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1 INDICATIONS AND USAGE PROAIR RESPICLICK 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 RESPICLICK 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 RESPICLICK is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

2 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 RESPICLICK 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 ) 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 RESPICLICK by oral inhalation only. PROAIR RESPICLICK inhaler does not require priming. Do not use PROAIR RESPICLICK 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 The PROAIR RESPICLICK inhaler has a dose counter attached to the actuator. When the patient receives the inhaler, the number 200 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 RESPICLICK 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)].

3 DOSAGE FORMS AND STRENGTHS Inhalation powder: a multi-dose breath-actuated dry powder inhaler that delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouth piece per actuation. Each inhaler is supplied for 200 inhalations. Inhalation powder: dry powder inhaler that delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouthpiece per actuation. The inhaler is supplied for 200 inhalation doses. ( 3 )

4 CONTRAINDICATIONS PROAIR RESPICLICK is contraindicated in patients with a history of hypersensitivity to albuterol and/or severe hypersensitivity to milk proteins. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate. There have been reports of anaphylactic reactions in patients using inhalation therapies containing lactose [see Warnings and Precautions ( 5.6 )] . Patients with hypersensitivity to albuterol. ( 4 ) Patients with severe hypersensitivity to milk proteins. ( 4 )

5 WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur. Discontinue PROAIR RESPICLICK immediately and treat with alternative therapy. ( 5.1 ) Need for more doses of PROAIR RESPICLICK than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 ) PROAIR RESPICLICK 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 RESPICLICK immediately. ( 5.6 ) Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm PROAIR RESPICLICK can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, PROAIR RESPICLICK 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 RESPICLICK, 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, eg, 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 RESPICLICK, 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 RESPICLICK 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 RESPICLICK, 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 RESPICLICK 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 RESPICLICK).

aryngeal edema. PROAIR RESPICLICK 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 RESPICLICK). The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving PROAIR RESPICLICK. 5.7 Coexisting Conditions PROAIR RESPICLICK, 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 RESPICLICK 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.

6 ADVERSE REACTIONS Use of PROAIR RESPICLICK may be associated with the following: Paradoxical bronchospasm [see Warnings and Precautions ( 5.1 )] Cardiovascular Effects [see Warnings and Precautions ( 5.4 )] Immediate hypersensitivity reactions [see Warnings and Precautions ( 5.6 )] Hypokalemia [see Warnings and Precautions ( 5.8 ) Most common adverse reactions (≥1% and >placebo) are back pain, pain, gastroenteritis viral, sinus headache, urinary tract infection, nasopharyngitis, oropharyngeal pain and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Respiratory, LLC at 1-888-482-9522 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience A total of 1289 subjects were treated with PROAIR RESPICLICK during the clinical development program. The most common adverse reactions (≥1% and > placebo) were back pain, pain, gastroenteritis viral, sinus headache, and urinary tract infection. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 years of Age and Older : The adverse reaction information presented in Table 1 below concerning PROAIR RESPICLICK is derived from the 12-week blinded treatment period of three studies which compared PROAIR RESPICLICK 180 mcg four times daily with a double-blinded matched placebo in 653 asthmatic patients 12 to 76 years of age. Table 1: Adverse Reactions Experienced by Greater Than or Equal to 1.0% of Adult and Adolescent Patients in the PROAIR RESPICLICK Group and Greater Than Placebo in three 12-Week Clinical Trials 1 Preferred Term Number (%) of patients PROAIR RESPICLICK 180 mcg QID N=321 Placebo N=333 Back pain 6 (2%) 4 (1%) Pain 5 (2%) 2 (<1%) Gastroenteritis viral 4 (1%) 3 (<1%) Sinus headache 4 (1%) 3 (<1%) Urinary tract infection 4 (1%) 3 (<1%) 1. This table includes all adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of greater than or equal to 1.0% in the PROAIR RESPICLICK group and greater than placebo. In a long-term study of 168 patients treated with PROAIR RESPICLICK for up to 52 weeks (including a 12-week double-blind period), the most commonly reported adverse events greater than or equal to 5% were upper respiratory infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia. In a small cumulative dose study, tremor, palpitations, and headache were the most frequently occurring (≥5%) adverse events. Pediatric Patients 4 to 11 Years of Age : The adverse reaction information presented in Table 2 below concerning PROAIR RESPICLICK is derived from a 3‑week pediatric clinical trial which compared PROAIR RESPICLICK 180 mcg albuterol 4 times daily with a double‑blinded matched placebo in 185 asthmatic patients 4 to 11 years of age.

atients 4 to 11 Years of Age : The adverse reaction information presented in Table 2 below concerning PROAIR RESPICLICK is derived from a 3‑week pediatric clinical trial which compared PROAIR RESPICLICK 180 mcg albuterol 4 times daily with a double‑blinded matched placebo in 185 asthmatic patients 4 to 11 years of age. Table 2: Adverse Reactions Experienced by Greater Than or Equal to 2.0% of Patients 4 to 11 Years of Age in the PROAIR RESPICLICK Group and Greater Than Placebo in the 3 Week Trial Preferred Term Number (%) of patients PROAIR RESPICLICK 180 mcg QID N=93 Placebo N=92 Nasopharyngitis 2 (2%) 1 (1%) Oropharyngeal pain 2 (2%) 1 (1%) Vomiting 3 (3%) 1 (1%) 6.2 Postmarketing Experience In addition to the adverse reactions reported from clinical trials with PROAIR RESPICLICK, the following adverse events have been reported during use of other inhaled albuterol sulfate products: Urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), rare cases of aggravated bronchospasm, lack of efficacy, asthma exacerbation (potentially fatal), muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste, glossitis, tongue ulceration, and gagging. 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. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as: angina, hypertension or hypotension, palpitations, central nervous system stimulation, insomnia, headache, nervousness, tremor, muscle cramps, drying or irritation of the oropharynx, hypokalemia, hyperglycemia, and metabolic acidosis.

<table><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" rowspan="2"><content styleCode="bold">Preferred Term</content></th><th styleCode=" Botrule Toprule Rrule" colspan="2"><content styleCode="bold">Number (%) of patients</content></th></tr><tr><th align="center" styleCode=" Botrule Rrule"><content styleCode="bold">PROAIR RESPICLICK 180 mcg QID</content> <content styleCode="bold">N=321</content></th><th align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">N=333</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Back pain</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>6 (2%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>4 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Pain</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>5 (2%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>2 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Gastroenteritis viral</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>4 (1%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Sinus headache</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>4 (1%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>4 (1%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr></tbody></table>

<paragraph>3 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>4 (1%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr></tbody></table> <table><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" rowspan="2"><content styleCode="bold">Preferred Term</content></th><th styleCode=" Botrule Toprule Rrule" colspan="2"><content styleCode="bold">Number (%) of patients</content></th></tr><tr><th align="center" styleCode=" Botrule Rrule"><content styleCode="bold">PROAIR RESPICLICK 180 mcg QID</content> <content styleCode="bold">N=93</content></th><th align="center" styleCode=" Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">N=92</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Nasopharyngitis</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>2 (2%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Oropharyngeal pain</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>2 (2%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>3 (3%)</paragraph></td><td align="center" styleCode=" Botrule Rrule"><paragraph>1 (1%)</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS Other short-acting sympathomimetic bronchodilators should not be used concomitantly with PROAIR RESPICLICK. 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 RESPICLICK 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 RESPICLICK, 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, 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 RESPICLICK. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants PROAIR RESPICLICK 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are clinical considerations with use of albuterol in pregnant women [see Clinical Considerations]. In animal reproduction studies, when albuterol sulfate was administered subcutaneously to pregnant mice there was evidence of cleft palate at less than and up to 9 times the maximum recommended human daily inhalation dose (MRHDID) [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control. Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of PROAIR RESPICLICK for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. PROAIR RESPICLICK has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure nine-tenths the maximum recommended human dose (MRHDID) for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Similar effects were not observed at approximately one-eleventh the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg). 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. 8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production.

rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus. 8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, albuterol has a low oral bioavailability [see Clinical Pharmacology ( 12.3 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for albuterol and any potential adverse effects on the breastfed child from albuterol or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of PROAIR RESPICLICK for the treatment or prevention of bronchospasm with reversible obstructive airway disease have been established in pediatric patients 12 to 17 years of age. Use of PROAIR RESPICLICK for this indication is supported by evidence from two 12-week clinical trials in 318 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, one long-term safety study in children 12 years of age and older, and one single-dose crossover study comparing doses of 90 and 180 mcg with albuterol sulfate inhalation aerosol (ProAir ® HFA) in 71 patients [see Clinical Studies ( 14.1 )]. The safety and effectiveness of PROAIR RESPICLICK for treatment of exercise-induced bronchospasm have been established in children 12 years of age and older. Use of PROAIR RESPICLICK for this indication is supported by evidence from one single-dose crossover study in 38 patients age 16 and older with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies (14.2)] . The safety profile for patients ages 12 to 17 was consistent with the overall safety profile seen in these studies. The safety of PROAIR RESPICLICK in children 4 to 11 years of age is based on two single-dose, controlled, crossover studies: one with 61 patients comparing doses of 90 and 180 mcg with matched placebo and albuterol HFA MDI and one with 15 patients comparing a dose of 180 mcg with matched albuterol HFA MDI; and one 3-week clinical trial in 185 patients 4 to 11 years of age with asthma comparing a dose of 180 mcg four times daily with matched albuterol HFA MDI. The effectiveness of PROAIR RESPICLICK in children 4 to 11 years with exercise-induced bronchospasm is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of PROAIR RESPICLICK 90 mcg and 180 mcg with placebo in 61 patients with asthma, and data from a 3-week clinical trial in 185 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol 4 times daily with placebo [see Clinical Studies ( 14.1 )] . The safety and effectiveness of PROAIR RESPICLICK in pediatric patients below the age of 4 years have not been established. 8.5 Geriatric Use Clinical studies of PROAIR RESPICLICK did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions ( 5.4 , 5.7 )].

d younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions ( 5.4 , 5.7 )]. All beta 2 -adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.1 Pregnancy Risk Summary There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are clinical considerations with use of albuterol in pregnant women [see Clinical Considerations]. In animal reproduction studies, when albuterol sulfate was administered subcutaneously to pregnant mice there was evidence of cleft palate at less than and up to 9 times the maximum recommended human daily inhalation dose (MRHDID) [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control. Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of PROAIR RESPICLICK for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. PROAIR RESPICLICK has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure nine-tenths the maximum recommended human dose (MRHDID) for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Similar effects were not observed at approximately one-eleventh the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg). 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.

8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, albuterol has a low oral bioavailability [see Clinical Pharmacology ( 12.3 )]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for albuterol and any potential adverse effects on the breastfed child from albuterol or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of PROAIR RESPICLICK for the treatment or prevention of bronchospasm with reversible obstructive airway disease have been established in pediatric patients 12 to 17 years of age. Use of PROAIR RESPICLICK for this indication is supported by evidence from two 12-week clinical trials in 318 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, one long-term safety study in children 12 years of age and older, and one single-dose crossover study comparing doses of 90 and 180 mcg with albuterol sulfate inhalation aerosol (ProAir ® HFA) in 71 patients [see Clinical Studies ( 14.1 )]. The safety and effectiveness of PROAIR RESPICLICK for treatment of exercise-induced bronchospasm have been established in children 12 years of age and older. Use of PROAIR RESPICLICK for this indication is supported by evidence from one single-dose crossover study in 38 patients age 16 and older with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies (14.2)] . The safety profile for patients ages 12 to 17 was consistent with the overall safety profile seen in these studies. The safety of PROAIR RESPICLICK in children 4 to 11 years of age is based on two single-dose, controlled, crossover studies: one with 61 patients comparing doses of 90 and 180 mcg with matched placebo and albuterol HFA MDI and one with 15 patients comparing a dose of 180 mcg with matched albuterol HFA MDI; and one 3-week clinical trial in 185 patients 4 to 11 years of age with asthma comparing a dose of 180 mcg four times daily with matched albuterol HFA MDI. The effectiveness of PROAIR RESPICLICK in children 4 to 11 years with exercise-induced bronchospasm is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of PROAIR RESPICLICK 90 mcg and 180 mcg with placebo in 61 patients with asthma, and data from a 3-week clinical trial in 185 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol 4 times daily with placebo [see Clinical Studies ( 14.1 )] . The safety and effectiveness of PROAIR RESPICLICK in pediatric patients below the age of 4 years have not been established.

8.5 Geriatric Use Clinical studies of PROAIR RESPICLICK did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions ( 5.4 , 5.7 )]. All beta 2 -adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE 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, eg, 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 PROAIR RESPICLICK. Treatment consists of discontinuation of PROAIR RESPICLICK 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 PROAIR RESPICLICK.

11 DESCRIPTION The active ingredient of PROAIR RESPICLICK inhalation powder is albuterol sulfate, a racemic salt of albuterol. Albuterol sulfate is a beta 2 -adrenergic agonist. It has the chemical name α 1 -[( tert -butylamino) methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1) (salt), and the following chemical structure: The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 . Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official U.S. Adopted Name in the United States, and salbutamol sulfate is the recommended World Health Organization international nonproprietary name. PROAIR RESPICLICK is an inhalation-driven, multi-dose inhalation powder (dry powder inhaler) for oral inhalation only. It contains a formulation blend of albuterol sulfate with alpha-lactose monohydrate. Each actuation provides a metered dose of 2.6 mg of the formulation containing 117 mcg of albuterol sulfate (equivalent to 97 mcg of albuterol base) and lactose from the device reservoir. Under standardized in vitro test conditions with fixed flow rates ranging from 58 to 71 L/min, and with a total air volume of 2 L, the PROAIR RESPICLICK inhaler delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) with lactose from the mouthpiece. The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. In a study that investigated the peak inspiratory flow rate (PIFR) in asthma (n=27, ages 12 to 17 years old and n=50, ages 18 to 45 years old) and COPD (n=50, over 50 years old) patients, the mean PIFR achieved by subjects was >60 L/min (range = 31 to 110 L/min.), indicating that patients would be able to achieve the required inspiratory flow to operate the MDPI device correctly. The inhaler is provided for 200 actuations (inhalations). structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors 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 is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle 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. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 )] . 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. However, 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 [ see Warnings and Precautions ( 5.4 )]. 12.2 Pharmacodynamics In a pharmacodynamic (PD) trial conducted in 47 patients, the PD and safety profiles were similar for PROAIR RESPICLICK and ProAir HFA. Comparable changes from baseline in the PD measures (serum glucose and potassium concentrations, QTcB, QTcF, heart rate, systolic blood pressure, and diastolic blood pressure) were observed following cumulative dose administration up to 1440 mcg of both PROAIR RESPICLICK and ProAir HFA. The overall safety, efficacy and PD profile of PROAIR RESPICLICK and ProAir HFA were comparable. Following 90 or 180 mcg single-dose inhalation, the bronchodilatory effect of PROAIR RESPICLICK was significantly greater than placebo and comparable to that of ProAir HFA in patients 12 years of age and older (N=71) and pediatric patients 4 to 11 years of age (N=61) with persistent asthma. Cardiac Electrophysiology As with other beta 2 -adrenergic agonists, PROAIR RESPICLICK prolonged QT intervals following a 1440 mcg cumulative dose. The prolongation was comparable to that of ProAir HFA. 12.3 Pharmacokinetics Absorption Albuterol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hour following single- or multiple-dose oral inhalation(s) of PROAIR RESPICLICK. In a cumulative dose study, the AUC 0-t was comparable between PROAIR RESPICLICK group and ProAir HFA group; C max value was approximately one-third higher in PROAIR RESPICLICK group than ProAir HFA group. Distribution The volume of distribution has not been determined for PROAIR RESPICLICK.

on(s) of PROAIR RESPICLICK. In a cumulative dose study, the AUC 0-t was comparable between PROAIR RESPICLICK group and ProAir HFA group; C max value was approximately one-third higher in PROAIR RESPICLICK group than ProAir HFA group. Distribution The volume of distribution has not been determined for PROAIR RESPICLICK. Published literature suggests that albuterol exhibits low in vitro plasma protein binding (10%). Elimination The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-life was approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-dose administration. Metabolism Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. Excretion The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Specific Populations No pharmacokinetic studies for PROAIR RESPICLICK have been conducted in neonates or elderly subjects. The systemic exposure in children 6 to 11 years of age is similar to that of adults following 180 mcg single dose inhalation of PROAIR RESPICLICK. The influence of gender or race on the pharmacokinetics of PROAIR RESPICLICK has not been studied. Patients with Renal Impairment : The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of PROAIR RESPICLICK to patients with renal impairment [see Use in Specific Populations ( 8.5 )] . Patients with Hepatic Impairment : The effect of hepatic impairment on the pharmacokinetics of PROAIR RESPICLICK has not been evaluated. Drug Interaction Studies : In vitro and in vivo drug interaction studies have not been conducted with PROAIR RESPICLICK. Known clinically significant drug interactions are outlined in Drug Interactions ( 7 ).

12.1 Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors 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 is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle 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. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 )] . 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. However, 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 [ see Warnings and Precautions ( 5.4 )].

12.2 Pharmacodynamics In a pharmacodynamic (PD) trial conducted in 47 patients, the PD and safety profiles were similar for PROAIR RESPICLICK and ProAir HFA. Comparable changes from baseline in the PD measures (serum glucose and potassium concentrations, QTcB, QTcF, heart rate, systolic blood pressure, and diastolic blood pressure) were observed following cumulative dose administration up to 1440 mcg of both PROAIR RESPICLICK and ProAir HFA. The overall safety, efficacy and PD profile of PROAIR RESPICLICK and ProAir HFA were comparable. Following 90 or 180 mcg single-dose inhalation, the bronchodilatory effect of PROAIR RESPICLICK was significantly greater than placebo and comparable to that of ProAir HFA in patients 12 years of age and older (N=71) and pediatric patients 4 to 11 years of age (N=61) with persistent asthma. Cardiac Electrophysiology As with other beta 2 -adrenergic agonists, PROAIR RESPICLICK prolonged QT intervals following a 1440 mcg cumulative dose. The prolongation was comparable to that of ProAir HFA.

12.3 Pharmacokinetics Absorption Albuterol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hour following single- or multiple-dose oral inhalation(s) of PROAIR RESPICLICK. In a cumulative dose study, the AUC 0-t was comparable between PROAIR RESPICLICK group and ProAir HFA group; C max value was approximately one-third higher in PROAIR RESPICLICK group than ProAir HFA group. Distribution The volume of distribution has not been determined for PROAIR RESPICLICK. Published literature suggests that albuterol exhibits low in vitro plasma protein binding (10%). Elimination The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-life was approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-dose administration. Metabolism Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. Excretion The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Specific Populations No pharmacokinetic studies for PROAIR RESPICLICK have been conducted in neonates or elderly subjects. The systemic exposure in children 6 to 11 years of age is similar to that of adults following 180 mcg single dose inhalation of PROAIR RESPICLICK. The influence of gender or race on the pharmacokinetics of PROAIR RESPICLICK has not been studied. Patients with Renal Impairment : The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of PROAIR RESPICLICK to patients with renal impairment [see Use in Specific Populations ( 8.5 )] . Patients with Hepatic Impairment : The effect of hepatic impairment on the pharmacokinetics of PROAIR RESPICLICK has not been evaluated. Drug Interaction Studies : In vitro and in vivo drug interaction studies have not been conducted with PROAIR RESPICLICK. Known clinically significant drug interactions are outlined in Drug Interactions ( 7 ).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximum recommended daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m 2 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 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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 380 times the MRHDID for adults on a mg/m 2 basis). 13.2 Animal Toxicology and/or Pharmacology 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 β‑agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximum recommended daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m 2 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 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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 380 times the MRHDID for adults on a mg/m 2 basis).

