeletal pain 5 5 4 Adverse reactions reported by <3% of the adult and adolescent subjects receiving albuterol sulfate HFA and by a greater proportion of subjects receiving albuterol sulfate HFA than receiving HFA-134a placebo inhaler and that have the potential to be related to albuterol sulfate HFA include diarrhea, laryngitis, oropharyngeal edema, cough, lung disorders, tachycardia, and extrasystoles. Palpitations and dizziness have also been observed with albuterol sulfate HFA. 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 HFA in subjects between birth and 4 years of age. The results of these trials did not establish the efficacy of albuterol sulfate HFA in this age group [see Use in Specific Populations ( 8.4 )] . Since the efficacy of albuterol sulfate HFA has not been demonstrated in children between birth and 48 months of age, the safety of albuterol sulfate HFA 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 HFA. 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.