13.2 Animal Toxicology and/or Pharmacology 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 β‑agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

14 CLINICAL STUDIES 14.1 Bronchospasm Associated with Asthma Adult and Adolescent Patients 12 Years of Age and Older In two 12-week, randomized, double-blind, placebo-controlled studies of identical design (Study 1 and Study 2), PROAIR RESPICLICK (153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. Patients were maintained on inhaled corticosteroid treatment. Serial FEV 1 measurements, shown below in Figure 1 as average of the mean changes from test-day baseline at Day 1 and Day 85, demonstrated that two inhalations of PROAIR RESPICLICK produced significantly greater improvement in FEV 1 AUC 0‑6hr over the pre-treatment value than placebo in Study 1. Consistent results were observed in Study 2. Figure 1: FEV 1 as Mean Change from Test-Day, Pre-Dose Baseline in a 12-Week Clinical Trial (Study 1) In Study 1, 44 of 78 patients treated with PROAIR RESPICLICK achieved a 15% increase in FEV 1 within 30 minutes post‑dose on Day 1. The median time to onset was 5.7 minutes, and median duration of effect as measured by a 15% increase was approximately 2 hours. Consistent results were observed in Study 2. In a double‑blind, randomized, placebo–controlled, single‑dose crossover study evaluating PROAIR RESPICLICK and ProAir HFA in 71 adult and adolescent subjects ages 12 and older with persistent asthma, PROAIR RESPICLICK had bronchodilator efficacy that was significantly greater than placebo at administered doses of 90 and 180 mcg. Pediatric Patients 4 to 11 Years of Age In a 3‑week, randomized, double‑blind, placebo-controlled trial, PROAIR RESPICLICK (92 patients) was compared to a matched placebo (92 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily. Serial FEV 1 measurements, expressed as the baseline-adjusted percent-predicted FEV 1 AUC 0‑6h over the 3‑week treatment period, demonstrated that 2 inhalations of PROAIR RESPICLICK produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo. In this study, 48 of 92 patients treated with PROAIR RESPICLICK achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1. The median time to onset was 5.9 minutes, and the median duration of effect as measured by a 15% increase was approximately 1 hour. In a placebo-controlled, single-dose, crossover study in 61 patients 4 to 11 years of age, PROAIR RESPICLICK, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo and with albuterol HFA MDI. PROAIR RESPICLICK provided similar bronchodilation when administered as one or two inhalations (baseline-adjusted percent-predicted serial FEV 1 observed over 6 hours post-dose), whereas two inhalations from albuterol HFA MDI provided significantly greater bronchodilation compared to a single inhalation. Figure 1 14.2 Exercise-Induced Bronchospasm In a randomized, single-dose, crossover study in 38 adult and adolescent patients with exercise-induced bronchospasm (EIB), two inhalations of PROAIR RESPICLICK taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as the maintenance of FEV 1 within 80% of post-dose, pre-exercise baseline values) in 97% (37 of 38) of patients as compared to 42% (16 of 38) of patients when they received placebo.

spasm (EIB), two inhalations of PROAIR RESPICLICK taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as the maintenance of FEV 1 within 80% of post-dose, pre-exercise baseline values) in 97% (37 of 38) of patients as compared to 42% (16 of 38) of patients when they received placebo. Patients who participated in these clinical trials were allowed to use concomitant steroid therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING PROAIR RESPICLICK inhalation powder is supplied as a white inhaler with a red cap, in a sealed foil pouch, one pouch per carton. Actuations Net Contents NDC 200 0.65 g 59310-580-20 Store at room temperature (between 15°C and 25°C; 59°F and 77°F). Avoid exposure to extreme heat, cold, or humidity. Keep out of reach of children. PROAIR RESPICLICK inhaler has a dose counter. Patients should never try to alter the numbers for the dose counter. Discard the inhaler 13 months after opening the foil pouch, when the counter displays 0, or after the expiration date on the product, whichever comes first. The labeled amount of medication in each actuation cannot be assured after the counter displays 0, even though the inhaler is not completely empty and will continue to operate [see Dosage and Administration (2.4), Patient Counseling Information (17)].

<table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><col width="2.55in"/><col width="2.55in"/><tbody><tr><td><paragraph><content styleCode="bold">Actuations</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Net Contents</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">NDC</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.65 g</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>59310-580-20</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Patients should be given the following information: Frequency of Use The action of PROAIR RESPICLICK should last for 4 to 6 hours. Instruct patients to not use PROAIR RESPICLICK more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of PROAIR RESPICLICK without consulting the physician. If patients find that treatment with PROAIR RESPICLICK becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual, they should seek medical attention immediately [see Warnings and Precautions (5.2)]. Caring for and Storing the Inhaler Instruct patients to not open their inhaler unless they are taking a dose. Repeated opening and closing the cover without taking medication will waste medication and may damage the inhaler. Advise patients to keep their inhaler dry and clean at all times. Never wash or put any part of the inhaler in water. Patient should replace inhaler if washed or placed in water. Routine maintenance is not required. If the mouthpiece needs cleaning, instruct patients to gently wipe the mouthpiece with a dry cloth or tissue as needed. Instruct patients to store the inhaler at room temperature and to avoid exposure to extreme heat, cold, or humidity. Instruct patients to never take the inhaler apart. Inform patients that PROAIR RESPICLICK has a dose counter. When the patient receives the inhaler, the number 200 will be displayed. The dose counter will count down each time the mouthpiece cap is opened and closed. The dose counter window displays the number of actuations left in the inhaler in units of two (eg, 200, 198, 196, etc). When the counter displays 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. Inform patients to discard PROAIR RESPICLICK when the dose counter displays 0 or after the expiration date on the product, whichever comes first [see Dosage and Administration (2.3), (2.4)]. Paradoxical Bronchospasm Inform patients that PROAIR RESPICLICK can produce paradoxical bronchospasm. Instruct patients to discontinue PROAIR RESPICLICK if paradoxical bronchospasm occurs [see Warnings and Precautions (5.1)]. Concomitant Drug Use Inform patients that, while they are taking PROAIR RESPICLICK, they should take other inhaled drugs and asthma medications only as directed by a physician [see Drug Interactions (7)]. Common Adverse Events Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, and nervousness. Pregnancy Inform patients who are pregnant or nursing that they should contact their physician about the use of PROAIR RESPICLICK [see Use in Specific Populations (8.1)]. General Information on Use Effective and safe use of PROAIR RESPICLICK includes an understanding of the way that it should be administered. Do not use a spacer or volume holding chamber with PROAIR RESPICLICK. Patients should be instructed on the proper use of the inhaler. See the FDA-approved Patient Information and Patient Instructions for Use.

ffective and safe use of PROAIR RESPICLICK includes an understanding of the way that it should be administered. Do not use a spacer or volume holding chamber with PROAIR RESPICLICK. Patients should be instructed on the proper use of the inhaler. See the FDA-approved Patient Information and Patient Instructions for Use. Discard PROAIR RESPICLICK 13 months after opening the foil pouch, when the dose counter displays 0 or after the expiration date on the product, whichever comes first. In general, the technique for administering PROAIR RESPICLICK to children is similar to that for adults. Children should use PROAIR RESPICLICK under adult supervision, as instructed by the patient’s physician. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2020, Teva Respiratory, LLC. All rights reserved. United States Patent Nos. 6701917, 6718972, 6748947, 6871646, 7540282, 8006690, 8651103, 8978966, 9216260, 9463288, 9731087 PROR-006 Rev. 09/2020 Teva logo

PATIENT INFORMATION PROAIR ® RESPICLICK ® ( prō´ār res-pē-klik) (albuterol sulfate) inhalation powder What is PROAIR RESPICLICK? PROAIR RESPICLICK is a prescription medicine used in people 4 years of age and older to: treat or prevent bronchospasm in people who have reversible obstructive airway disease prevent exercise-induced bronchospasm It is not known if PROAIR RESPICLICK is safe and effective in children under 4 years of age. Do not use PROAIR RESPICLICK if you are allergic to albuterol sulfate, lactose, milk proteins, or any of the ingredients in PROAIR RESPICLICK. See the end of this leaflet for a complete list of ingredients in PROAIR RESPICLICK. Before using PROAIR RESPICLICK, tell your doctor about all of your medical conditions, including if you: have heart problems have high blood pressure (hypertension) have convulsions (seizures) have thyroid problems have diabetes have low potassium levels in your blood are pregnant or plan to become pregnant. It is not known if PROAIR RESPICLICK will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if PROAIR RESPICLICK passes into your breast milk. Talk to your doctor about the best way to feed your baby if you are using PROAIR RESPICLICK. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. PROAIR RESPICLICK and other medicines may affect each other and cause side effects. PROAIR RESPICLICK may affect the way other medicines work, and other medicines may affect the way PROAIR RESPICLICK works. Especially tell your doctor if you take: ● other inhaled medicines or asthma medicines ● digoxin ● beta blocker medicines ● monoamine oxidase inhibitors ● diuretics ● tricyclic antidepressants Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use PROAIR RESPICLICK? For detailed instructions on how to use the inhaler, see “Instructions for Use” at the end of this Patient Information. Use PROAIR RESPICLICK exactly as your doctor tells you to use it. If your child needs to use PROAIR RESPICLICK, watch your child closely to make sure your child uses the inhaler correctly. Your doctor will show you how your child should use PROAIR RESPICLICK. Each dose of PROAIR RESPICLICK should last up to 4 hours to 6 hours. Do not increase your dose or take extra doses of PROAIR RESPICLICK without first talking to your doctor. Do not use a spacer or volume holding chamber with PROAIR RESPICLICK. PROAIR RESPICLICK does not need priming. Get medical help right away if PROAIR RESPICLICK no longer helps your symptoms. Get medical help right away if your symptoms get worse or if you need to use your inhaler more often. While you are using PROAIR RESPICLICK, do not use other inhaled rescue medicines and asthma medicines unless your doctor tells you to do so. Call your doctor if your asthma symptoms like wheezing and trouble breathing become worse over a few hours or days. Your doctor may need to give you another medicine (for example, corticosteroids) to treat your symptoms. What are the possible side effects of PROAIR RESPICLICK? PROAIR RESPICLICK may cause serious side effects, including: worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm).

few hours or days. Your doctor may need to give you another medicine (for example, corticosteroids) to treat your symptoms. What are the possible side effects of PROAIR RESPICLICK? PROAIR RESPICLICK may cause serious side effects, including: worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm). If this happens stop using PROAIR RESPICLICK and call your doctor or get emergency help right away. heart problems, including faster heart rate and higher blood pressure possible death in people with asthma who use too much PROAIR RESPICLICK allergic reactions. Call your doctor right away if you have the following symptoms of an allergic reaction: ○ itchy skin ○ rash ○ swelling beneath your skin or in your throat ○ worsening trouble breathing worsening of other medical problems in people who also use PROAIR RESPICLICK including increases in blood sugar low potassium levels in your blood The most common side effects of PROAIR RESPICLICK include: ● back pain ● fast heart rate ● pain ● shakiness ● upset stomach ● nervousness ● sinus headache ● headache ● urinary tract infection ● dizziness ● your heart feels like it is pounding or racing (palpitations) ● sore throat ● chest pain ● runny nose ● vomiting These are not all of the possible side effects of PROAIR RESPICLICK. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store PROAIR RESPICLICK? Store PROAIR RESPICLICK at room temperature between 59ºF and 77ºF (15ºC and 25ºC). Avoid exposure to extreme heat, cold, or humidity. Keep the cap on the inhaler closed during storage. Keep your PROAIR RESPICLICK inhaler dry and clean at all times. Do not wash or put any part of your PROAIR RESPICLICK inhaler in water. Replace your inhaler if washed or placed in water. Keep PROAIR RESPICLICK and all medicines out of the reach of children. General information about the safe and effective use of PROAIR RESPICLICK. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROAIR RESPICLICK for a condition for which it was not prescribed. Do not give PROAIR RESPICLICK to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about PROAIR RESPICLICK that was written for health professionals. For more information, go to www.MyProAir.com or call 1-888-482-9522. What are the ingredients in PROAIR RESPICLICK? Active ingredient: albuterol sulfate Inactive ingredients: lactose (may contain milk proteins) Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2020 Teva Respiratory, LLC. All rights reserved. PRORPL-005 This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 09/2020 Teva logo

<table cellspacing="0" cellpadding="0" border="1"><col width="1pt"/><tbody><tr><td><paragraph><content styleCode="bold">PROAIR^&#xAE; RESPICLICK^&#xAE;</content><content styleCode="bold">(</content><content styleCode="bold">pr&#x14D;&#xB4;&#x101;r res-p&#x113;-klik)</content></paragraph><paragraph><content styleCode="bold">(albuterol sulfate)</content></paragraph><paragraph><content styleCode="bold">inhalation powder</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is </content><content styleCode="bold">PROAIR RESPICLICK?</content></paragraph><paragraph>PROAIR RESPICLICK is a prescription medicine used in people 4 years of age and older to:</paragraph><list listType="unordered" styleCode="Disc"><item>treat or prevent bronchospasm in people who have reversible obstructive airway disease</item><item>prevent exercise-induced bronchospasm</item></list><paragraph>It is not known if PROAIR RESPICLICK is safe and effective in children under 4 years of age.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Do not use </content><content styleCode="bold">PROAIR RESPICLICK if you</content> are allergic to albuterol sulfate, lactose, milk proteins, or any of the ingredients in PROAIR RESPICLICK. See the end of this leaflet for a complete list of ingredients in PROAIR RESPICLICK.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Before using </content><content styleCode="bold">PROAIR RESPICLICK, tell your doctor about all of your medical conditions, including if you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have heart problems</item><item>have high blood pressure (hypertension)</item><item>have convulsions (seizures)</item><item>have thyroid problems</item><item>have diabetes</item><item>have low potassium levels in your blood</item><item>are pregnant or plan to become pregnant. It is not known if PROAIR RESPICLICK will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.</item><item>are breastfeeding or plan to breastfeed. It is not known if PROAIR RESPICLICK passes into your breast milk. Talk to your doctor about the best way to feed your baby if you are using PROAIR RESPICLICK.</item></list><paragraph><content styleCode="bold">Tell your doctor about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>PROAIR RESPICLICK and other medicines may affect each other and cause side effects. PROAIR RESPICLICK may affect the way other medicines work, and other medicines may affect the way PROAIR RESPICLICK works.</paragraph><paragraph>Especially tell your doctor if you take:</paragraph><paragraph>&#x25CF; other inhaled medicines or asthma medicines &#x25CF; digoxin</paragraph><paragraph>&#x25CF; beta blocker medicines &#x25CF; monoamine oxidase inhibitors</paragraph><paragraph>&#x25CF; diuretics &#x25CF; tricyclic antidepressants</paragraph><paragraph>Ask your doctor or pharmacist for a list of these medicines if you are not sure.</paragraph><paragraph>Know the medicines you take.

paragraph><paragraph>&#x25CF; beta blocker medicines &#x25CF; monoamine oxidase inhibitors</paragraph><paragraph>&#x25CF; diuretics &#x25CF; tricyclic antidepressants</paragraph><paragraph>Ask your doctor or pharmacist for a list of these medicines if you are not sure.</paragraph><paragraph>Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I use </content><content styleCode="bold">PROAIR RESPICLICK?</content></paragraph><list listType="unordered" styleCode="Disc"><item>For detailed instructions on how to use the inhaler, see<content styleCode="bold"> &#x201C;Instructions for Use&#x201D;</content> at the end of this Patient Information.</item><item>Use PROAIR RESPICLICK exactly as your doctor tells you to use it.</item><item>If your child needs to use PROAIR RESPICLICK, watch your child closely to make sure your child uses the inhaler correctly. Your doctor will show you how your child should use PROAIR RESPICLICK.</item><item>Each dose of PROAIR RESPICLICK should last up to 4 hours to 6 hours.</item><item><content styleCode="bold">Do not</content> increase your dose or take extra doses of PROAIR RESPICLICK without first talking to your doctor.</item><item>Do not use a spacer or volume holding chamber with PROAIR RESPICLICK. </item><item>PROAIR RESPICLICK does not need priming.</item><item>Get medical help right away if PROAIR RESPICLICK no longer helps your symptoms.</item><item>Get medical help right away if your symptoms get worse or if you need to use your inhaler more often.</item><item>While you are using PROAIR RESPICLICK, <content styleCode="bold">do not</content> use other inhaled rescue medicines and asthma medicines unless your doctor tells you to do so.</item><item>Call your doctor if your asthma symptoms like wheezing and trouble breathing become worse over a few hours or days. Your doctor may need to give you another medicine (for example, corticosteroids) to treat your symptoms.</item></list></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the possible side effects of </content><content styleCode="bold">PROAIR RESPICLICK?</content></paragraph><paragraph><content styleCode="bold">PROAIR RESPICLICK may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm). </content>If this happens stop using PROAIR RESPICLICK and call your doctor or get emergency help right away. </item><item><content styleCode="bold">heart problems, including faster heart rate and higher blood pressure</content></item><item><content styleCode="bold">possible death in people with asthma who use too much </content><content styleCode="bold">PROAIR RESPICLICK</content></item><item><content styleCode="bold">allergic reactions.

><content styleCode="bold">heart problems, including faster heart rate and higher blood pressure</content></item><item><content styleCode="bold">possible death in people with asthma who use too much </content><content styleCode="bold">PROAIR RESPICLICK</content></item><item><content styleCode="bold">allergic reactions. </content>Call your doctor right away if you have the following symptoms of an allergic reaction:</item></list><paragraph>&#x25CB; itchy skin &#x25CB; rash</paragraph><paragraph> &#x25CB; swelling beneath your skin or in your throat &#x25CB; worsening trouble breathing</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">worsening of other medical problems in people who also use </content><content styleCode="bold">PROAIR RESPICLICK including increases in blood sugar</content></item><item><content styleCode="bold">low potassium levels in your blood</content></item></list><paragraph>The most common side effects of PROAIR RESPICLICK include:</paragraph><paragraph>&#x25CF; back pain &#x25CF; fast heart rate</paragraph><paragraph>&#x25CF; pain &#x25CF; shakiness</paragraph><paragraph>&#x25CF; upset stomach &#x25CF; nervousness</paragraph><paragraph>&#x25CF; sinus headache &#x25CF; headache</paragraph><paragraph>&#x25CF; urinary tract infection &#x25CF; dizziness</paragraph><paragraph>&#x25CF; your heart feels like it is pounding or racing (palpitations) &#x25CF; sore throat</paragraph><paragraph>&#x25CF; chest pain &#x25CF; runny nose</paragraph><paragraph> &#x25CF; vomiting</paragraph><paragraph>These are not all of the possible side effects of PROAIR RESPICLICK. </paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">How should I store </content><content styleCode="bold">PROAIR RESPICLICK?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Store PROAIR RESPICLICK at room temperature between 59&#xBA;F and 77&#xBA;F (15&#xBA;C and 25&#xBA;C).</item><item>Avoid exposure to extreme heat, cold, or humidity.</item><item>Keep the cap on the inhaler closed during storage.</item><item>Keep your PROAIR RESPICLICK inhaler dry and clean at all times.</item><item><content styleCode="bold">Do not wash or put any part of your </content><content styleCode="bold">PROAIR RESPICLICK</content><content styleCode="bold"> inhaler in water. </content>Replace your inhaler if washed or placed in water.</item></list><paragraph><content styleCode="bold">Keep </content><content styleCode="bold">PROAIR RESPICLICK and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General information about the safe and effective use of </content><content styleCode="bold">PROAIR RESPICLICK.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROAIR RESPICLICK for a condition for which it was not prescribed. Do not give PROAIR RESPICLICK to other people, even if they have the same symptoms that you have.

CLICK.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROAIR RESPICLICK for a condition for which it was not prescribed. Do not give PROAIR RESPICLICK to other people, even if they have the same symptoms that you have. It may harm them.</paragraph><paragraph>You can ask your pharmacist or doctor for information about PROAIR RESPICLICK that was written for health professionals.</paragraph><paragraph>For more information, go to www.MyProAir.com or call 1-888-482-9522.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in </content><content styleCode="bold">PROAIR RESPICLICK?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> albuterol sulfate</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> lactose (may contain milk proteins)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Distributed by: </paragraph><paragraph>Teva Pharmaceuticals USA, Inc.</paragraph><paragraph>Parsippany, NJ 07054</paragraph><paragraph>&#xA9;2020 Teva Respiratory, LLC. All rights reserved.</paragraph><renderMultiMedia referencedObject="MM4"/><paragraph>PRORPL-005</paragraph></td></tr></tbody></table>

Instructions for Use PROAIR ® RESPICLICK ® (prō´ār res-pē-klik) (albuterol sulfate) inhalation powder Your PROAIR RESPICLICK Inhaler When you are ready to use PROAIR RESPICLICK for the first time, remove the PROAIR RESPICLICK inhaler from the foil pouch. There are 2 main parts of your PROAIR RESPICLICK inhaler including: the white inhaler with the mouthpiece. See Figure A. the red cap that covers the mouthpiece of the inhaler. See Figure A. There is a dose counter in the back of the inhaler with a viewing window that shows you how many doses of medicine you have left. See Figure A . Figure A Your PROAIR RESPICLICK inhaler contains 200 doses (inhalations). See Figure B . The dose counter shows the number of doses left in your inhaler. When there are 20 doses left, the dose counter will change to red, and you should refill your prescription or ask your doctor for another prescription. When the dose counter displays ‘0,’ your inhaler is empty, and you should stop using the inhaler and throw it away. See Figure B . Figure B IMPORTANT: Always close the cap after each inhalation so your inhaler will be ready for you to take your next dose . Do not open the cap unless you are ready for your next dose. You will hear a “click” sound when the cap is opened fully. If you do not hear the “click” sound the inhaler may not be activated to give you a dose of medicine. PROAIR RESPICLICK does not have an activation button or medicine canister . When you open the cap, a dose of PROAIR will be activated for delivery of the medicine. In general, the technique for administering PROAIR RESPICLICK to children is similar to that for adults. Children should use PROAIR RESPICLICK under adult supervision, as instructed by the patient’s physician. Do not use a spacer or volume holding chamber with PROAIR RESPICLICK. PROAIR RESPICLICK does not need priming. Using your PROAIR RESPICLICK inhaler: Important: Make sure the red cap is closed before you start using your inhaler. Step 1. Open Hold the inhaler upright and open the red cap fully until you feel and hear a “click”. See Figure C . Each time you open the red cap and it “clicks”, a dose of PROAIR RESPICLICK is ready to be inhaled. Figure C Remember: For the correct use of PROAIR RESPICLICK, hold the inhaler upright as you open the red cap. See Figure D . Do not hold the inhaler in any other way as you open the red cap. Do not open the red cap until you are ready to take a dose of PROAIR RESPICLICK. Figure D Step 2. Inhale Before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can. See Figure E. Do not exhale into the inhaler mouthpiece. Figure E Put the mouthpiece in your mouth and close your lips tightly around it. See Figure F. Figure F Do not block the vent above the mouthpiece with your lips or fingers. See Figure G . Figure G Breathe in quickly and deeply through your mouth, to deliver the dose of medicine to your lungs. Remove the inhaler from your mouth. Hold your breath for about 10 seconds or for as long as you comfortably can. Your PROAIR RESPICLICK inhaler delivers your dose of medicine as a very fine powder that you may or may not taste or feel. Do not take an extra dose from the inhaler even if you do not taste or feel the medicine. Step 3. Close Figure H Close the red cap firmly over the mouthpiece. See Figure H . Make sure you close the red cap after each inhalation so that the inhaler will be ready for your next dose.

that you may or may not taste or feel. Do not take an extra dose from the inhaler even if you do not taste or feel the medicine. Step 3. Close Figure H Close the red cap firmly over the mouthpiece. See Figure H . Make sure you close the red cap after each inhalation so that the inhaler will be ready for your next dose. If you need another dose close the red cap and then repeat steps 1-3. Storing your PROAIR RESPICLICK inhaler Store PROAIR RESPICLICK at room temperature between 59°F and 77°F (15°C and 25°C). Avoid exposure to extreme heat, cold, or humidity. Keep the red cap on the inhaler closed during storage. Keep your PROAIR RESPICLICK inhaler dry and clean at all times. Do not wash or put any part of your PROAIR RESPICLICK inhaler in water. Replace your inhaler if washed or placed in water. Keep your PROAIR RESPICLICK inhaler and all medicines out of the reach of children. Cleaning your PROAIR RESPICLICK inhaler Do not wash or put any part of your PROAIR RESPICLICK inhaler in water. Replace your inhaler if washed or placed in water. PROAIR RESPICLICK contains a powder and must be kept clean and dry at all times. If the mouthpiece needs cleaning, gently wipe it with a dry cloth or tissue. Replacing your PROAIR RESPICLICK inhaler The dose counter on the back of your inhaler shows how many doses you have left. Do not try to change the numbers for the dose counter. When there are 20 doses left, the dose counter color will change to red, and you should refill your prescription or ask your doctor for another prescription. When the dose counter displays ‘0’ your PROAIR RESPICLICK inhaler is empty, and you should stop using the inhaler and throw it away. Throw away your PROAIR RESPICLICK inhaler 13 months after removing it from the foil pouch for the first time, when the dose counter displays ‘0’, or after the expiration date on the package, whichever comes first. Important information Do not open the red cap unless you are taking a dose. Repeatedly opening and closing the cap without inhaling a dose will waste the medicine and may damage your inhaler. Your PROAIR RESPICLICK inhaler contains dry powder so it is important that you do not blow or breathe into it. Do not take the inhaler apart. Support If you have any questions about PROAIR RESPICLICK or how to use your inhaler, go to www.ProAir.com or call 1-888-482-9522. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2020 Teva Respiratory, LLC. All rights reserved. PRORIFU-005 Revised September 2020 Figure A Figure B Figure C IFU Figure D Figure E Figure F Figure G Figure H Steps 1-3 Teva logo

Rx only Manufactured by: ALKALOIDA Chemical Company Zrt. 4440 Tiszavasvári, Kabay János u. 29., Hungary Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Revised: 03/2023 Marketed by: GSMS, Inc. Camarillo, CA 93012 USA

DESCRIPTION Albuterol tablets contain albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta 2 -adrenergic bronchodilator. Albuterol sulfate has the chemical name α 1 -[( tert -Butylamino)methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1)(salt) and the following structural formula: Albuterol sulfate has a molecular weight of 576.71, and the molecular formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 . Albuterol sulfate is a white or practically white powder, freely soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol base is salbutamol. Each albuterol sulfate tablet, for oral administration contains 2 or 4 mg of albuterol as 2.4 or 4.8 mg of albuterol sulfate, respectively. Each tablet also contains the following inactive ingredients: anhydrous lactose, magnesium stearate, pregelatinized (corn) starch, and sodium starch glycolate. R:\Regulatory\spl\Jennifer\Albuterol\Pictures\Albuterol-01.jpg

CLINICAL PHARMACOLOGY In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicate that there is a population of beta 2 -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. 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 amounting to approximately 5% 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. Pharmacokinetics Albuterol is rapidly absorbed after oral administration of one 4 mg albuterol tablet in normal volunteers. Maximum plasma concentrations of about 18 ng/mL of albuterol are achieved within 2 hours, and the drug is eliminated with a half-life of about 5 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 maximum midexpiratory flow rate (MMEF), was within 30 minutes after a dose of albuterol tablets, with peak improvement occurring between 2 and 3 hours. In controlled clinical trials in which measurements were conducted for 6 hours, clinically significant improvement (defined as maintaining a 15% or more increase in forced expiratory volume in 1 second [FEV 1 ] and a 20% or more increase in MMEF over baseline values) was observed in 60% of patients at 4 hours and in 40% at 6 hours.

clinical trials in which measurements were conducted for 6 hours, clinically significant improvement (defined as maintaining a 15% or more increase in forced expiratory volume in 1 second [FEV 1 ] and a 20% or more increase in MMEF over baseline values) was observed in 60% of patients at 4 hours and in 40% at 6 hours. In other single-dose, controlled clinical trials, clinically significant improvement was observed in at least 40% of the patients at 8 hours. No decrease in the effectiveness of albuterol tablets was reported in patients who received long-term treatment with the drug in uncontrolled studies for periods up to 6 months.

Pharmacokinetics Albuterol is rapidly absorbed after oral administration of one 4 mg albuterol tablet in normal volunteers. Maximum plasma concentrations of about 18 ng/mL of albuterol are achieved within 2 hours, and the drug is eliminated with a half-life of about 5 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 maximum midexpiratory flow rate (MMEF), was within 30 minutes after a dose of albuterol tablets, with peak improvement occurring between 2 and 3 hours. In controlled clinical trials in which measurements were conducted for 6 hours, clinically significant improvement (defined as maintaining a 15% or more increase in forced expiratory volume in 1 second [FEV 1 ] and a 20% or more increase in MMEF over baseline values) was observed in 60% of patients at 4 hours and in 40% at 6 hours. In other single-dose, controlled clinical trials, clinically significant improvement was observed in at least 40% of the patients at 8 hours. No decrease in the effectiveness of albuterol tablets was reported in patients who received long-term treatment with the drug in uncontrolled studies for periods up to 6 months.

WARNINGS Paradoxical Bronchospasm Albuterol tablets can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs, albuterol tablets should be discontinued immediately and alternative therapy instituted. Cardiovascular Effects Albuterol tablets, 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 albuterol tablets 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, albuterol tablets, 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 albuterol tablets 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. 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. 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. Albuterol, like other beta-adrenergic agonists, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes. Rarely, erythema multiforme and Stevens-Johnson syndrome have been associated with the administration of oral albuterol sulfate in children.

PRECAUTIONS General 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 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 The action of albuterol tablets may last up to 8 hours or longer. Albuterol tablets should not be taken more frequently than recommended. Do not increase the dose or frequency of albuterol tablets without consulting your physician. If you find that treatment with albuterol tablets becomes less effective for symptomatic relief, your symptoms get worse, and/or you need to take the product more frequently than usual, you should seek medical attention immediately. While you are taking albuterol tablets, other asthma medications and inhaled drugs 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 albuterol tablets. Effective and safe use of albuterol tablets includes an understanding of the way that it should be administered. Drug Interactions The concomitant use of albuterol tablets 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 albuterol tablets. 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. 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. Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol tablets, 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 could be considered, although they should be administered with caution.

s. 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 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. 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, 10, and 50 mg/kg (approximately 1 / 2 , 3 and 15 times, respectively, the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, 2 ⁄ 5 , 2 and 10 times, respectively, the maximum recommended daily oral dose for children on a mg/m 2 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 65 times the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, approximately 50 times the maximum recommended daily oral dose for children on a mg/m 2 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 8 times the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, approximately 7 times the maximum recommended daily oral dose for children on a mg/m 2 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 15 times the maximum recommended daily oral dose for adults on a mg/m 2 basis). Pregnancy Teratogenic Effects. Pregnancy Category C Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg, (approximately 3/1000, 3/100, and 3/10 times, respectively, the maximum recommended daily oral dose for adults on a mg/m 2 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.

y in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg, (approximately 3/1000, 3/100, and 3/10 times, respectively, the maximum recommended daily oral dose for adults on a mg/m 2 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 3/10 times the maximum recommended daily oral dose for adults on a mg/m 2 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 25 times the maximum recommended daily oral dose for adults on a mg/m 2 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 albuterol tablets 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 beta 2 -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 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 6 years of age have not been established.

General 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 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 The action of albuterol tablets may last up to 8 hours or longer. Albuterol tablets should not be taken more frequently than recommended. Do not increase the dose or frequency of albuterol tablets without consulting your physician. If you find that treatment with albuterol tablets becomes less effective for symptomatic relief, your symptoms get worse, and/or you need to take the product more frequently than usual, you should seek medical attention immediately. While you are taking albuterol tablets, other asthma medications and inhaled drugs 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 albuterol tablets. Effective and safe use of albuterol tablets includes an understanding of the way that it should be administered.

Drug Interactions The concomitant use of albuterol tablets 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 albuterol tablets. 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. 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. Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol tablets, 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 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.

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, 10, and 50 mg/kg (approximately 1 / 2 , 3 and 15 times, respectively, the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, 2 ⁄ 5 , 2 and 10 times, respectively, the maximum recommended daily oral dose for children on a mg/m 2 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 65 times the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, approximately 50 times the maximum recommended daily oral dose for children on a mg/m 2 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 8 times the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, approximately 7 times the maximum recommended daily oral dose for children on a mg/m 2 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 15 times the maximum recommended daily oral dose for adults on a mg/m 2 basis).

Pregnancy Teratogenic Effects. Pregnancy Category C Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg, (approximately 3/1000, 3/100, and 3/10 times, respectively, the maximum recommended daily oral dose for adults on a mg/m 2 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 3/10 times the maximum recommended daily oral dose for adults on a mg/m 2 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 25 times the maximum recommended daily oral dose for adults on a mg/m 2 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.

Teratogenic Effects. Pregnancy Category C Albuterol has been shown to be teratogenic in mice. A study in CD-1 mice at subcutaneous (sc) doses of 0.025, 0.25, and 2.5 mg/kg, (approximately 3/1000, 3/100, and 3/10 times, respectively, the maximum recommended daily oral dose for adults on a mg/m 2 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 3/10 times the maximum recommended daily oral dose for adults on a mg/m 2 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 25 times the maximum recommended daily oral dose for adults on a mg/m 2 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 albuterol tablets for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk.

Nursing Mothers It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for albuterol in 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.

ADVERSE REACTIONS In clinical trials, the most frequent adverse reactions to albuterol tablets were: Percent Incidence of Adverse Reactions Reaction Percent Incidence Central nervous system Nervous 20% Tremor 20% Headache 7% Sleeplessness 2% Weakness 2% Dizziness 2% Drowsiness <1% Restlessness <1% Irritability <1% Cardiovascular Tachycardia 5% Palpitations 5% Chest discomfort <1% Flushing <1% Musculoskeletal Muscle cramps 3% Gastrointestinal Nausea 2% Genitourinary Difficulty in micturition <1% Rare cases of urticaria, angioedema, rash, bronchospasm, and oropharyngeal edema have been reported after the use of albuterol. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as hypertension, angina, vomiting, vertigo, central nervous system stimulation, unusual taste, and drying or irritation of the oropharynx. The reactions are generally transient in nature, and it is usually not necessary to discontinue treatment with albuterol tablets. 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.

<table ID="_RefID0ELPAE" width="60%"><caption>Percent Incidence of Adverse Reactions</caption><col width="36%"/><col width="24%"/><thead><tr><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">Reaction</content></th><th align="left" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">Percent Incidence</content></th></tr></thead><tbody><tr><td styleCode="Toprule " valign="top"><paragraph>Central nervous system</paragraph></td><td styleCode="Toprule " valign="top"/></tr><tr><td valign="top"><paragraph> Nervous</paragraph></td><td valign="top"><paragraph>20%</paragraph></td></tr><tr><td valign="top"><paragraph> Tremor</paragraph></td><td valign="top"><paragraph>20%</paragraph></td></tr><tr><td valign="top"><paragraph> Headache</paragraph></td><td valign="top"><paragraph>7%</paragraph></td></tr><tr><td valign="top"><paragraph> Sleeplessness</paragraph></td><td valign="top"><paragraph>2%</paragraph></td></tr><tr><td valign="top"><paragraph> Weakness</paragraph></td><td valign="top"><paragraph>2%</paragraph></td></tr><tr><td valign="top"><paragraph> Dizziness</paragraph></td><td valign="top"><paragraph>2%</paragraph></td></tr><tr><td valign="top"><paragraph> Drowsiness</paragraph></td><td valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td valign="top"><paragraph> Restlessness</paragraph></td><td valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td valign="top"><paragraph> Irritability</paragraph></td><td valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td valign="top"><paragraph>Cardiovascular</paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph> Tachycardia</paragraph></td><td valign="top"><paragraph>5%</paragraph></td></tr><tr><td valign="top"><paragraph> Palpitations</paragraph></td><td valign="top"><paragraph>5%</paragraph></td></tr><tr><td valign="top"><paragraph> Chest discomfort</paragraph></td><td valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td valign="top"><paragraph> Flushing</paragraph></td><td valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td valign="top"><paragraph>Musculoskeletal</paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph> Muscle cramps</paragraph></td><td valign="top"><paragraph>3%</paragraph></td></tr><tr><td valign="top"><paragraph>Gastrointestinal</paragraph></td><td valign="top"/></tr><tr><td valign="top"><paragraph> Nausea</paragraph></td><td valign="top"><paragraph>2%</paragraph></td></tr><tr><td valign="top"><paragraph>Genitourinary</paragraph></td><td valign="top"/></tr><tr><td styleCode="Botrule " valign="top"><paragraph> Difficulty in micturition</paragraph></td><td styleCode="Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr></tbody></table>

OVERDOSAGE 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/min, arrhythmias, nervousness, headache, tremor, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, and sleeplessness. Hypokalemia may also occur. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of albuterol tablets. Treatment consists of discontinuation of albuterol tablets 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 albuterol tablets. The oral median lethal dose of albuterol sulfate in mice is greater than 2000 mg/kg (approximately 250 times the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, approximately 200 times the maximum recommended daily oral dose for children on a mg/m 2 basis). In mature rats, the subcutaneous (sc) median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 110 times the maximum recommended daily oral dose for adults on a mg/m 2 basis or, approximately 90 times the maximum recommended daily oral dose for children on a mg/m 2 basis). In small young rats, the subcutaneous median lethal dose is approximately 2000 mg/kg (approximately 500 times the maximum recommended daily oral dose for adults on a mg/m 2 basis, or, approximately 400 times the maximum recommended daily oral dose for children on a mg/m 2 basis).

DOSAGE AND ADMINISTRATION The following dosages of albuterol tablets are expressed in terms of albuterol base. Usual Dosage Adults and Children Over 12 Years of Age The usual starting dosage for adults and children 12 years and older is 2 or 4 mg three or four times a day. Children 6 to 12 Years of Age The usual starting dosage for children 6 to 12 years of age is 2 mg three or four times a day. Dosage Adjustment Adults and Children Over 12 Years of Age For adults and children 12 years and older, a dosage above 4 mg four times a day should be used only when the patient fails to respond. If a favorable response does not occur with the 4 mg initial dosage, it should be cautiously increased stepwise up to a maximum of 8 mg four times a day as tolerated. Children 6 to 12 Years of Age Who Fail to Respond to the Initial Starting Dosage of 2 mg Four Times a Day For children from 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, but not to exceed 24 mg/day (given in divided doses). Elderly Patients and Those Sensitive to Beta-adrenergic Stimulators An initial dosage of 2 mg three or four times a day is recommended for elderly patients and for those with a history of unusual sensitivity to beta-adrenergic stimulators. If adequate bronchodilation is not obtained, dosage may be increased gradually to as much as 8 mg three or four times a day. The total daily dose should not exceed 32 mg in adults and children 12 years and older.

HOW SUPPLIED Albuterol tablets, USP; 2 mg of albuterol as the sulfate, are white, round, scored, debossed MP 47 Bottles of 100 NDC 51407-367-01 Albuterol tablets, USP; 4 mg of albuterol as the sulfate, are white, round, scored, debossed MP 88 Bottles of 100 NDC 51407-368-01 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature] DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

<table width="60%"><colgroup><col width="30%"/><col width="30%"/></colgroup><tbody><tr><td valign="top"><paragraph>Bottles of 100</paragraph></td><td valign="top"><paragraph>NDC 51407-367-01</paragraph></td></tr></tbody></table> <table width="60%"><colgroup><col width="30%"/><col width="30%"/></colgroup><tbody><tr><td valign="top"><paragraph>Bottles of 100</paragraph></td><td valign="top"><paragraph>NDC 51407-368-01</paragraph></td></tr></tbody></table>

1 INDICATIONS AND USAGE Albuterol sulfate inhalation aerosol 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 Albuterol sulfate inhalation aerosol 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 Albuterol sulfate inhalation aerosol is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

2 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. In some patients, one 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. ( 2.2 ) • Priming information: Prime albuterol sulfate inhalation aerosol before using for the first time, or when the inhaler has not been used for more than 2 weeks. To prime albuterol sulfate inhalation aerosol, release 3 sprays into the air away from the face. Shake well before each spray. ( 2.3 ) • Cleaning information: At least once a week, wash the actuator with warm water, shake off excess, and air dry thoroughly. ( 2.3 ) • Albuterol sulfate inhalation aerosol inhaler should be discarded when the dose indicator displays 0 or after the expiration date on the product, whichever comes first. ( 2.3 ) 2.1 Bronchospasm For treatment of acute episodes of bronchospasm or prevention of symptoms associated with bronchospasm, the usual dosage for adults and children 4 years 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. 2.2 Exercise-Induced Bronchospasm The usual dosage for adults and children 4 years of age or older is two inhalations 15 to 30 minutes before exercise. 2.3 Administration Information Administer albuterol sulfate inhalation aerosol by oral inhalation only. Shake well before each spray. To maintain proper use of this product and to prevent medication build-up and blockage, it is important to follow the cleaning directions carefully. Priming 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 three sprays into the air, away from the face. Cleaning As with all HFA-containing albuterol inhalers, to maintain proper use of this product and to prevent medication build-up and blockage, it is important to clean the plastic mouthpiece regularly. The inhaler may cease to deliver medication if the plastic actuator mouthpiece is not properly cleaned and dried. To clean: Wash the plastic mouthpiece with warm running water for 30 seconds, shake off excess water, and air dry thoroughly at least once a week . If the patient has more than one albuterol sulfate inhalation aerosol inhaler, the patient should wash each one separately to prevent attaching the wrong canister to the wrong plastic actuator. In this way, the patient can be sure to always know the correct number of remaining doses. Never attach a canister of medication from any other inhaler to the albuterol sulfate inhalation aerosol actuator and never attach the albuterol sulfate inhalation aerosol canister to an actuator from any other inhaler. If the mouthpiece becomes blocked, washing the mouthpiece will remove the blockage. If it is necessary to use the inhaler before it is completely dry, shake off excess water, replace canister, spray twice into the air away from face, and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly [see FDA-APPROVED PATIENT LABELING ( 17.9 )] . Dose Indicator Albuterol sulfate inhaler comes with a dose indicator appearing as small window above the plastic mouthpiece.

twice into the air away from face, and take the prescribed dose. After such use, the mouthpiece should be rewashed and allowed to air dry thoroughly [see FDA-APPROVED PATIENT LABELING ( 17.9 )] . Dose Indicator Albuterol sulfate inhaler comes with a dose indicator appearing as small window above the plastic mouthpiece. A new inhaler first shows "200" in the dose indicator window. The dose indicator will show the approximate number of actuations (sprays) of medicine remaining in the inhaler. As you use the inhaler, the dose indicator will typically rotate during every 5 to 7 actuations (sprays) towards the next decreasing number. When the dose indicator displays "40," where the background changes from white to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. The background color will be all red when the indicator approaches 20. The indicator will stop moving at "0". Albuterol sulfate inhaler should be discarded when the dose indicator displays "0" or after the expiration date on the product, whichever comes first.

3 DOSAGE FORMS AND STRENGTHS Albuterol sulfate inhalation aerosol is an inhalation aerosol. Albuterol sulfate inhalation aerosol is supplied as an 8.5 g/200 actuations pressurized aluminum canister with a blue plastic actuator with a dose indicator and green dust cap each in boxes of one. Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Inhalation Aerosol: Each actuation delivers 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Supplied in 8.5-g canister containing 200 actuations. ( 3 )

4 CONTRAINDICATIONS Albuterol sulfate inhalation aerosol is contraindicated in patients with a history of hypersensitivity to albuterol and any other albuterol sulfate inhalation aerosol components. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate [see WARNINGS AND PRECAUTIONS ( 5.6 )] . Hypersensitivity to albuterol and any other albuterol sulfate inhalation aerosol Components. ( 4 )

5 WARNINGS AND PRECAUTIONS • Life-threatening paradoxical bronchospasm may occur. Discontinue albuterol sulfate inhalation aerosol immediately and treat with 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 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 that may be life threatening. If paradoxical bronchospasm occurs, albuterol sulfate 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. 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 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 Albuterol sulfate inhalation aerosol, 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 albuterol sulfate 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, albuterol sulfate inhalation aerosol, 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 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.

ent of a severe acute asthmatic crisis and subsequent hypoxia is suspected. 5.6 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. The potential for hypersensitivity must be considered in the clinical evaluation of patients who experience immediate hypersensitivity reactions while receiving albuterol sulfate inhalation aerosol. 5.7 Coexisting Conditions Albuterol sulfate inhalation aerosol, 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, albuterol sulfate inhalation aerosol 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.

6 ADVERSE REACTIONS Use of albuterol sulfate may be associated with the following: • Paradoxical bronchospasm [see WARNINGS AND PRECAUTIONS ( 5.1 )] • Cardiovascular Effects [see WARNINGS AND PRECAUTIONS ( 5.4 )] • Immediate hypersensitivity reactions [see WARNINGS AND PRECAUTIONS ( 5.6 )] • Hypokalemia [see WARNINGS AND PRECAUTIONS ( 5.8 )] Most common adverse reactions (≥3.0% and >placebo) are headache, tachycardia, pain, dizziness, pharyngitis, and rhinitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience A total of 1090 subjects were treated with albuterol sulfate inhalation aerosol, or with the same formulation of albuterol as in albuterol sulfate inhalation aerosol, during the worldwide clinical development program. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult and Adolescents 12 Years of Age and Older The adverse reaction information presented in the table below concerning albuterol sulfate is derived from a 6-week, blinded study which compared albuterol sulfate inhalation aerosol (180 mcg four times daily) with a double-blinded matched placebo HFA-Inhalation Aerosol and an evaluator-blinded marketed active comparator HFA-134a albuterol inhaler in 172 asthmatic patients 12 to 76 years of age. The 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 albuterol sulfate inhalation aerosol treatment group and more frequently in the albuterol sulfate inhalation aerosol treatment group than in the matched placebo group. Overall, the incidence and nature of the adverse events reported for albuterol sulfate inhalation aerosol and the marketed active comparator HFA-134a albuterol inhaler were comparable. Adverse Experience Incidences (% of Patients) in a Six-Week Clinical Trial 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 albuterol sulfate inhalation aerosol group and more frequently in the albuterol sulfate inhalation aerosol group than in the placebo HFA Inhalation Aerosol group. Body System/ Adverse Event (as Preferred Term) Albuterol Sulfate Inhalation Aerosol (N = 58) Marketed active comparator HFA-134a albuterol inhaler (N = 56) Matched Placebo HFA-134a Inhalation Aerosol (N = 58) Body as a Whole Headache 7 5 2 Cardiovascular Tachycardia 3 2 0 Musculoskeletal Pain 3 0 0 Nervous System Dizziness 3 0 0 Respiratory System Pharyngitis Rhinitis 14 5 7 4 9 2 Adverse events reported by less than 3% of the patients receiving albuterol sulfate inhalation aerosol but by a greater proportion of albuterol sulfate inhalation aerosol patients than the matched placebo patients, which have the potential to be related to albuterol sulfate inhalation aerosol, included chest pain, infection, diarrhea, glossitis, accidental injury (nervous system), anxiety, dyspnea, ear disorder, ear pain, and urinary tract infection. In small cumulative dose studies, tremor, nervousness, and headache were the most frequently occurring adverse events.

to albuterol sulfate inhalation aerosol, included chest pain, infection, diarrhea, glossitis, accidental injury (nervous system), anxiety, dyspnea, ear disorder, ear pain, and urinary tract infection. In small cumulative dose studies, tremor, nervousness, and headache were the most frequently occurring adverse events. Pediatric Patients 4 to 11 Years of Age Adverse events reported in a 3-week pediatric clinical trial comparing the same formulation of albuterol as in albuterol sulfate inhalation aerosol (180 mcg albuterol four times daily) to a matching placebo HFA inhalation aerosol occurred at a low incidence rate (no greater than 2% in the active treatment group) and were similar to those seen in adult and adolescent trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of albuterol sulfate inhalation aerosol. 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. Reports have included rare cases of aggravated bronchospasm, lack of efficacy, asthma exacerbation (reported fatal in one case), muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste, glossitis, tongue ulceration, and gagging. The following adverse events have been observed in postapproval use of inhaled albuterol: urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles). In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as: angina, hypertension or hypotension, palpitations, central nervous system stimulation, insomnia, headache, nervousness, tremor, muscle cramps, drying or irritation of the oropharynx, hypokalemia, hyperglycemia, and metabolic acidosis.

<table ID="ID52" width="100%" styleCode="Noautorules"><caption>Adverse Experience Incidences (% of Patients) in a Six-Week Clinical Trial <footnote ID="ID52_0">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 albuterol sulfate inhalation aerosol group and more frequently in the albuterol sulfate inhalation aerosol group than in the placebo HFA Inhalation Aerosol group.</footnote></caption><col width="136"/><col width="122"/><col width="143"/><col width="156"/><col width="150"/><tbody><tr><td align="left" styleCode="Lrule Toprule Botrule Rrule" valign="top"><content styleCode="bold">Body System/ Adverse Event (as Preferred Term)</content> </td><td align="left" styleCode=" Toprule Botrule Rrule" valign="top"> </td><td align="left" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Albuterol Sulfate Inhalation Aerosol</content> <content styleCode="bold">(N = 58)</content> </td><td align="left" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Marketed active comparator HFA-134a</content> <content styleCode="bold">albuterol inhaler</content> <content styleCode="bold">(N = 56)</content> </td><td align="left" styleCode=" Toprule Botrule Rrule" valign="top"><content styleCode="bold">Matched Placebo HFA-134a</content> <content styleCode="bold">Inhalation Aerosol</content> <content styleCode="bold">(N = 58)</content> </td></tr><tr><td align="left" styleCode=" Lrule Botrule Rrule" valign="top">Body as a Whole </td><td align="left" styleCode=" Botrule Rrule" valign="top">Headache </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 </td><td align="center" styleCode=" Botrule Rrule" valign="top">5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td></tr><tr><td align="left" styleCode=" Lrule Botrule Rrule" valign="top">Cardiovascular </td><td align="left" styleCode=" Botrule Rrule" valign="top">Tachycardia </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">2 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td></tr><tr><td align="left" styleCode=" Lrule Botrule Rrule" valign="top">Musculoskeletal </td><td align="left" styleCode=" Botrule Rrule" valign="top">Pain </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nervous System </td><td align="left" styleCode=" Botrule Rrule" valign="top">Dizziness </td><td align="center" styleCode=" Botrule Rrule" valign="top">3 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td><td align="center" styleCode=" Botrule Rrule" valign="top">0 </td></tr><tr><td align="left" styleCode="Lrule Botrule Rrule" valign="top">Respiratory System </td><td align="left" styleCode=" Botrule Rrule" valign="top">Pharyngitis Rhinitis </td><td align="center" styleCode=" Botrule Rrule" valign="top">14 5 </td><td align="center" styleCode=" Botrule Rrule" valign="top">7 4 </td><td align="center" styleCode=" Botrule Rrule" valign="top">9 2 </td></tr></tbody></table>

7 DRUG INTERACTIONS Other short-acting sympathomimetic aerosol bronchodilators and adrenergic drugs: May potentiate effect. ( 7 ) Beta-blockers: May decrease effectiveness of albuterol sulfate 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 ) Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol sulfate inhalation aerosol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. 7.1 Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol sulfate 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, 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 albuterol sulfate inhalation aerosol. 7.4 Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Albuterol sulfate 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. Consider alternative therapy in patients taking MAO inhibitors or tricyclic antidepressants.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the Mothers To Baby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1-877-311-8972 or visit http://mothertobaby.org/pregnancystudies/. Risk Summary There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are clinical considerations with use of albuterol in pregnant women [see CLINICAL CONSIDERATIONS] . In animal reproduction studies, when albuterol sulfate was administered subcutaneously to pregnant mice there was evidence of cleft palate at less than and up to 9 times the maximum recommended human daily inhalation dose (MRHDID) [see DATA] . The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control. Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of albuterol sulfate inhalation aerosol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Albuterol sulfate inhalation aerosol has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol. Data Animal Data In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure nine-tenths of the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Similar effects were not observed at approximately one-eleventh the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg).

ximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg). 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. 8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, albuterol has a low oral bioavailability [see CLINICAL PHARMACOLOGY ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for albuterol and any potential adverse effects on the breastfed child from albuterol or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of albuterol sulfate inhalation aerosol are for the treatment or prevention of bronchospasm in children 12 years of age and older with reversible obstructive airway disease is based on one 6-week clinical trial in 116 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, and one single-dose crossover study comparing doses of 90, 180, and 270 mcg with placebo in 58 patients [see CLINICAL STUDIES ( 14.1 )] . The safety and effectiveness of albuterol sulfate inhalation aerosol for treatment of exercise-induced bronchospasm in children 12 years of age and older is based on one single-dose crossover study in 24 adults and adolescents with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see CLINICAL STUDIES ( 14.2 )]. The safety of albuterol sulfate inhalation aerosol are in children 4 to 11 years of age is based on one 3-week clinical trial in 50 patients 4 to 11 years of age with asthma using the same formulation of albuterol as in albuterol sulfate inhalation aerosol are comparing doses of 180 mcg four times daily with placebo. The effectiveness of albuterol sulfate inhalation aerosol are in children 4 to 11 years of age is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of albuterol sulfate 90 mcg and 180 mcg with placebo in 55 patients with asthma and a 3-week clinical trial using the same formulation of albuterol as in albuterol sulfate inhalation aerosol are in 95 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol four times daily with placebo [see CLINICAL STUDIES ( 14.1 )]. The safety and effectiveness of albuterol sulfate inhalation aerosol are in pediatric patients below the age of 4 years have not been established. 8.5 Geriatric Use Clinical studies of albuterol sulfate inhalation aerosol did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see WARNINGS AND PRECAUTIONS ( 5.4 , 5.7 )] .

younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see WARNINGS AND PRECAUTIONS ( 5.4 , 5.7 )] . All beta 2 -adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the Mothers To Baby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1-877-311-8972 or visit http://mothertobaby.org/pregnancystudies/. Risk Summary There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are clinical considerations with use of albuterol in pregnant women [see CLINICAL CONSIDERATIONS] . In animal reproduction studies, when albuterol sulfate was administered subcutaneously to pregnant mice there was evidence of cleft palate at less than and up to 9 times the maximum recommended human daily inhalation dose (MRHDID) [see DATA] . The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control. Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of albuterol sulfate inhalation aerosol for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Albuterol sulfate inhalation aerosol has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta2-agonists, including albuterol. Data Animal Data In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure nine-tenths of the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Similar effects were not observed at approximately one-eleventh the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg). 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.

on did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg). 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. 17.7 Pregnancy Patients who are pregnant or nursing should contact their physician about the use of albuterol sulfate inhalation aerosol. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy [see USE IN SPECIFIC POPULATIONS ( 8.1 )] .

8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, albuterol has a low oral bioavailability [see CLINICAL PHARMACOLOGY ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for albuterol and any potential adverse effects on the breastfed child from albuterol or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of albuterol sulfate inhalation aerosol are for the treatment or prevention of bronchospasm in children 12 years of age and older with reversible obstructive airway disease is based on one 6-week clinical trial in 116 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, and one single-dose crossover study comparing doses of 90, 180, and 270 mcg with placebo in 58 patients [see CLINICAL STUDIES ( 14.1 )] . The safety and effectiveness of albuterol sulfate inhalation aerosol for treatment of exercise-induced bronchospasm in children 12 years of age and older is based on one single-dose crossover study in 24 adults and adolescents with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see CLINICAL STUDIES ( 14.2 )]. The safety of albuterol sulfate inhalation aerosol are in children 4 to 11 years of age is based on one 3-week clinical trial in 50 patients 4 to 11 years of age with asthma using the same formulation of albuterol as in albuterol sulfate inhalation aerosol are comparing doses of 180 mcg four times daily with placebo. The effectiveness of albuterol sulfate inhalation aerosol are in children 4 to 11 years of age is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of albuterol sulfate 90 mcg and 180 mcg with placebo in 55 patients with asthma and a 3-week clinical trial using the same formulation of albuterol as in albuterol sulfate inhalation aerosol are in 95 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol four times daily with placebo [see CLINICAL STUDIES ( 14.1 )]. The safety and effectiveness of albuterol sulfate inhalation aerosol are in pediatric patients below the age of 4 years have not been established.

8.5 Geriatric Use Clinical studies of albuterol sulfate inhalation aerosol did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see WARNINGS AND PRECAUTIONS ( 5.4 , 5.7 )] . All beta 2 -adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE 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 albuterol sulfate inhalation aerosol. Treatment consists of discontinuation of albuterol sulfate 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 albuterol sulfate inhalation aerosol. The oral median lethal dose of albuterol sulfate in mice is greater than 2,000 mg/kg (approximately 6,800 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis and approximately 3,200 times the maximum recommended daily inhalation dose for children on a mg/m 2 basis). In mature rats, the subcutaneous median lethal dose of albuterol sulfate is approximately 450 mg/kg (approximately 3,000 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis and approximately 1,400 times the maximum recommended daily inhalation dose for children on a mg/m 2 basis). In young rats, the subcutaneous median lethal dose is approximately 2,000 mg/kg (approximately 14,000 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis and approximately 6,400 times the maximum recommended daily inhalation dose for children on a mg/m 2 basis). The inhalation median lethal dose has not been determined in animals.

11 DESCRIPTION The active ingredient of albuterol sulfate inhalation aerosol is albuterol sulfate, a racemic salt, of albuterol. Albuterol sulfate has the chemical name α 1 -[( tert -butylamino) methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1) (salt), and has the following chemical structure: The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C 13 H 21 NO 3 ) 2 • H 2 SO 4 . Albuterol sulfate is a white or almost white crystalline powder. It is freely soluble in water and very slightly soluble in ethanol. Albuterol sulfate is the official generic name in the United States, and salbutamol sulfate is the World Health Organization recommended generic name. Albuterol sulfate inhalation aerosol is a pressurized metered-dose aerosol unit with a dose indicator. Albuterol sulfate inhalation aerosol is for oral inhalation only. It contains a microcrystalline suspension of albuterol sulfate in propellant HFA-134a (1, 1, 1, 2-tetrafluoroethane) and ethanol. 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 three sprays into the air, away from the face. After priming, each actuation delivers 108 mcg albuterol sulfate, from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). Each canister provides 200 actuations (inhalations). This product does not contain chlorofluorocarbons (CFCs) as the propellant. Albuterol sulfate

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors 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 is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle 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. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see WARNINGS AND PRECAUTIONS ( 5.4 )] . 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. However, 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 [see WARNINGS AND PRECAUTIONS ( 5.4 )] . 12.2 Pharmacokinetics The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of albuterol sulfate inhalation aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (C max ) and systemic exposure (AUC inf ) of approximately 4,100 pg/mL and 28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, respectively following the same dose of an active HFA-134a albuterol inhaler comparator. The terminal plasma half-life of albuterol delivered by albuterol sulfate inhalation aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products. The pharmacokinetic profile of albuterol sulfate inhalation aerosol was evaluated in a two-way cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age. A single dose administration of albuterol sulfate (180 mcg albuterol base) yielded a least square mean (SE) C max and AUC 0 to ∞ of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The least square mean (SE) terminal plasma half-life of albuterol delivered by albuterol sulfate was 166 (7.8) minutes. Metabolism and Elimination Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase).

vely. The least square mean (SE) terminal plasma half-life of albuterol delivered by albuterol sulfate was 166 (7.8) minutes. Metabolism and Elimination Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)- albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Geriatric, Pediatric, Hepatic/Renal Impairment No pharmacokinetic studies for albuterol sulfate inhalation aerosol have been conducted in neonates or elderly subjects. The effect of hepatic impairment on the pharmacokinetics of albuterol sulfate inhalation aerosol has not been evaluated. The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of albuterol sulfate inhalation aerosol to patients with renal impairment [see USE IN SPECIFIC POPULATIONS ( 8.5 )] .

12.1 Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors 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 is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle 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. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see WARNINGS AND PRECAUTIONS ( 5.4 )] . 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. However, 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 [see WARNINGS AND PRECAUTIONS ( 5.4 )] .

12.2 Pharmacokinetics The systemic levels of albuterol are low after inhalation of recommended doses. In a crossover study conducted in healthy male and female volunteers, high cumulative doses of albuterol sulfate inhalation aerosol (1,080 mcg of albuterol base administered over one hour) yielded mean peak plasma concentrations (C max ) and systemic exposure (AUC inf ) of approximately 4,100 pg/mL and 28,426 pg/mL*hr, respectively compared to approximately 3,900 pg/mL and 28,395 pg/mL*hr, respectively following the same dose of an active HFA-134a albuterol inhaler comparator. The terminal plasma half-life of albuterol delivered by albuterol sulfate inhalation aerosol was approximately 6 hours. Comparison of the pharmacokinetic parameters demonstrated no differences between the products. The pharmacokinetic profile of albuterol sulfate inhalation aerosol was evaluated in a two-way cross-over study in 11 healthy pediatric volunteers, 4 to 11 years of age. A single dose administration of albuterol sulfate (180 mcg albuterol base) yielded a least square mean (SE) C max and AUC 0 to ∞ of 1,100 (1.18) pg/mL and 5,120 (1.15) pg/mL*hr, respectively. The least square mean (SE) terminal plasma half-life of albuterol delivered by albuterol sulfate was 166 (7.8) minutes. Metabolism and Elimination Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)- albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Geriatric, Pediatric, Hepatic/Renal Impairment No pharmacokinetic studies for albuterol sulfate inhalation aerosol have been conducted in neonates or elderly subjects. The effect of hepatic impairment on the pharmacokinetics of albuterol sulfate inhalation aerosol has not been evaluated. The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of albuterol sulfate inhalation aerosol to patients with renal impairment [see USE IN SPECIFIC POPULATIONS ( 8.5 )] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximum recommended human daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m 2 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 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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 380 times the MRHDID for adults on a mg/m 2 basis). 13.2 Animal Toxicology and/or Pharmacology 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 β-agonists 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 to 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 (T max ) and mean residence time are both extremely short leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

14 CLINICAL STUDIES 14.1 Bronchospasm Associated with Asthma Adult and Adolescent Patients 12 Years of Age and Older In a 6-week, randomized, double-blind, placebo-controlled trial, albuterol sulfate (58 patients) was compared to a matched placebo HFA inhalation aerosol (58 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. An evaluator-blind marketed active comparator HFA-134a albuterol inhaler arm (56 patients) was included. Serial FEV 1 measurements, shown below as percent change from test-day baseline at Day 1 and at Day 43, demonstrated that two inhalations of albuterol sulfate produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo, as well as a comparable bronchodilator effect to the marketed active comparator HFA-134a albuterol inhaler. FEV 1 as Mean Percent Change from Test-Day Pre-Dose in a 6-Week Clinical Trial Day 1 Day 43 In this study, 31 of 58 patients treated with albuterol sulfate inhalation aerosol achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect, and median duration of effect were 8.2 minutes, 47 minutes, and approximately 3 hours, respectively. In some patients, the duration of effect was as long as 6 hours. In a placebo-controlled, single-dose, crossover study, albuterol sulfate inhalation aerosol, administered at albuterol doses of 90, 180 and 270 mcg, produced bronchodilator responses significantly greater than those observed with a matched placebo HFA inhalation aerosol and comparable to a marketed active comparator HFA-134a albuterol inhaler. Pediatric Patients 4 to 11 Years of Age In a 3-week, randomized, double-blind, placebo- controlled trial, the same formulation of albuterol as in albuterol sulfate inhalation aerosol (50 patients) was compared to a matched placebo HFA inhalation aerosol (45 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily. Serial FEV 1 measurements, expressed as the maximum percent change from test-day baseline in percent predicted FEV 1 at Day 1 and at Day 22 observed within two hours post-dose, demonstrated that two inhalations of HFA albuterol sulfate produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo. In this study, 21 of 50 pediatric patients treated with the same formulation of albuterol as in albuterol sulfate inhalation aerosol achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1. In these patients, the median time to onset, median time to peak effect and median duration of effect were 10 minutes, 31 minutes, and approximately 4 hours, respectively. In some pediatric patients, the duration of effect was as long as 6 hours. In a placebo-controlled, single-dose, crossover study in 55 pediatric patients 4 to 11 years of age, albuterol sulfate inhalation aerosol, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo HFA inhalation aerosol. Serial FEV 1 measurements, expressed as the baseline-adjusted percent predicted FEV 1 observed over 6 hours post-dose, demonstrated that one and two inhalations of albuterol sulfate inhalation aerosol produced significantly greater bronchodilator responses than the matched placebo.

tched placebo HFA inhalation aerosol. Serial FEV 1 measurements, expressed as the baseline-adjusted percent predicted FEV 1 observed over 6 hours post-dose, demonstrated that one and two inhalations of albuterol sulfate inhalation aerosol produced significantly greater bronchodilator responses than the matched placebo. Figure Day 1 Day 43 14.2 Exercise-Induced Bronchospasm In a randomized, single-dose, crossover study in 24 adults and adolescents with exercise-induced bronchospasm (EIB), two inhalations of albuterol sulfate inhalation aerosol taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as maintenance of FEV 1 within 80% of post-dose, pre-exercise baseline values) in 83% (20 of 24) of patients as compared to 25% (6 of 24) of patients when they received placebo. Some patients who participated in these clinical trials were using concomitant steroid therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING Albuterol sulfate inhalation aerosol is supplied as a pressurized aluminum canister with a blue plastic actuator with a dose indicator and green dust cap each in boxes of one. Each canister contains 8.5 g of the formulation and provides 200 actuations (NDC 85766-062-90 relabeled from 68180-963-01). Each actuation delivers 120 mcg of albuterol sulfate from the canister valve and 108 mcg of albuterol sulfate from the actuator mouthpiece (equivalent to 90 mcg of albuterol base). SHAKE WELL BEFORE USE. Store between 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] Contents under pressure. Do not puncture or incinerate. Protect from freezing temperatures and prolonged exposure to direct sunlight. Exposure to temperatures above 120 o F may cause bursting. For best results, canister should be at room temperature before use. Avoid spraying in eyes. Keep out of reach of children. See FDA-Approved Patient Labeling (17.9) for priming and cleaning instructions. The blue actuator supplied with albuterol sulfate inhalation aerosol should not be used with the canister from any other inhalation aerosol products. The albuterol sulfate inhalation aerosol canister should not be used with the actuator from any other inhalation aerosol products. Albuterol sulfate inhalation aerosol has a dose indicator attached to the actuator. Patients should never try to alter the numbers for the dose indicator or tamper with the dose indicator button mechanism. Discard the albuterol sulfate inhalation aerosol when the indicator displays 0 or after the expiration date on the product, whichever comes first. The labeled amount of medication in each actuation cannot be assured after the indicator displays 0, even though the canister is not completely empty and will continue to operate. Never immerse the canister into water to determine how full the canister is ("float test"). Albuterol sulfate inhalation aerosol does not contain chlorofluorocarbons (CFCs) as the propellant.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling ( 17.9 ) Patients should be given the following information: 17.1 Frequency of Use The action of albuterol sulfate inhalation aerosol should last for 4 to 6 hours. Do not use albuterol sulfate inhalation aerosol more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of albuterol sulfate inhalation aerosol without consulting the physician. If patients find that treatment with albuterol sulfate inhalation aerosol becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual, they should seek medical attention immediately. 17.2 Priming and Cleaning Priming Priming is essential to ensure appropriate albuterol content in each actuation. Instruct patients 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 three sprays into the air, away from the face. Cleaning To ensure proper dosing and prevent actuator orifice blockage, instruct patients to wash the blue plastic actuator mouthpiece and dry thoroughly at least once a week. Instruct patients that if they have more than one albuterol sulfate inhaler, they should wash each one at separate times to prevent attaching the wrong canister to the wrong plastic actuator. In this way, they can be sure they will always know the correct number of remaining doses. Patients should be instructed to never attach a canister of medicine from any other inhaler to the albuterol sulfate inhalation aerosol actuator and never attach the albuterol sulfate inhalation aerosol canister to an actuator from any other inhaler. Patients should not remove the canister from the actuator except during cleaning because reattachment may release a dose into the air and the dose indicator will typically rotate during every 5 to 7 actuations (sprays) towards the next decreasing number. Detailed cleaning instructions are included in the illustrated Information for the Patient leaflet. 17.3 Dose Indicator Patients should be informed that albuterol sulfate inhalation aerosol has a dose indicator attached to the actuator. When the patient receives the inhaler, new inhaler first shows "200" in the dose indicator window. The dose indicator will show the approximate number of actuations (sprays) of medicine remaining in the inhaler. As you use the inhaler, the dose indicator will typically rotate during every 5 to 7 actuations (sprays) towards the next decreasing number. The dose-indicator window displays the number of sprays left in the inhaler in units of twenty (e.g., 200, 180, 160, etc). When the dose indicator displays "40," where the background changes from white to red to remind the patient to contact their pharmacist for a refill of medication or consult their physician for a prescription refill. The background color will be all red when the indicator approaches 20. The indicator will stop moving at "0". Discard the inhaler once the dose indicator displays "0". Patients should be informed to discard albuterol sulfate inhalation aerosol inhaler when the dose indicator displays 0 or after the expiration date on the product, whichever comes first. 17.4 Paradoxical Bronchospasm Inform patients that albuterol sulfate inhalation aerosol can produce paradoxical bronchospasm.

ys "0". Patients should be informed to discard albuterol sulfate inhalation aerosol inhaler when the dose indicator displays 0 or after the expiration date on the product, whichever comes first. 17.4 Paradoxical Bronchospasm Inform patients that albuterol sulfate inhalation aerosol can produce paradoxical bronchospasm. Instruct patients to discontinue albuterol sulfate inhalation aerosol if paradoxical bronchospasm occurs. 17.5 Concomitant Drug Use While patients are taking albuterol sulfate inhalation aerosol, other inhaled drugs and asthma medications should be taken only as directed by a physician. 17.6 Common Adverse Events Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, or nervousness. 17.7 Pregnancy Patients who are pregnant or nursing should contact their physician about the use of albuterol sulfate inhalation aerosol. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy [see USE IN SPECIFIC POPULATIONS ( 8.1 )] . 17.8 General Information on Use Effective and safe use of albuterol sulfate inhalation aerosol includes an understanding of the way that it should be administered. Shake well before each spray. Use albuterol sulfate inhalation aerosol only with the actuator supplied with the product. Discard the albuterol sulfate inhalation aerosol inhaler when the dose indicator displays 0 or after the expiration date on the product, whichever comes first. Never immerse the canister in water to determine how full the canister is ("float test"). In general, the technique for administering albuterol sulfate inhalation aerosol to children is similar to that for adults. Children should use albuterol sulfate inhalation aerosol under adult supervision, as instructed by the patient's physician . 17.9 FDA-Approved Patient Labeling See tear-off illustrated Information for the Patient leaflet. Distributed by: Sportpharm LLC 379 Van Ness Ave 1401, Torrance, CA 90501 Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501 Attention Pharmacist: Detach Patient's Instructions for use from package insert and dispense with the product.

Patient Information Albuterol Sulfate (al bue' ter ol) (sul' fate) Inhalation Aerosol Read this Patient Information before you start using albuterol sulfate inhalation aerosol and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. What is albuterol sulfate inhalation aerosol? Albuterol sulfate inhalation aerosol is a prescription medicine used in people 4 years of age and older to: • treat or prevent bronchospasm in people who have reversible obstructive airway disease • prevent exercise induced bronchospasm It is not known if albuterol sulfate inhalation aerosol is safe and effective in children under 4 years of age. Who should not use albuterol sulfate inhalation aerosol? Do not use albuterol sulfate inhalation aerosol if you are allergic to albuterol sulfate or any of the ingredients in albuterol sulfate inhalation aerosol. See the end of this leaflet for a complete list of ingredients in albuterol sulfate inhalation aerosol. What should I tell my doctor before I use albuterol sulfate inhalation aerosol? Before you use albuterol sulfate inhalation aerosol, tell your doctor if you: • have heart problems • have high blood pressure (hypertension) • have convulsions (seizures) • have thyroid problems • have diabetes • have low potassium levels in your blood • are pregnant or plan to become pregnant. It is not known if albuterol sulfate inhalation aerosol will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. • are breastfeeding or plan to breastfeed. It is not known if albuterol sulfate passes into your breast milk. Talk to your doctor about the best way to feed your baby if you are using albuterol sulfate inhalation aerosol. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Albuterol sulfate inhalation aerosol and other medicines may affect each other and cause side effects. Albuterol sulfate inhalation aerosol may affect the way other medicines work, and other medicines may affect the way albuterol sulfate inhalation aerosol works. Especially tell your doctor if you take: • other inhaled medicines or asthma medicines • beta blocker medicines • diuretics • digoxin • monoamine oxidase inhibitors • tricyclic antidepressants Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use albuterol sulfate inhalation aerosol? • For detailed instructions, see " Instructions for Use " at the end of this Patient Information. • Use albuterol sulfate inhalation aerosol exactly as your doctor tells you to use it. • If your child needs to use albuterol sulfate inhalation aerosol, watch your child closely to make sure your child uses the inhaler correctly. Your doctor will show you how your child should use albuterol sulfate inhalation aerosol. • Each dose of albuterol sulfate inhalation aerosol should last up to 4 hours to 6 hours. • Do not increase your dose or take extra doses of albuterol sulfate inhalation aerosol without first talking to your doctor. • Get medical help right away if albuterol sulfate inhalation aerosol no longer helps your symptoms.

ol. • Each dose of albuterol sulfate inhalation aerosol should last up to 4 hours to 6 hours. • Do not increase your dose or take extra doses of albuterol sulfate inhalation aerosol without first talking to your doctor. • Get medical help right away if albuterol sulfate inhalation aerosol no longer helps your symptoms. • Get medical help right away if your symptoms get worse or if you need to use your inhaler more often. • While you are using albuterol sulfate inhalation aerosol, do not use other inhaled rescue medicines and asthma medicines unless your doctor tells you to do so. • Call your doctor if your asthma symptoms like wheezing and trouble breathing become worse over a few hours or days. Your doctor may need to give you another medicine (for example, corticosteroids) to treat your symptoms. What are the possible side effects of albuterol sulfate inhalation aerosol? Albuterol sulfate inhalation aerosol may cause serious side effects, including: • worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm). If this happens stop using albuterol sulfate inhalation aerosol and call your doctor or get emergency help right away. Paradoxical bronchospasm is more likely to happen with your first use of a new canister of medicine. • heart problems including faster heart rate and higher blood pressure • possible death in people with asthma who use too much albuterol sulfate inhalation aerosol • allergic reactions. Call your doctor right away if you have the following symptoms of an allergic reaction: o itchy skin o swelling beneath your skin or in your throat o rash o worsening trouble breathing • low potassium levels in your blood • worsening of other medical problems in people who also use albuterol sulfate inhalation aerosol including increases in blood sugar The most common side effects of albuterol sulfate inhalation aerosol include: • your heart feels like it is pounding or racing (palpitations) • chest pain • fast heart rate • shakiness • nervousness • headache • dizziness • sore throat • runny nose Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of albuterol sulfate inhalation aerosol. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store albuterol sulfate inhalation aerosol? • Store albuterol sulfate inhalation aerosol at room temperature between 20°C to 25°C (68°F to 77°F). [See USP Controlled Room Temperature.] • Avoid exposure to extreme heat and cold. • Shake the albuterol sulfate inhalation aerosol canister well before use. • Do not puncture the albuterol sulfate inhalation aerosol canister. • Do not store the albuterol sulfate inhalation aerosol canister near heat or a flame. Temperatures above 120° F may cause the canister to burst. • Do not throw the albuterol sulfate inhalation aerosol canister into a fire or an incinerator. • Avoid spraying albuterol sulfate inhalation aerosol in your eyes. Keep albuterol sulfate inhalation aerosol and all medicines out of the reach of children. General Information about the safe and effective use of albuterol sulfate inhalation aerosol Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use albuterol sulfate inhalation aerosol for a condition for which it was not prescribed. Do not give albuterol sulfate inhalation aerosol to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information summarizes the most important information about albuterol sulfate inhalation aerosol. If you would like more information, talk with your doctor.

not prescribed. Do not give albuterol sulfate inhalation aerosol to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information summarizes the most important information about albuterol sulfate inhalation aerosol. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about albuterol sulfate inhalation aerosol that is written for health professionals . This Patient Information has been approved by the U.S. Food and Drug Administration. Instructions for Use Albuterol Sulfate (al bue'ter ol) (sul'fate) Inhalation Aerosol Read this Instructions for Use before you start using albuterol sulfate inhalation aerosol and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. The Parts of Your Albuterol Sulfate inhalation aerosol Inhaler Device: There are 2 main parts of your albuterol sulfate inhalation aerosol inhaler device including a: • blue plastic actuator that sprays the medicine from the canister. See Figure A. • protective green color dust cap that covers the mouthpiece of the actuator. See Figure A. There is also a metal canister that holds the medicine. See Figure A. There is also a dose indicator attached around the valve sitting of the actuator with a viewing window that shows you approximately how many sprays of medicine you have left. See Figure B. You will see the number "200" in the dose indicator window on the actuator. See Figure B. The dose indicator will show the approximate number of actuations (sprays) of medicine remaining in the inhaler. Before you use the inhaler you will need to prime it first. See " Priming Your Albuterol Sulfate Inhalation Aerosol Device " below. Figure A Figure A Figure B Figure B Do not use the albuterol sulfate inhalation aerosol actuator with a canister of medicine from any other inhaler. Do not use an albuterol sulfate inhalation aerosol canister with an actuator from any other inhaler, including another albuterol sulfate inhalation aerosol inhaler. Priming Your Albuterol Sulfate Inhalation Aerosol Device: Your albuterol sulfate inhalation aerosol device must be primed before you use it for the first time or if your device has not been used for more than 14 days in a row. Do not prime your albuterol sulfate inhalation aerosol device every day. • Remove your albuterol sulfate inhalation aerosol device from its package. • Remove the protective dust cap from the mouthpiece. • Shake the inhaler well, and spray it into the air away from your face. See Figure C. Figure C Figure C • Shake and spray the inhaler like this 2 more times to finish priming it. The dose indicator on the actuator should show the number "200" after you prime the inhaler for the first time. See Figure D. Figure D Figure D Each Time You Use Your Albuterol Sulfate Inhalation Aerosol Device: • Make sure the canister fits firmly in the plastic actuator. • Look into the mouthpiece to make sure there are no foreign objects there, especially if the cap has not been used to cover the mouthpiece. Reading the Dose Indicator on Your Albuterol Sulfate Inhalation Aerosol Actuator: • The dose indicator will count down each time a spray is released. The dose-indicator window will show the number of sprays left in the inhaler in units of 20 sprays. For example, during every 5 to 7 sprays the dose indicator will count down by 20 towards the next decreasing number. See Figure E. • When the dose indicator reaches "0", it will stop moving. Throw away (discard) the inhaler when the dose indicator shows "0" and replace your Albuterol Sulfate Inhalation Aerosol device.

For example, during every 5 to 7 sprays the dose indicator will count down by 20 towards the next decreasing number. See Figure E. • When the dose indicator reaches "0", it will stop moving. Throw away (discard) the inhaler when the dose indicator shows "0" and replace your Albuterol Sulfate Inhalation Aerosol device. • The dose indicator cannot be reset and is permanently attached to the actuator. Do not change the numbers for the dose indicator. • Do not remove the canister from the plastic actuator except during cleaning. Reattaching the canister to the actuator may accidently release a dose of albuterol sulfate inhalation aerosol into the air. Figure E Figure E Using Your Albuterol Sulfate Inhalation Aerosol Device: Step 1. Shake the inhaler well before each spray. Take the cap off the mouthpiece of the actuator. Step 2. Hold the inhaler with the mouthpiece down. See Figure F. Figure F Figure F Step 3. Breathe out through your mouth and push as much air from your lungs as you can. Put the mouthpiece in your mouth and close your lips around it. See Figure G. Step 4. Push the top of the canister all the way down while you breathe in deeply and slowly through your mouth . See Figure G. Figure G Figure G Step 5. Right after the spray comes out, take your finger off the canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth. Step 6. Hold your breath as long as you can , up to 10 seconds, then breathe normally. If your doctor has told you to use more sprays , wait 1 minute and shake the inhaler again. Repeat Steps 2 through Step 6. Step 7. Put the cap back on the mouthpiece after every time you use the inhaler. Make sure the cap snaps firmly into place. Cleaning Your Albuterol Sulfate Inhalation Aerosol Device: It is very important to keep the plastic actuator clean so the medicine will not build-up and block the spray. See Figure H and Figure I. Figure H Figure H Figure I Figure I • Do not try to clean the metal canister or let it get wet. The inhaler may stop spraying if it is not cleaned correctly. • If you have more than 1 albuterol sulfate inhalation aerosol inhaler, wash each device at separate times to prevent putting the wrong canister together with the wrong plastic actuator. This way you can be sure you will always know the correct number of remaining doses of albuterol sulfate inhalation aerosol. • Wash the actuator at least 1 time each week as follows : o Take the canister out of the actuator, and take the cap off the mouthpiece. o Hold the actuator under the faucet and run warm water through it for about 30 seconds. See Figure J. Figure J Figure J o Turn the actuator upside down and run warm water through the mouthpiece for about 30 seconds. See Figure K. Figure K Figure K o Shake off as much water from the actuator as you can. Look into the mouthpiece to make sure any medicine build-up has been completely washed away. If there is any build-up, repeat the washing instructions. o Let the actuator air-dry completely, such as overnight. See Figure L. Figure L Figure L o When the actuator is dry, put the canister in the actuator and make sure it fits firmly. Shake the inhaler well and spray it twice into the air away from your face. Put the cap back on the mouthpiece. If you need to use your inhaler before the actuator is completely dry: • Shake as much water off the actuator as you can. • Put the canister in the actuator and make sure it fits firmly. • Shake the inhaler well and spray it twice into the air away from your face. • Take your albuterol sulfate inhalation aerosol dose as prescribed. • Follow the Cleaning Instructions above.

completely dry: • Shake as much water off the actuator as you can. • Put the canister in the actuator and make sure it fits firmly. • Shake the inhaler well and spray it twice into the air away from your face. • Take your albuterol sulfate inhalation aerosol dose as prescribed. • Follow the Cleaning Instructions above. Replacing Your Albuterol Sulfate Inhalation Aerosol Device • There are approximately 40 sprays left when the dose indicator shows the number "40," and the background color changes from white to red. See Figure M. o The red background will remind you to refill your prescription or ask your doctor for another prescription for albuterol sulfate inhalation aerosol. o The background color will be all red when the dose indicator approaches "20". o The dose indicator will stop moving at "0". Throw away (discard) the inhaler once the dose indicator displays "0" See Figure N. Figure M Figure M Figure N Figure N • Throw the albuterol sulfate inhalation aerosol inhaler away as soon as the dose indicator says "0" or after the expiration date on the albuterol sulfate inhalation aerosol packaging, whichever comes first. You should not keep using the inhaler after 200 sprays even though the canister may not be completely empty. You cannot be sure you will receive any medicine in each actuation (spray) once the dose indicator displays "0". • Do not use the inhaler after the expiration date on the albuterol sulfate inhalation aerosol packaging. For more information about Albuterol Sulfate Inhalation Aerosol Device go to https://lupin.com/albuterol or call Lupin Pharmaceuticals, Inc. at 1-800-399-2561. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Sportpharm LLC 379 Van Ness Ave 1401, Torrance, CA 90501 Relabeled by: Enovachem PHARMACEUTICALS Torrance, CA 90501 Figure A Figure B Figure C Figure D Figure E Figure F Figure G figure H figure I figure J Figure K Figure L Figure M Figure N

1 INDICATIONS AND USAGE Albuterol Sulfate HFA is a beta 2 -adrenergic agonist indicated for: Treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older with reversible obstructive airway disease. ( 1.1 ) Prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older. ( 1.2 ) 1.1 Bronchospasm Albuterol Sulfate HFA Inhalation Aerosol is indicated for the treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older with reversible obstructive airway disease. 1.2 Exercise-Induced Bronchospasm Albuterol Sulfate HFA is indicated for the prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older.

2 DOSAGE AND ADMINISTRATION For oral inhalation only. ( 2 ) Treatment or prevention of bronchospasm in adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation every 4 to 6 hours. For some patients, 1 inhalation every 4 hours may be sufficient. ( 2.1 ) Prevention of exercise-induced bronchospasm in adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation 15 to 30 minutes before exercise. ( 2.2 ) Priming information: Prime Albuterol Sulfate HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime Albuterol Sulfate HFA, release 4 sprays into the air away from the face, shaking well before each spray. ( 2.3 ) Cleaning information: At least once a week, wash the actuator with warm water and let it air-dry completely. ( 2.3 ) 2.1 Recommended Dosage for Bronchospasm (Acute Episodes or Symptoms Associated with Bronchospasm) Adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation repeated every 4 to 6 hours; in some patients, 1 inhalation every 4 hours may be sufficient. More frequent administration or a greater number of inhalations is not recommended. 2.2 Recommended Dosage for Prevention of Exercise-Induced Bronchospasm Adult and pediatric patients aged 4 years and older: 2 inhalations by oral inhalation 15 to 30 minutes before exercise. 2.3 Administration Information Albuterol Sulfate HFA should be administered by the orally inhaled route only. Priming Priming Albuterol Sulfate HFA is essential to ensure appropriate albuterol content in each actuation. Prime Albuterol Sulfate HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime Albuterol Sulfate HFA, release 4 sprays into the air away from the face, shaking well before each spray. Avoid spraying in eyes. Cleaning To ensure proper dosing and to prevent actuator orifice blockage, wash the actuator with warm water and let it air-dry completely at least once a week.

3 DOSAGE FORMS AND STRENGTHS Inhalation aerosol: 108 mcg of albuterol sulfate (90 mcg of albuterol base) from the mouthpiece per actuation. Blue plastic inhaler with a blue cap containing a pressurized metered-dose aerosol canister containing 200 metered inhalations and fitted with a counter. Inhalation aerosol: 108 mcg albuterol sulfate (90 mcg albuterol base) per actuation. ( 3 )

4 CONTRAINDICATIONS Albuterol Sulfate HFA is contraindicated in patients with a history of hypersensitivity to any of the ingredients [see Warnings and Precautions ( 5.6 ), Description ( 11 )] . Hypersensitivity to any ingredient. ( 4 )

5 WARNINGS AND PRECAUTIONS Life-threatening paradoxical bronchospasm may occur. Discontinue Albuterol Sulfate HFA immediately and institute alternative therapy. ( 5.1 ) Need for more doses of Albuterol Sulfate HFA than usual may be a sign of deterioration of asthma and requires reevaluation of treatment. ( 5.2 ) Albuterol Sulfate HFA 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 HFA immediately. ( 5.6 ) Hypokalemia and changes in blood glucose may occur. ( 5.7 , 5.8 ) 5.1 Paradoxical Bronchospasm Albuterol Sulfate HFA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with Albuterol Sulfate HFA, 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 HFA 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 HFA, 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 HFA 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 HFA, 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 HFA [see Contraindications ( 4 )] .

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 HFA [see Contraindications ( 4 )] . 5.7 Coexisting Conditions Albuterol Sulfate HFA, 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 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.

eiving 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.

<table ID="_Ref29379712" width="98.52%"><caption>Table 1. Adverse Reactions with Albuterol Sulfate HFA with &#x2265;3% Incidence and More Common than Placebo in Adult and Adolescent Subjects</caption><col width="25%"/><col width="25%"/><col width="25%"/><col width="25%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Percent of Subjects</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Albuterol Sulfate HFA</content></paragraph><paragraph><content styleCode="bold">(n = 202)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">CFC 11/12-Propelled</content></paragraph><paragraph><content styleCode="bold">Albuterol Inhaler</content></paragraph><paragraph><content styleCode="bold">(n = 207)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content> <content styleCode="bold">HFA-134a</content></paragraph><paragraph><content styleCode="bold">(n = 201)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Ear, nose, and throat</paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Throat irritation</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Upper respiratory inflammation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Lower respiratory</paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Viral respiratory infections</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Cough</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Musculoskeletal</paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " val

nter" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Musculoskeletal</paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " val ign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Musculoskeletal pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS Other short-acting sympathomimetic aerosol bronchodilators should not be used concomitantly with albuterol. If additional adrenergic drugs are to be administered by any route, they should be used with caution to avoid deleterious cardiovascular effects. Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.1 ) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.2 ) Digoxin: May decrease serum digoxin levels. Consider monitoring digoxin levels. ( 7.3 ) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of albuterol on vascular system. ( 7.4 ) 7.1 Beta-Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as albuterol sulfate HFA, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution. 7.2 Non–Potassium-Sparing Diuretics 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 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 Albuterol Sulfate HFA with non–potassium-sparing diuretics. 7.3 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 relevance of these findings for patients with obstructive airway disease who are receiving inhaled 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. 7.4 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Albuterol Sulfate HFA 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1‑877-311-8972 or visit https://mothertobaby.org/ongoing-study/asthma. Risk Summary There are no randomized clinical studies of use of albuterol sulfate during pregnancy. Available data from epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are, however, clinical considerations in pregnant women with asthma. (See Clinical Considerations.) Administration of albuterol sulfate HFA to mice and rabbits during the period of organogenesis revealed evidence of adverse developmental outcomes (cleft palate in mice, delayed ossification in rabbits) at less than the maximum recommended human daily inhaled dose (MRHDID). (See Data.) The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery: Because of the potential for beta-agonist interference with uterine contractility, use of Albuterol Sulfate HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Albuterol sulfate HFA has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Human Data: While available studies cannot definitively establish the absence of risk, published data from epidemiological studies and case reports have not consistently demonstrated an association with use of albuterol sulfate HFA during pregnancy and major birth defects, specific birth defects, or miscarriage. The available studies have methodologic limitations, including inconsistent comparator groups, definitions of outcomes, and assessment of disease impact. Animal Data: In a study in pregnant mice, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure less than the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol, another beta 2 -agonist. In a study in pregnant rabbits, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg).

red in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol, another beta 2 -agonist. In a study in pregnant rabbits, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a study in pregnant rabbits, an albuterol/HFA-134a formulation administered by inhalation produced enlargement of the frontal portion of the fetal fontanelles at approximately one third of the MRHDID on a mg/m 2 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. 8.2 Lactation Risk Summary There are no available data on the presence of albuterol or the components of Albuterol Sulfate HFA in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, are likely to be correspondingly low [see Clinical Pharmacology ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Albuterol Sulfate HFA and any potential adverse effects on the breastfed child from Albuterol Sulfate HFA or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of albuterol sulfate HFA for treatment or prevention of bronchospasm and for prevention of exercised-induced bronchospasm in pediatric patients aged 4 years and older have been established. Use of albuterol sulfate HFA for this indication is supported by evidence from adequate and well-controlled studies of two 12-week clinical trials in subjects aged 12 years and older with asthma and one 2-week clinical trial in subjects aged 4 to 11 years with asthma [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )] . The safety and effectiveness of albuterol sulfate HFA in pediatric patients younger than 4 years have not been established. Three trials have been conducted to evaluate the safety and efficacy of albuterol sulfate HFA in subjects younger than 4 years and the findings are described below. Two 4-week randomized, double-blind, placebo-controlled trials were conducted in 163 pediatric subjects aged from birth to 48 months with symptoms of bronchospasm associated with obstructive airway disease (presenting symptoms included: wheeze, cough, dyspnea, or chest tightness). Albuterol sulfate HFA or placebo HFA was delivered with either an AeroChamber Plus Valved Holding Chamber or an Optichamber Valved Holding Chamber with mask 3 times daily. In one trial, albuterol sulfate HFA 90 mcg (n = 26), albuterol sulfate HFA 180 mcg (n = 25), and placebo HFA (n = 26) were administered to children aged between 24 and 48 months. In the second trial, albuterol sulfate HFA 90 mcg (n = 29), albuterol sulfate HFA 180 mcg (n = 29), and placebo HFA (n = 28) were administered to children aged between birth and 24 months. Over the 4-week treatment period, there were no treatment differences in asthma symptom scores between the groups receiving albuterol sulfate HFA 90 mcg, albuterol sulfate HFA 180 mcg, and placebo in either trial. In a third trial, albuterol sulfate HFA was evaluated in 87 pediatric subjects younger than 24 months for the treatment of acute wheezing. Albuterol sulfate HFA was delivered with an AeroChamber Plus Valved Holding Chamber in this trial. There were no significant differences in asthma symptom scores and mean change from baseline in an asthma symptom score between albuterol sulfate HFA 180 mcg and albuterol sulfate HFA 360 mcg.

treatment of acute wheezing. Albuterol sulfate HFA was delivered with an AeroChamber Plus Valved Holding Chamber in this trial. There were no significant differences in asthma symptom scores and mean change from baseline in an asthma symptom score between albuterol sulfate HFA 180 mcg and albuterol sulfate HFA 360 mcg. In vitro dose characterization studies were performed to evaluate the delivery of albuterol sulfate HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers with masks (small and medium size). The in vitro study data when simulating patient breathing suggest that the dose of albuterol sulfate HFA presented for inhalation via a valved holding chamber with mask will be comparable to the dose delivered in adults without a spacer and mask per kilogram of body weight ( Table 2 ). However, clinical trials in children younger than 4 years described above suggest that either the optimal dose of albuterol sulfate HFA has not been defined in this age group or albuterol sulfate HFA is not effective in this age group. The safety and effectiveness of albuterol sulfate HFA administered with or without a spacer device in children younger than 4 years have not been demonstrated. Table 2. In Vitro Medication Delivery through AeroChamber Plus Valved Holding Chamber with a Mask a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50 th percentile weight for boys and girls at the ages indicated. b A single inhalation of albuterol sulfate HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 90 mcg, or 1.3 mcg/kg. Age Mask Flow Rate (L/min) Holding Time (seconds) Mean Medication Delivery through AeroChamber Plus (mcg/actuation) Body Weight 50 th Percentile (kg) a Medication Delivered per Actuation (mcg/kg) b 6 to 12 Months Small 4.9 0 2 5 10 18.2 19.8 13.8 15.4 7.5-9.9 1.8-2.4 2.0-2.6 1.4-1.8 1.6-2.1 2 to 5 Years Small 8.0 0 2 5 10 17.8 16.0 16.3 18.3 12.3-18.0 1.0-1.4 0.9-1.3 0.9-1.3 1.0-1.5 2 to 5 Years Medium 8.0 0 2 5 10 21.1 15.3 18.3 18.2 12.3-18.0 1.2-1.7 0.8-1.2 1.0-1.5 1.0-1.5 >5 Years Medium 12.0 0 2 5 10 26.8 20.9 19.6 20.3 18.0 1.5 1.2 1.1 1.1 8.5 Geriatric Use Clinical trials of albuterol sulfate HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

<table ID="_Ref29379733" width="98.3%"><caption>Table 2. In Vitro Medication Delivery through AeroChamber Plus Valved Holding Chamber with a Mask</caption><col width="15%"/><col width="10%"/><col width="11%"/><col width="13%"/><col width="19%"/><col width="15%"/><col width="17%"/><tfoot><tr><td align="left" colspan="7" valign="top">^a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50 ^thpercentile weight for boys and girls at the ages indicated. ^b A single inhalation of albuterol sulfate HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 90 mcg, or 1.3 mcg/kg.

ntion and Health Promotion (2000). Ranges correspond to the average of the 50 ^thpercentile weight for boys and girls at the ages indicated. ^b A single inhalation of albuterol sulfate HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 90 mcg, or 1.3 mcg/kg. </td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Age</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Mask</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Flow Rate (L/min)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Holding Time (seconds)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Mean Medication Delivery through AeroChamber Plus (mcg/actuation)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Body Weight 50 ^thPercentile (kg) ^a</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Medication Delivered per Actuation (mcg/kg) ^b</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 to 12 Months</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Small</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph><paragraph>2</paragraph><paragraph>5</paragraph><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18.2</paragraph><paragraph>19.8</paragraph><paragraph>13.8</paragraph><paragraph>15.4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.5-9.9</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.8-2.4</paragraph><paragraph>2.0-2.6</paragraph><paragraph>1.4-1.8</paragraph><paragraph>1.6-2.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 to 5 Years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Small</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph><paragraph>2</paragraph><paragraph>5</paragraph><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17.8</paragraph><paragraph>16.0</paragraph><paragraph>16.3</paragraph><paragraph>18.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12.3-18.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.0-1.4</paragraph><paragraph>0.9-1.3</paragraph><paragraph>0.9-1.3</paragraph><paragraph>1.0-1.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 to 5 Years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Medium</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph><paragraph>2</paragraph><paragraph>5</paragraph><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21.

align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph><paragraph>2</paragraph><paragraph>5</paragraph><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21. 1</paragraph><paragraph>15.3</paragraph><paragraph>18.3</paragraph><paragraph>18.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12.3-18.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.2-1.7</paragraph><paragraph>0.8-1.2</paragraph><paragraph>1.0-1.5</paragraph><paragraph>1.0-1.5</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>&gt;5 Years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Medium</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph><paragraph>2</paragraph><paragraph>5</paragraph><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26.8</paragraph><paragraph>20.9</paragraph><paragraph>19.6</paragraph><paragraph>20.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5</paragraph><paragraph>1.2</paragraph><paragraph>1.1</paragraph><paragraph>1.1</paragraph></td></tr></tbody></table>

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications during pregnancy. For more information, contact the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists at 1‑877-311-8972 or visit https://mothertobaby.org/ongoing-study/asthma. Risk Summary There are no randomized clinical studies of use of albuterol sulfate during pregnancy. Available data from epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are, however, clinical considerations in pregnant women with asthma. (See Clinical Considerations.) Administration of albuterol sulfate HFA to mice and rabbits during the period of organogenesis revealed evidence of adverse developmental outcomes (cleft palate in mice, delayed ossification in rabbits) at less than the maximum recommended human daily inhaled dose (MRHDID). (See Data.) The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryofetal Risk: In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery: Because of the potential for beta-agonist interference with uterine contractility, use of Albuterol Sulfate HFA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Albuterol sulfate HFA has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Human Data: While available studies cannot definitively establish the absence of risk, published data from epidemiological studies and case reports have not consistently demonstrated an association with use of albuterol sulfate HFA during pregnancy and major birth defects, specific birth defects, or miscarriage. The available studies have methodologic limitations, including inconsistent comparator groups, definitions of outcomes, and assessment of disease impact. Animal Data: In a study in pregnant mice, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure less than the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol, another beta 2 -agonist. In a study in pregnant rabbits, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg).

red in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol, another beta 2 -agonist. In a study in pregnant rabbits, orally administered albuterol sulfate produced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a study in pregnant rabbits, an albuterol/HFA-134a formulation administered by inhalation produced enlargement of the frontal portion of the fetal fontanelles at approximately one third of the MRHDID on a mg/m 2 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.

8.4 Pediatric Use The safety and effectiveness of albuterol sulfate HFA for treatment or prevention of bronchospasm and for prevention of exercised-induced bronchospasm in pediatric patients aged 4 years and older have been established. Use of albuterol sulfate HFA for this indication is supported by evidence from adequate and well-controlled studies of two 12-week clinical trials in subjects aged 12 years and older with asthma and one 2-week clinical trial in subjects aged 4 to 11 years with asthma [see Adverse Reactions ( 6.1 ), Clinical Studies ( 14.1 )] . The safety and effectiveness of albuterol sulfate HFA in pediatric patients younger than 4 years have not been established. Three trials have been conducted to evaluate the safety and efficacy of albuterol sulfate HFA in subjects younger than 4 years and the findings are described below. Two 4-week randomized, double-blind, placebo-controlled trials were conducted in 163 pediatric subjects aged from birth to 48 months with symptoms of bronchospasm associated with obstructive airway disease (presenting symptoms included: wheeze, cough, dyspnea, or chest tightness). Albuterol sulfate HFA or placebo HFA was delivered with either an AeroChamber Plus Valved Holding Chamber or an Optichamber Valved Holding Chamber with mask 3 times daily. In one trial, albuterol sulfate HFA 90 mcg (n = 26), albuterol sulfate HFA 180 mcg (n = 25), and placebo HFA (n = 26) were administered to children aged between 24 and 48 months. In the second trial, albuterol sulfate HFA 90 mcg (n = 29), albuterol sulfate HFA 180 mcg (n = 29), and placebo HFA (n = 28) were administered to children aged between birth and 24 months. Over the 4-week treatment period, there were no treatment differences in asthma symptom scores between the groups receiving albuterol sulfate HFA 90 mcg, albuterol sulfate HFA 180 mcg, and placebo in either trial. In a third trial, albuterol sulfate HFA was evaluated in 87 pediatric subjects younger than 24 months for the treatment of acute wheezing. Albuterol sulfate HFA was delivered with an AeroChamber Plus Valved Holding Chamber in this trial. There were no significant differences in asthma symptom scores and mean change from baseline in an asthma symptom score between albuterol sulfate HFA 180 mcg and albuterol sulfate HFA 360 mcg. In vitro dose characterization studies were performed to evaluate the delivery of albuterol sulfate HFA via holding chambers with attached masks. The studies were conducted with 2 different holding chambers with masks (small and medium size). The in vitro study data when simulating patient breathing suggest that the dose of albuterol sulfate HFA presented for inhalation via a valved holding chamber with mask will be comparable to the dose delivered in adults without a spacer and mask per kilogram of body weight ( Table 2 ). However, clinical trials in children younger than 4 years described above suggest that either the optimal dose of albuterol sulfate HFA has not been defined in this age group or albuterol sulfate HFA is not effective in this age group. The safety and effectiveness of albuterol sulfate HFA administered with or without a spacer device in children younger than 4 years have not been demonstrated. Table 2.

at either the optimal dose of albuterol sulfate HFA has not been defined in this age group or albuterol sulfate HFA is not effective in this age group. The safety and effectiveness of albuterol sulfate HFA administered with or without a spacer device in children younger than 4 years have not been demonstrated. Table 2. In Vitro Medication Delivery through AeroChamber Plus Valved Holding Chamber with a Mask a Centers for Disease Control growth charts, developed by the National Center for Health Statistics in collaboration with the National Center for Chronic Disease Prevention and Health Promotion (2000). Ranges correspond to the average of the 50 th percentile weight for boys and girls at the ages indicated. b A single inhalation of albuterol sulfate HFA in a 70-kg adult without use of a valved holding chamber and mask delivers approximately 90 mcg, or 1.3 mcg/kg. Age Mask Flow Rate (L/min) Holding Time (seconds) Mean Medication Delivery through AeroChamber Plus (mcg/actuation) Body Weight 50 th Percentile (kg) a Medication Delivered per Actuation (mcg/kg) b 6 to 12 Months Small 4.9 0 2 5 10 18.2 19.8 13.8 15.4 7.5-9.9 1.8-2.4 2.0-2.6 1.4-1.8 1.6-2.1 2 to 5 Years Small 8.0 0 2 5 10 17.8 16.0 16.3 18.3 12.3-18.0 1.0-1.4 0.9-1.3 0.9-1.3 1.0-1.5 2 to 5 Years Medium 8.0 0 2 5 10 21.1 15.3 18.3 18.2 12.3-18.0 1.2-1.7 0.8-1.2 1.0-1.5 1.0-1.5 >5 Years Medium 12.0 0 2 5 10 26.8 20.9 19.6 20.3 18.0 1.5 1.2 1.1 1.1

8.5 Geriatric Use Clinical trials of albuterol sulfate HFA did not include sufficient numbers of subjects aged 65 years and older to determine whether older subjects respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE The expected signs and symptoms with overdosage of albuterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of Albuterol Sulfate HFA Inhalation Aerosol. Treatment consists of discontinuation of Albuterol Sulfate HFA 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 Albuterol Sulfate HFA.

11 DESCRIPTION The active component of Albuterol Sulfate HFA is albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta 2 -adrenergic bronchodilator. Albuterol sulfate has the chemical name α 1 -[( tert -butylamino)methyl]-4-hydroxy- m -xylene-α, α′-diol sulfate (2:1)(salt) and the following chemical structure: Albuterol sulfate is a white crystalline powder with a molecular weight of 576.7, and the empirical formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 . It is soluble in water and slightly soluble in ethanol. The World Health Organization recommended name for albuterol base is salbutamol. Albuterol Sulfate HFA is a blue plastic inhaler with a blue cap containing a pressurized metered-dose aerosol canister fitted with a counter. Each canister contains a microcrystalline suspension of albuterol sulfate in propellant HFA‑134a (1,1,1,2‑tetrafluoroethane). It contains no other excipients. After priming, each actuation of the inhaler delivers 120 mcg of albuterol sulfate, USP in 75 mg of suspension from the valve and 108 mcg of albuterol sulfate, USP from the mouthpiece (equivalent to 90 mcg of albuterol base from the mouthpiece). Prime Albuterol Sulfate HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime Albuterol Sulfate HFA, release 4 sprays into the air away from the face, shaking well before each spray. Avoid spraying in eyes. Albuterol Sulfate chemical structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase 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 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 [see Warnings and Precautions ( 5.4 )] . 12.3 Pharmacokinetics The systemic levels of albuterol are low after inhalation of recommended doses. A trial conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when albuterol was delivered using propellant HFA-134a. The mean time to peak concentrations (T max ) was delayed after administration of Albuterol Sulfate HFA (T max = 0.42 hours) as compared with CFC-propelled albuterol inhaler (T max = 0.17 hours). Apparent terminal plasma half-life of albuterol is approximately 4.6 hours. No further pharmacokinetic trials for albuterol sulfate HFA were conducted in neonates, children, or elderly subjects.

12.1 Mechanism of Action In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. Although beta 2 -adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -adrenoceptors are the predominant receptors in the heart, there are also beta 2 -adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta 2 -agonists may have cardiac effects. Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase 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 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 [see Warnings and Precautions ( 5.4 )] .

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 and 6 times the MRHDID for adults and children, respectively, on a mg/m 2 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 1,900 and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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. Fertility and reproductive performance in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 380 times the MRHDID for adults on a mg/m 2 basis). 13.2 Animal Toxicology and/or Pharmacology 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 beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 and 6 times the MRHDID for adults and children, respectively, on a mg/m 2 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 1,900 and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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. Fertility and reproductive performance in rats demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 380 times the MRHDID for adults on a mg/m 2 basis).

13.2 Animal Toxicology and/or Pharmacology 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 beta-agonists and methylxanthines are administered concurrently. The clinical relevance of these findings is unknown.

14 CLINICAL STUDIES 14.1 Bronchospasm Associated with Asthma Adult and Adolescent Subjects Aged 12 Years and Older The efficacy of albuterol sulfate HFA was evaluated in two 12-week, randomized, double-blind, placebo-controlled trials in subjects aged 12 years and older with mild to moderate asthma. These trials included a total of 610 subjects (323 males, 287 females). In each trial, subjects received 2 inhalations of albuterol sulfate HFA, CFC 11/12-propelled albuterol, or HFA-134a placebo 4 times daily for 12 weeks’ duration. Subjects taking the HFA-134a placebo inhaler also took albuterol sulfate HFA for asthma symptom relief on an as-needed basis. Some subjects who participated in these clinical trials were using concomitant inhaled steroid therapy. Efficacy was assessed by serial forced expiratory volume in 1 second (FEV 1 ). In each of these trials, 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in FEV 1 over the pretreatment value than placebo. Results from the 2 clinical trials are described below. In a 12-week, randomized, double-blind trial, albuterol sulfate HFA (101 subjects) was compared with CFC 11/12-propelled albuterol (99 subjects) and an HFA-134a placebo inhaler (97 subjects) in adolescent and adult subjects aged 12 to 76 years with mild to moderate asthma. Serial FEV 1 measurements [shown below as percent change from test-day baseline at Day 1 (n = 297) and at Week 12 (n = 249)] demonstrated that 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in FEV 1 over the pretreatment value than placebo. FEV 1 as Percent Change from Predose in a Large, 12-Week Clinical Trial Day 1 Week 12 In the responder population (≥15% increase in FEV 1 within 30 minutes postdose) treated with albuterol sulfate HFA, the mean time to onset of a 15% increase in FEV 1 over the pretreatment value was 5.4 minutes, and the mean time to peak effect was 56 minutes. The mean duration of effect as measured by a 15% increase in FEV 1 over the pretreatment value was approximately 4 hours. In some subjects, duration of effect was as long as 6 hours. The second 12-week randomized, double-blind trial was conducted to evaluate the efficacy and safety of switching subjects from CFC 11/12-propelled albuterol to albuterol sulfate HFA. During the 3-week run-in phase of the trial, all subjects received CFC 11/12-propelled albuterol. During the double-blind treatment phase, albuterol sulfate HFA (91 subjects) was compared to CFC 11/12-propelled albuterol (100 subjects) and an HFA-134a placebo inhaler (95 subjects) in adult and adolescent subjects with mild to moderate asthma. Serial FEV 1 measurements demonstrated that 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in pulmonary function than placebo. The switching from CFC 11/12-propelled albuterol inhaler to albuterol sulfate HFA did not reveal any clinically significant changes in the efficacy profile. In the 2 adult trials, the efficacy results from albuterol sulfate HFA were significantly greater than placebo and were clinically comparable to those achieved with CFC 11/12-propelled albuterol, although small numerical differences in mean FEV 1 response and other measures were observed. Physicians should recognize that individual responses to beta-adrenergic agonists administered via different propellants may vary and that equivalent responses in individual patients should not be assumed.

propelled albuterol, although small numerical differences in mean FEV 1 response and other measures were observed. Physicians should recognize that individual responses to beta-adrenergic agonists administered via different propellants may vary and that equivalent responses in individual patients should not be assumed. Pediatric Subjects Aged 4 to 11 Years The efficacy of albuterol sulfate HFA was evaluated in one 2-week, randomized, double-blind, placebo-controlled trial in 135 pediatric subjects aged 4 to 11 years with mild to moderate asthma. In this trial, subjects received albuterol sulfate HFA, CFC 11/12-propelled albuterol, or HFA-134a placebo. Serial pulmonary function measurements demonstrated that 2 inhalations of albuterol sulfate HFA produced significantly greater improvement in pulmonary function than placebo and that there were no significant differences between the groups treated with albuterol sulfate HFA and CFC 11/12-propelled albuterol. In the responder population treated with albuterol sulfate HFA, the mean time to onset of a 15% increase in peak expiratory flow rate (PEFR) over the pretreatment value was 7.8 minutes, and the mean time to peak effect was approximately 90 minutes. The mean duration of effect as measured by a 15% increase in PEFR over the pretreatment value was greater than 3 hours. In some subjects, duration of effect was as long as 6 hours. FEV1 as Percent Change from Predose in a Large, 12-Week Clinical Trial, Day 1 FEV1 as Percent Change from Predose in a Large, 12-Week Clinical Trial, Week 12 14.2 Exercise-Induced Bronchospasm One controlled clinical trial in adult subjects with asthma (N = 24) demonstrated that 2 inhalations of albuterol sulfate HFA taken approximately 30 minutes prior to exercise significantly prevented exercise-induced bronchospasm (as measured by maximum percentage fall in FEV 1 following exercise) compared with an HFA-134a placebo inhaler. In addition, albuterol sulfate HFA was shown to be clinically comparable to a CFC 11/12-propelled albuterol inhaler for this indication.

16 HOW SUPPLIED/STORAGE AND HANDLING Albuterol Sulfate HFA Inhalation Aerosol is supplied in the following box of 1 as a pressurized aluminum canister fitted with a counter and supplied with a blue plastic actuator with a blue cap: NDC: 70518-2072-00 PACKAGING: 1 in 1 CARTON, 200 in INHALER, TYPE 2 Each inhaler is packaged with a Patient Information leaflet. The blue actuator supplied with Albuterol Sulfate HFA should not be used with any other product canisters, and actuators from other products should not be used with an Albuterol Sulfate HFA canister. Counter Albuterol Sulfate HFA has a counter attached to the canister. The counter starts at 204 and counts down each time a spray is released. The correct amount of medication in each actuation cannot be assured after the counter reads 000, even though the canister is not completely empty and will continue to operate. The inhaler should be discarded when the counter reads 000. Contents under Pressure Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw canister into fire or incinerator. Storage Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the inhaler should be at room temperature before use. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Frequency of Use Inform patients that the action of Albuterol Sulfate HFA should last up to 4 to 6 hours. Do not use Albuterol Sulfate HFA more frequently than recommended. Instruct patients not to increase the dose or frequency of doses of Albuterol Sulfate HFA without consulting the physician. Instruct patients to seek medical attention immediately if treatment with Albuterol Sulfate HFA becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual. Priming Instruct patients to prime Albuterol Sulfate HFA before using for the first time, when the inhaler has not been used for more than 2 weeks, or when the inhaler has been dropped. To prime Albuterol Sulfate HFA, release 4 sprays into the air away from the face, shaking well before each spray. Avoid spraying in eyes. Cleaning To ensure proper dosing and to prevent actuator orifice blockage, instruct patients to wash the actuator with warm water and let it air-dry completely at least once a week. Inform patients that detailed cleaning instructions are included in the Patient Information leaflet. Paradoxical Bronchospasm Inform patients that Albuterol Sulfate HFA can produce paradoxical bronchospasm. Instruct them to discontinue Albuterol Sulfate HFA if paradoxical bronchospasm occurs [see Warnings and Precautions (5.1)] . Concomitant Drug Use Advise patients that while they are using Albuterol Sulfate HFA, other inhaled drugs and asthma medications should be taken only as directed by the physician. Common Adverse Effects Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, and nervousness. Pregnancy Exposure Registry Inform women there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to asthma medications, including Albuterol Sulfate HFA, during pregnancy and that they can enroll in the Pregnancy Exposure Registry by calling 1-877-311-8972 or by visiting https://mothertobaby.org/ongoing-study/asthma [see Use in Specific Populations ( 8.1 )] . Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

PATIENT INFORMATION Albuterol Sulfate HFA Inhalation Aerosol for oral inhalation use What is Albuterol Sulfate HFA? Albuterol Sulfate HFA is a prescription inhaled medicine used in people aged 4 years and older to: treat or prevent bronchospasm in people who have reversible obstructive airway disease. prevent exercise-induced bronchospasm. It is not known if Albuterol Sulfate HFA is safe and effective in children younger than 4 years of age. Do not use Albuterol Sulfate HFA: if you are allergic to albuterol sulfate propionate or any of the ingredients in Albuterol Sulfate HFA. See the end of this Patient Information for a complete list of ingredients in Albuterol Sulfate HFA. Before using Albuterol Sulfate HFA, tell your healthcare provider about all of your medical conditions, including if you: have heart problems. have high blood pressure. have seizures. have thyroid problems. have diabetes. have low potassium levels in your blood. are pregnant or plan to become pregnant. It is not known if Albuterol Sulfate HFA may harm your unborn baby. ○Pregnancy Registry. There is a pregnancy registry for women with asthma who receive asthma medications, including Albuterol Sulfate HFA, while pregnant. The purpose of the registry is to collect information about the health of you and your baby. You can talk to your healthcare provider about how to take part in this registry or you can get more information and register by calling 1-877-311-8972 or go to https://mothertobaby.org/ongoing-study/asthma. are breastfeeding. It is not known if the medicine in Albuterol Sulfate HFA passes into your milk and if it can harm your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Albuterol Sulfate HFA and certain other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take: other inhaled medicines or asthma medicines beta-blocker medicines diuretics digoxin monoamine oxidase inhibitors tricyclic antidepressants Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use Albuterol Sulfate HFA? Read the step-by-step instructions for using Albuterol Sulfate HFA at the end of this Patient Information. Do not use Albuterol Sulfate HFA unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. Children should use Albuterol Sulfate HFA with an adult’s help, as instructed by the child’s healthcare provider. Use Albuterol Sulfate HFA exactly as your healthcare provider tells you to use it. Do not use Albuterol Sulfate HFA more often than prescribed. Do not increase your dose or take extra doses of Albuterol Sulfate HFA without first talking to your healthcare provider. Each dose of Albuterol Sulfate HFA should last up to 4 hours to 6 hours. Get medical help right away if Albuterol Sulfate HFA no longer helps your symptoms. Get medical help right away if your symptoms get worse or if you need to use your inhaler more often. While you are using Albuterol Sulfate HFA, use other inhaled medicines and asthma medicines only as directed by your healthcare provider. Call your healthcare provider if your asthma symptoms like wheezing and trouble breathing become worse over a few hours or days.

worse or if you need to use your inhaler more often. While you are using Albuterol Sulfate HFA, use other inhaled medicines and asthma medicines only as directed by your healthcare provider. Call your healthcare provider if your asthma symptoms like wheezing and trouble breathing become worse over a few hours or days. Your healthcare provider may need to give you another medicine to treat your symptoms. What are the possible side effects with Albuterol Sulfate HFA? Albuterol Sulfate HFA can cause serious side effects, including: worsening trouble breathing, coughing, and wheezing (paradoxical bronchospasm). If this happens, stop using Albuterol Sulfate HFA and call your healthcare provider or get emergency help right away. Paradoxical bronchospasm is more likely to happen with your first use of a new canister of medicine. heart problems, including faster heart rate and higher blood pressure. possible death in people with asthma who use too much Albuterol Sulfate HFA. serious allergic reactions. Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction: ○rash ○hives ○swelling of your face, mouth, and tongue ○breathing problems changes in laboratory blood levels (sugar, potassium). Common side effects of Albuterol Sulfate HFA include: sore throat upper respiratory tract infection, including viral infection cough muscle pain your heart feels like it is pounding or racing (palpitations) chest pain fast heart rate shakiness nervousness dizziness These are not all the possible side effects of Albuterol Sulfate HFA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store Albuterol Sulfate HFA? Store Albuterol Sulfate HFA at room temperature between 68°F and 77°F (20°C and 25°C) with the mouthpiece down. The contents of your Albuterol Sulfate HFA are under pressure: Do not puncture. Do not use or store near heat or open flame. Temperatures above 120°F may cause the canister to burst. Do not throw into fire or an incinerator. Keep Albuterol Sulfate HFA and all medicines out of the reach of children. General information about the safe and effective use of Albuterol Sulfate HFA. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Albuterol Sulfate HFA for a condition for which it was not prescribed. Do not give Albuterol Sulfate HFA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Albuterol Sulfate HFA that was written for health professionals. What are the ingredients in Albuterol Sulfate HFA? Active ingredient: albuterol sulfate Inactive ingredient: propellant HFA-134a For more information about Albuterol Sulfate HFA, call 1-866-525-0688. Manufactured for: Prasco Laboratories , Mason, OH 45040 USA Manufactured by: GlaxoSmithKline, Durham, NC 27701 VNT-PS:4PIL This Patient Information has been approved by the U.S. Food and Drug Administration Revised: April 2024 INSTRUCTIONS FOR USE Albuterol Sulfate HFA Inhalation Aerosol for oral inhalation use Your Albuterol Sulfate HFA inhaler Figure A The metal canister holds the medicine. See Figure A. The metal canister has a counter to show how many sprays of medicine you have left. The number shows through a window in the back of the blue plastic actuator. See Figure A. The counter starts at 204 . The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000 . Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the metal canister.

tic actuator. See Figure A. The counter starts at 204 . The number will count down by 1 each time you spray the inhaler. The counter will stop counting at 000 . Do not try to change the numbers or take the counter off the metal canister. The counter cannot be reset, and it is permanently attached to the metal canister. The blue plastic actuator sprays the medicine from the metal canister. The plastic actuator has a blue protective cap that covers the mouthpiece. See Figure A. Keep the protective cap on the mouthpiece when the metal canister is not in use. Do not use the plastic actuator with a canister of medicine from any other inhaler. Do not use an Albuterol Sulfate HFA metal canister with an actuator from any other inhaler. Before using your Albuterol Sulfate HFA inhaler The inhaler should be at room temperature before you use it. If your child needs to use Albuterol Sulfate HFA, watch your child closely to make sure your child uses the inhaler correctly. Your healthcare provider will show you how your child should use Albuterol Sulfate HFA. Priming your Albuterol Sulfate HFA inhaler Figure B Figure C Figure D Before you use Albuterol Sulfate HFA for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it. To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. See Figure B. Shake the inhaler well. Spray the inhaler 1 time into the air away from your face. Avoid spraying in eyes. See Figure C. Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read 200 . See Figure D. You must prime your inhaler again if you have not used it in more than 14 days or if you have dropped it. To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. Shake and spray the inhaler 4 times into the air away from your face. How to use your Albuterol Sulfate HFA inhaler Follow these steps every time you use Albuterol Sulfate HFA. Figure E Figure F Figure G Step 1. Make sure the metal canister fits firmly in the plastic actuator. The counter should show through the window in the actuator. To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. Look inside the mouthpiece for foreign objects and take out any you see. Step 2. Hold the inhaler with the mouthpiece down and shake it well . See Figure E. Step 3. Breathe out through your mouth and push as much air from your lungs as you can. See Figure F. Step 4. Put the mouthpiece in your mouth and close your lips around it. Push the top of the metal canister firmly all the way down while you breathe in deeply and slowly through your mouth. See Figure G. Step 5. After the spray comes out, take your finger off the metal canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth. Step 6. Hold your breath for about 10 seconds, or for as long as is comfortable. Breathe out slowly as long as you can. If your healthcare provider has told you to use more sprays , wait 1 minute and shake the inhaler again. Repeat Step 2 through Step 6. Put the cap back on the mouthpiece after you finish using the inhaler. Make sure it snaps firmly into place. Cleaning your Albuterol Sulfate HFA inhaler Figure H Figure I Figure J Figure K Clean your inhaler at least 1 time each week. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. See Figure H. Step 7. Take the canister out of the plastic actuator and take the cap off the mouthpiece by squeezing the sides of the cap and pulling it straight out. Step 8. Hold the plastic actuator under the faucet and run warm water through it for about 30 seconds. See Figure I. Step 9.

up will not block the spray. See Figure H. Step 7. Take the canister out of the plastic actuator and take the cap off the mouthpiece by squeezing the sides of the cap and pulling it straight out. Step 8. Hold the plastic actuator under the faucet and run warm water through it for about 30 seconds. See Figure I. Step 9. Turn the plastic actuator upside down and run warm water through the mouthpiece for about 30 seconds. See Figure J. Step 10. Shake off as much water from the plastic actuator as you can. Look into the mouthpiece to make sure any medicine build-up has been completely washed away. If there is any build-up, repeat Step 8 and Step 9. Step 11. Let the plastic actuator air-dry overnight. See Figure K. Step 12. When the plastic actuator is dry, put the protective cap on the mouthpiece and then put the canister in the plastic actuator and make sure it fits firmly. Shake the inhaler well, remove the cap, and spray the inhaler 1 time into the air away from your face. (The counter will count down by 1 number.) Put the cap back on the mouthpiece. If you need to use your inhaler before the plastic actuator is completely dry: Shake as much water off the plastic actuator as you can. Put the cap on the mouthpiece and then put the canister in the plastic actuator and make sure it fits firmly. Shake the inhaler well, remove the cap, and spray it 1 time into the air away from your face. Take your Albuterol Sulfate HFA dose as prescribed. Follow cleaning Step 7 through Step 12 above. Replacing your Albuterol Sulfate HFA inhaler When the counter reads 020 , you should refill your prescription or ask your healthcare provider if you need another prescription for Albuterol Sulfate HFA. When the counter reads 000, throw the inhaler away. You should not keep using the inhaler when the counter reads 000 because you will not receive the right amount of medicine. Do not use the inhaler after the expiration date, which is on the packaging it comes in. For correct use of your Albuterol Sulfate HFA inhaler, remember: The metal canister should always fit firmly in the plastic actuator. Breathe in deeply and slowly to make sure you get all the medicine. Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully. Always keep the protective cap on the mouthpiece when your inhaler is not in use. Always store your inhaler with the mouthpiece pointing down. Clean your inhaler at least 1 time each week. For more information about Albuterol Sulfate HFA or how to use your inhaler, call 1-866-525-0688. This Instructions for Use has been approved by the U.S. Food and Drug Administration Revised: April 2024 Figure A Figure B Figure C Figure D Figure E Figure F Figure G Figure H Figure I Figure J Figure K

<table width="100%"><colgroup><col width="4%"/><col width="45%"/><col width="51%"/></colgroup><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PATIENT INFORMATION</content></paragraph><paragraph><content styleCode="bold">Albuterol Sulfate HFA</content></paragraph><paragraph><content styleCode="bold">Inhalation Aerosol</content></paragraph><paragraph><content styleCode="bold">for oral inhalation use</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is Albuterol Sulfate HFA?</content></paragraph><list listType="unordered"><item>Albuterol Sulfate HFA is a prescription inhaled medicine used in people aged 4 years and older to: <list listType="unordered"><item>treat or prevent bronchospasm in people who have reversible obstructive airway disease.</item><item>prevent exercise-induced bronchospasm.</item></list></item><item>It is not known if Albuterol Sulfate HFA is safe and effective in children younger than 4 years of age.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not use Albuterol Sulfate HFA:</content></paragraph><list listType="unordered"><item>if you are allergic to albuterol sulfate propionate or any of the ingredients in Albuterol Sulfate HFA. See the end of this Patient Information for a complete list of ingredients in Albuterol Sulfate HFA.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Before using Albuterol Sulfate HFA, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item>have heart problems.</item><item>have high blood pressure.</item><item>have seizures.</item><item>have thyroid problems.</item><item>have diabetes.</item><item>have low potassium levels in your blood.</item><item>are pregnant or plan to become pregnant. It is not known if Albuterol Sulfate HFA may harm your unborn baby.</item><item><content styleCode="bold">&#x25CB;Pregnancy Registry.</content>There is a pregnancy registry for women with asthma who receive asthma medications, including Albuterol Sulfate HFA, while pregnant. The purpose of the registry is to collect information about the health of you and your baby. You can talk to your healthcare provider about how to take part in this registry or you can get more information and register by calling 1-877-311-8972 or go to https://mothertobaby.org/ongoing-study/asthma. </item><item>are breastfeeding. It is not known if the medicine in Albuterol Sulfate HFA passes into your milk and if it can harm your baby.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. Albuterol Sulfate HFA and certain other medicines may interact with each other. This may cause serious side effects. Especially tell your healthcare provider if you take: </paragraph><list listType="unordered"><item>other inhaled medicines or asthma medicines</item><item>beta-blocker medicines</item><item>diuretics</item><item>digoxin</item><item>monoamine oxidase inhibitors</item><item>tricyclic antidepressants</item></list><paragraph>Know the medicines you take.

provider if you take: </paragraph><list listType="unordered"><item>other inhaled medicines or asthma medicines</item><item>beta-blocker medicines</item><item>diuretics</item><item>digoxin</item><item>monoamine oxidase inhibitors</item><item>tricyclic antidepressants</item></list><paragraph>Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I use Albuterol Sulfate HFA?</content></paragraph><paragraph><content styleCode="bold">Read the step-by-step instructions for using Albuterol Sulfate HFA at the end of this Patient Information.</content></paragraph><list listType="unordered"><item><content styleCode="bold">Do not</content>use Albuterol Sulfate HFA unless your healthcare provider has taught you how to use the inhaler and you understand how to use it correctly. </item><item>Children should use Albuterol Sulfate HFA with an adult&#x2019;s help, as instructed by the child&#x2019;s healthcare provider.</item><item>Use Albuterol Sulfate HFA exactly as your healthcare provider tells you to use it. <content styleCode="bold">Do not</content>use Albuterol Sulfate HFA more often than prescribed. </item><item><content styleCode="bold">Do not</content>increase your dose or take extra doses of Albuterol Sulfate HFA without first talking to your healthcare provider. </item><item>Each dose of Albuterol Sulfate HFA should last up to 4 hours to 6 hours.</item><item>Get medical help right away if Albuterol Sulfate HFA no longer helps your symptoms.</item><item>Get medical help right away if your symptoms get worse or if you need to use your inhaler more often.</item><item>While you are using Albuterol Sulfate HFA, use other inhaled medicines and asthma medicines only as directed by your healthcare provider.</item><item>Call your healthcare provider if your asthma symptoms like wheezing and trouble breathing become worse over a few hours or days. Your healthcare provider may need to give you another medicine to treat your symptoms.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects with Albuterol Sulfate HFA?</content></paragraph><paragraph><content styleCode="bold">Albuterol Sulfate HFA can cause serious side effects, including:</content></paragraph><list listType="unordered"><item><content styleCode="bold">worsening trouble breathing, coughing, and wheezing (paradoxical bronchospasm).</content>If this happens, stop using Albuterol Sulfate HFA and call your healthcare provider or get emergency help right away. Paradoxical bronchospasm is more likely to happen with your first use of a new canister of medicine.

eCode="bold">worsening trouble breathing, coughing, and wheezing (paradoxical bronchospasm).</content>If this happens, stop using Albuterol Sulfate HFA and call your healthcare provider or get emergency help right away. Paradoxical bronchospasm is more likely to happen with your first use of a new canister of medicine. </item><item><content styleCode="bold">heart problems, including faster heart rate and higher blood pressure.</content></item><item><content styleCode="bold">possible death in people with asthma who use too much Albuterol Sulfate HFA.</content></item><item><content styleCode="bold">serious allergic reactions.</content>Call your healthcare provider or get emergency medical care if you get any of the following symptoms of a serious allergic reaction: </item></list></td></tr><tr><td styleCode="Lrule " valign="top"/><td valign="top"><list listType="ordered"><item>&#x25CB;rash</item><item>&#x25CB;hives</item></list></td><td styleCode="Rrule " valign="top"><list listType="ordered"><item>&#x25CB;swelling of your face, mouth, and tongue</item><item>&#x25CB;breathing problems</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item><content styleCode="bold">changes in laboratory blood levels (sugar, potassium).</content></item></list><paragraph><content styleCode="bold">Common side effects of Albuterol Sulfate HFA include:</content></paragraph></td></tr><tr><td colspan="2" styleCode="Lrule " valign="top"><list listType="unordered"><item>sore throat</item><item>upper respiratory tract infection, including viral infection</item><item>cough</item><item>muscle pain</item><item>your heart feels like it is pounding or racing (palpitations)</item></list></td><td styleCode="Rrule " valign="top"><list listType="unordered"><item>chest pain</item><item>fast heart rate</item><item>shakiness</item><item>nervousness</item><item>dizziness</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>These are not all the possible side effects of Albuterol Sulfate HFA.</paragraph><paragraph>Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store Albuterol Sulfate HFA?</content></paragraph><list listType="unordered"><item>Store Albuterol Sulfate HFA at room temperature between 68&#xB0;F and 77&#xB0;F (20&#xB0;C and 25&#xB0;C) with the mouthpiece down.</item><item><content styleCode="bold">The contents of your Albuterol Sulfate HFA are under pressure: Do not</content>puncture. <content styleCode="bold">Do not</content>use or store near heat or open flame. Temperatures above 120&#xB0;F may cause the canister to burst. </item><item><content styleCode="bold">Do not</content>throw into fire or an incinerator. </item></list><paragraph><content styleCode="bold">Keep Albuterol Sulfate HFA and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of Albuterol Sulfate HFA.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Albuterol Sulfate HFA for a condition for which it was not prescribed. Do not give Albuterol Sulfate HFA to other people, even if they have the same symptoms that you have.

content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Albuterol Sulfate HFA for a condition for which it was not prescribed. Do not give Albuterol Sulfate HFA to other people, even if they have the same symptoms that you have. It may harm them.</paragraph><paragraph>You can ask your healthcare provider or pharmacist for information about Albuterol Sulfate HFA that was written for health professionals.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in Albuterol Sulfate HFA?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>albuterol sulfate </paragraph><paragraph><content styleCode="bold">Inactive ingredient:</content>propellant HFA-134a </paragraph><paragraph>For more information about Albuterol Sulfate HFA, call 1-866-525-0688.</paragraph><paragraph>Manufactured for: <content styleCode="bold">Prasco Laboratories</content>, Mason, OH 45040 USA </paragraph><paragraph>Manufactured by: GlaxoSmithKline, Durham, NC 27701</paragraph><paragraph>VNT-PS:4PIL</paragraph></td></tr></tbody></table>

rmation about Albuterol Sulfate HFA, call 1-866-525-0688.</paragraph><paragraph>Manufactured for: <content styleCode="bold">Prasco Laboratories</content>, Mason, OH 45040 USA </paragraph><paragraph>Manufactured by: GlaxoSmithKline, Durham, NC 27701</paragraph><paragraph>VNT-PS:4PIL</paragraph></td></tr></tbody></table> <table width="77.78%"><colgroup><col width="43%"/><col width="27%"/><col width="19%"/></colgroup><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">INSTRUCTIONS FOR USE</content></paragraph><paragraph><content styleCode="bold">Albuterol Sulfate HFA</content></paragraph><paragraph><content styleCode="bold">Inhalation Aerosol</content></paragraph><paragraph><content styleCode="bold">for oral inhalation use</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Your Albuterol Sulfate HFA inhaler</content></paragraph></td></tr><tr><td align="center" styleCode="Lrule " valign="top"><renderMultiMedia referencedObject="ID_750bcad9-9e0f-4375-ace8-367c3b0421c0"/><paragraph><content styleCode="bold">Figure A</content></paragraph></td><td colspan="2" styleCode="Rrule " valign="top"><list listType="unordered"><item>The metal canister holds the medicine. <content styleCode="bold">See Figure A.</content></item><item>The metal canister has a counter to show how many sprays of medicine you have left. The number shows through a window in the back of the blue plastic actuator. <content styleCode="bold">See Figure A.</content></item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><list listType="unordered"><item>The counter starts at <content styleCode="bold">204</content>. The number will count down by 1 each time you spray the inhaler. The counter will stop counting at <content styleCode="bold">000</content>. </item><item><content styleCode="bold">Do not try to change the numbers or take the counter off the metal canister.</content>The counter cannot be reset, and it is permanently attached to the metal canister. </item><item>The blue plastic actuator sprays the medicine from the metal canister. The plastic actuator has a blue protective cap that covers the mouthpiece. <content styleCode="bold">See Figure A.</content>Keep the protective cap on the mouthpiece when the metal canister is not in use. </item><item><content styleCode="bold">Do not</content>use the plastic actuator with a canister of medicine from any other inhaler. </item><item><content styleCode="bold">Do not</content>use an Albuterol Sulfate HFA metal canister with an actuator from any other inhaler. </item></list><paragraph><content styleCode="bold">Before using your Albuterol Sulfate HFA inhaler</content></paragraph><list listType="unordered"><item>The inhaler should be at room temperature before you use it.</item><item>If your child needs to use Albuterol Sulfate HFA, watch your child closely to make sure your child uses the inhaler correctly.

t styleCode="bold">Before using your Albuterol Sulfate HFA inhaler</content></paragraph><list listType="unordered"><item>The inhaler should be at room temperature before you use it.</item><item>If your child needs to use Albuterol Sulfate HFA, watch your child closely to make sure your child uses the inhaler correctly. Your healthcare provider will show you how your child should use Albuterol Sulfate HFA.</item></list><paragraph><content styleCode="bold">Priming your Albuterol Sulfate HFA inhaler</content></paragraph></td></tr><tr><td align="center" styleCode="Lrule " valign="top"><renderMultiMedia referencedObject="EC0FC32A-9814-4C30-BECA-AED253F0453D"/><paragraph><content styleCode="bold">Figure B</content></paragraph><renderMultiMedia referencedObject="DE1FA9B3-462E-4822-BB33-222214252DD4"/><paragraph><content styleCode="bold">Figure C</content></paragraph><renderMultiMedia referencedObject="ID_43500fbd-97fc-448c-a59e-75dd8d71852b"/><paragraph><content styleCode="bold">Figure D</content></paragraph></td><td colspan="2" styleCode="Rrule " valign="top"><paragraph>Before you use Albuterol Sulfate HFA for the first time, you must prime the inhaler so that you will get the right amount of medicine when you use it.</paragraph><list listType="unordered"><item>To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. <content styleCode="bold">See Figure B.</content></item><item>Shake the inhaler well.</item><item>Spray the inhaler 1 time into the air away from your face. <content styleCode="bold">Avoid spraying in eyes. See Figure C.</content></item><item>Shake and spray the inhaler like this 3 more times to finish priming it. The counter should now read <content styleCode="bold">200</content>. <content styleCode="bold">See Figure D.</content></item><item>You must prime your inhaler again if you have not used it in more than 14 days or if you have dropped it. To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out. Shake and spray the inhaler 4 times into the air away from your face.</item></list></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">How to use your Albuterol Sulfate HFA inhaler</content></paragraph><paragraph><content styleCode="bold">Follow these steps every time you use Albuterol Sulfate HFA.</content></paragraph></td></tr><tr><td align="center" rowspan="4" styleCode="Lrule " valign="top"><renderMultiMedia referencedObject="ID_5437be4a-6450-4c6f-a135-1350488be58b"/><paragraph><content styleCode="bold">Figure E</content></paragraph><renderMultiMedia referencedObject="D18FB662-4E94-4443-AD1C-9FF74C29F8F3"/><paragraph><content styleCode="bold">Figure F</content></paragraph><renderMultiMedia referencedObject="C641ED82-A4F3-4D35-AA8F-A8FB8A9B430B"/><paragraph><content styleCode="bold">Figure G</content></paragraph></td><td valign="top"><paragraph><content styleCode="bold">Step 1.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Make sure the metal canister fits firmly in the plastic actuator. The counter should show through the window in the actuator.</paragraph><paragraph>To take the cap off the mouthpiece, squeeze the sides of the cap and pull it straight out.</paragraph><paragraph>Look inside the mouthpiece for foreign objects and take out any you see.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 2.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Hold the inhaler with the mouthpiece down and <content styleCode="bold">shake it well</content>.

de the mouthpiece for foreign objects and take out any you see.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 2.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Hold the inhaler with the mouthpiece down and <content styleCode="bold">shake it well</content>. <content styleCode="bold">See Figure E.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 3.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Breathe out through your mouth and push as much air from your lungs as you can. <content styleCode="bold">See Figure F.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 4.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Put the mouthpiece in your mouth and close your lips around it. Push the top of the metal canister firmly <content styleCode="bold">all the way down</content>while you breathe in deeply and slowly through your mouth. <content styleCode="bold">See Figure G.</content></paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Step 5.</content></paragraph></td><td colspan="2" styleCode="Rrule " valign="top"><paragraph>After the spray comes out, take your finger off the metal canister. After you have breathed in all the way, take the inhaler out of your mouth and close your mouth.</paragraph></td></tr><tr><td styleCode="Lrule " valign="top"><paragraph><content styleCode="bold">Step 6.</content></paragraph></td><td colspan="2" styleCode="Rrule " valign="top"><paragraph><content styleCode="bold">Hold your breath for about 10 seconds,</content>or for as long as is comfortable. <content styleCode="bold">Breathe out slowly as long as you can.</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">If your healthcare provider has told you to use more sprays</content>, wait 1 minute and shake the inhaler again. Repeat Step 2 through Step 6. </paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph>Put the cap back on the mouthpiece after you finish using the inhaler. Make sure it snaps firmly into place.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Cleaning your Albuterol Sulfate HFA inhaler</content></paragraph></td></tr><tr><td align="center" rowspan="7" styleCode="Lrule " valign="top"><renderMultiMedia referencedObject="ID_79ae1de2-7c68-43b5-8f01-899ecbbeeaa9"/><paragraph><content styleCode="bold">Figure H</content></paragraph><renderMultiMedia referencedObject="C70AB10B-CA76-4257-ABDD-5313C3215EC9"/><paragraph><content styleCode="bold">Figure I</content></paragraph><renderMultiMedia referencedObject="ID_6da678f6-81dd-4da4-a596-0a5efdab0262"/><paragraph><content styleCode="bold">Figure J</content></paragraph><renderMultiMedia referencedObject="FBDFDED3-1085-4D3B-9C2B-5B90E80C4859"/><paragraph><content styleCode="bold">Figure K</content></paragraph></td><td colspan="2" styleCode="Rrule " valign="top"><paragraph>Clean your inhaler at least 1 time each week. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray.

859"/><paragraph><content styleCode="bold">Figure K</content></paragraph></td><td colspan="2" styleCode="Rrule " valign="top"><paragraph>Clean your inhaler at least 1 time each week. You may not see any medicine build-up on the inhaler, but it is important to keep it clean so medicine build-up will not block the spray. <content styleCode="bold">See Figure H.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 7.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Take the canister out of the plastic actuator and take the cap off the mouthpiece by squeezing the sides of the cap and pulling it straight out.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 8.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Hold the plastic actuator under the faucet and run warm water through it for about 30 seconds. <content styleCode="bold">See Figure I.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 9.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Turn the plastic actuator upside down and run warm water through the mouthpiece for about 30 seconds. <content styleCode="bold">See Figure J.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 10.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Shake off as much water from the plastic actuator as you can. Look into the mouthpiece to make sure any medicine build-up has been completely washed away. If there is any build-up, repeat Step 8 and Step 9.</paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 11.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>Let the plastic actuator air-dry overnight. <content styleCode="bold">See Figure K.</content></paragraph></td></tr><tr><td valign="top"><paragraph><content styleCode="bold">Step 12.</content></paragraph></td><td styleCode="Rrule " valign="top"><paragraph>When the plastic actuator is dry, put the protective cap on the mouthpiece and then put the canister in the plastic actuator and make sure it fits firmly. Shake the inhaler well, remove the cap, and spray the inhaler 1 time into the air away from your face. (The counter will count down by 1 number.) Put the cap back on the mouthpiece.</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Botrule Lrule " valign="top"><paragraph><content styleCode="bold">If you need to use your inhaler before the plastic actuator is completely dry:</content></paragraph><list listType="unordered"><item>Shake as much water off the plastic actuator as you can.</item><item>Put the cap on the mouthpiece and then put the canister in the plastic actuator and make sure it fits firmly.</item><item>Shake the inhaler well, remove the cap, and spray it 1 time into the air away from your face.</item><item>Take your Albuterol Sulfate HFA dose as prescribed.</item><item>Follow cleaning Step 7 through Step 12 above.</item></list><paragraph><content styleCode="bold">Replacing your Albuterol Sulfate HFA inhaler</content></paragraph><list listType="unordered"><item><content styleCode="bold">When the counter reads 020</content>, you should refill your prescription or ask your healthcare provider if you need another prescription for Albuterol Sulfate HFA. </item><item><content styleCode="bold">When the counter reads 000, throw the inhaler away.</content>You should not keep using the inhaler when the counter reads <content styleCode="bold">000</content>because you will not receive the right amount of medicine. </item><item><content styleCode="bold">Do not use the inhaler</content>after the expiration date, which is on the packaging it comes in.

e inhaler away.</content>You should not keep using the inhaler when the counter reads <content styleCode="bold">000</content>because you will not receive the right amount of medicine. </item><item><content styleCode="bold">Do not use the inhaler</content>after the expiration date, which is on the packaging it comes in. </item></list><paragraph><content styleCode="bold">For correct use of your Albuterol Sulfate HFA inhaler, remember:</content></paragraph><list listType="unordered"><item>The metal canister should always fit firmly in the plastic actuator.</item><item>Breathe in deeply and slowly to make sure you get all the medicine.</item><item>Hold your breath for about 10 seconds after breathing in the medicine. Then breathe out fully.</item><item>Always keep the protective cap on the mouthpiece when your inhaler is not in use.</item><item>Always store your inhaler with the mouthpiece pointing down.</item><item>Clean your inhaler at least 1 time each week.</item></list><paragraph>For more information about Albuterol Sulfate HFA or how to use your inhaler, call 1-866-525-0688.</paragraph></td></tr></tbody></table>

FOR ORAL INHALATION ONLY Prescribing Information OVERDOSAGE The expected symptoms with overdosage are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the symptoms listed under , 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 albuterol sulfate inhalation aerosol. Treatment consists of discontinuation of albuterol sulfate 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 albuterol sulfate 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/m 2 basis and approximately 3200 times the maximum recommended daily inhalation dose for children on a mg/m 2 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/m 2 basis and approximately 1400 times the maximum recommended daily inhalation dose for children on a mg/m 2 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/m 2 basis and approximately 6400 times the maximum recommended daily inhalation dose for children on a mg/m 2 basis). The inhalation median lethal dose has not been determined in animals.

DESCRIPTION The active component of albuterol sulfate inhalation aerosol is albuterol sulfate, USP racemic α 1 [( tert- Butylamino)methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1)(salt), a relatively selective beta 2 -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 molecular formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 . Albuterol sulfate is a white to off-white crystalline solid. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate 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. Chemical Structure

CLINICAL PHARMACOLOGY Mechanism of Action In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta 2 -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 section.) Activation of beta 2 -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 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. 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 beta 2 -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 to 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 (T max ) and mean residence time are both extremely short, leading to a transient appearance of HFA-134a in the blood with no evidence of accumulation.

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 (T max ) 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate inhalation aerosol taken 30 minutes before exercise provided comparable protection against exercise-induced bronchospasm as a CFC 11/12 propelled albuterol inhaler. FEV1 Graph

Mechanism of Action In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta 2 -adrenergic receptors compared with isoproterenol. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there is a population of beta 2 -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 section.) Activation of beta 2 -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 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.

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 albuterol sulfate 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.

INDICATIONS AND USAGE Albuterol sulfate 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.

WARNINGS 1. Paradoxical Bronchospasm Inhaled albuterol sulfate can produce paradoxical bronchospasm that may be life threatening. If paradoxical bronchospasm occurs, albuterol sulfate 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. 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 re-evaluation of the patient and treatment regimen, giving special consideration to the possible need for anti-inflammatory treatment, e.g., corticosteroids. 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. 4. Cardiovascular Effects Albuterol sulfate inhalation aerosol, 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 albuterol sulfate 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, albuterol sulfate inhalation aerosol, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 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. 6. 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 albuterol sulfate inhalation aerosol should last up to 4 to 6 hours. Albuterol sulfate inhalation aerosol should not be used more frequently than recommended. Do not increase the dose or frequency of doses of albuterol sulfate inhalation aerosol without consulting your physician. If you find that treatment with albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate inhalation aerosol. Effective and safe use of albuterol sulfate inhalation aerosol includes an understanding of the way that it should be administered.

uterol include palpitations, chest pain, rapid heart rate, tremor, or nervousness. If you are pregnant or nursing, contact your physician about use of albuterol sulfate inhalation aerosol. Effective and safe use of albuterol sulfate inhalation aerosol includes an understanding of the way that it should be administered. Use albuterol sulfate 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 albuterol sulfate inhalation aerosolto children is similar to that for adults. Children should use albuterol sulfate inhalation aerosolunder adult supervision, as instructed by the patient's physician. (See Patient's Instructions for Use .) Drug Interactions 1. Beta-Blockers Beta-adrenergic-receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol sulfate 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. 2. 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 nonpotassium-sparing diuretics. 3. 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. 4. Monoamine Oxidase Inhibitors or Tricyclic Antidepressants Albuterol sulfate 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 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/m 2 basis and approximately 6 times the maximum recommended daily inhalation dose for children on a mg/m 2 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 of up to 500 mg/kg (approximately 1700 times the maximum recommended daily inhalation dose for adults on a mg/m 2 basis and approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m 2 basis).

h 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/m 2 basis and approximately 800 times the maximum recommended daily inhalation dose for children on a mg/m 2 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/m 2 basis and approximately 110 times the maximum recommended daily inhalation dose for children on a mg/m 2 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/m 2 basis). Pregnancy Teratogenic Effects 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/m 2 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/m 2 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/m 2 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/m 2 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/m 2 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 albuterol sulfate inhalation aerosol or albuterol sulfate in pregnant women. Albuterol sulfate 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 albuterol sulfate 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.

e 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 beta 2 -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 albuterol sulfate 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 albuterol sulfate 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 albuterol sulfate inhalation aerosol in pediatric patients below the age of 4 years have not been established. Geriatrics Albuterol sulfate inhalation aerosol has not been studied in a geriatric population. As with other beta 2 -agonists, special caution should be observed when using albuterol sulfate inhalation aerosol in elderly patients who have concomitant cardiovascular disease that could be adversely affected by this class of drug.

ADVERSE REACTIONS Adverse reaction information concerning albuterol sulfate inhalation aerosol is derived from a 12-week, double-blind, double-dummy study which compared albuterol sulfate 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 albuterol sulfate inhalation aerosol treatment group and more frequently in the albuterol sulfate inhalation aerosol treatment group than in the placebo group. 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. Adverse Experience Incidences (% of patients) in a Large 12-week Clinical Trial* Body System/ Adverse Event (Preferred Term) Albuterol SulfateInhalation Aerosol (N=193) CFC 11/12 Propelled Albuterol Inhaler (N=186) HFA-134a Placebo Inhaler (N=186) *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 albuterol sulfate inhalation aerosol group and more frequently in the albuterol sulfate inhalation aerosol group than in the HFA-134a placebo inhaler group. 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 Adverse events reported by less than 3% of the patients receiving albuterol sulfate inhalation aerosol, and by a greater proportion of albuterol sulfate inhalation aerosol patients than placebo patients, which have the potential to be related to albuterol sulfate 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 albuterol sulfate inhalation aerosol. Adverse events reported in a 4-week pediatric clinical trial comparing albuterol sulfate 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. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table ID="_Reft300" width="100%"><caption>Adverse Experience Incidences (% of patients) in a Large 12-week Clinical Trial* </caption><col width="21%"/><col width="22%"/><col width="21%"/><col width="18%"/><col width="16%"/><thead><tr><th align="left" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Body System/</content> <content styleCode="bold">Adverse Event (Preferred Term) </content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Albuterol SulfateInhalation Aerosol (N=193) </content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">CFC 11/12 Propelled Albuterol Inhaler (N=186) </content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">HFA-134a Placebo Inhaler (N=186) </content></th></tr></thead><tfoot><tr><td align="left" colspan="5" valign="top">*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 albuterol sulfate inhalation aerosol group and more frequently in the albuterol sulfate inhalation aerosol group than in the HFA-134a placebo inhaler group.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>Application Site Disorders </paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph>Inhalation Site Sensation </paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>9 </paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Inhalation Taste Sensation </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Body as a Whole </paragraph></td><td styleCode="Rrule Lrule " valign="top"><paragraph>Allergic Reaction/Symptoms </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>&lt;1 </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"><paragraph>Back Pain </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fever </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule B

/paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule B otrule " valign="top"><paragraph>Central and Peripheral Nervous System </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tremor </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Gastrointestinal System </paragraph></td><td styleCode="Rrule Lrule " valign="top"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>9 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Heart Rate and Rhythm Disorder </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tachycardia </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>&lt;1 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Psychiatric Disorders </paragraph></td><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nervousness </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Respiratory System Disorders </paragraph></td><td styleCode="Rrule Lrule " valign="top"><paragraph>Respiratory Disorder </paragraph></td><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/><td styleCode="Rrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"><paragraph>(unspecified) </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5 </paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"><paragraph>Rhinitis </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>16 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>22 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>14 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper Resp Tract Infection </paragraph></td><td align="center" styleCode="Rrule Botrule "

agraph>22 </paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>14 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper Resp Tract Infection </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>20 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>18 </paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Urinary System Disorder </paragraph></td><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Urinary Tract Infection </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2 </paragraph></td></tr></tbody></table>

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 albuterol sulfate 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. Albuterol sulfate Inhalation Aerosol contains 200 inhalations per canister. The canister has an attached dose indicator, which indicates how many inhalations remain. The dose indicator display will move after every tenth actuation. When nearing the end of the usable inhalations, the background behind the number in the dose indicator display window changes to red at 20 actuations or lower. Albuterol sulfate Inhalation Aerosol should be discarded when the dose indicator display window shows zero. 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 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 Albuterol sulfate inhalation aerosol is supplied as a pressurized aluminum canister with an attached dose indicator, a light blue plastic actuator and dark blue 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 68788-8787-2 Rx only. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, canister should be at room temperature before use. SHAKE WELL BEFORE USING. The light blue actuator supplied with albuterol sulfate inhalation aerosolshould not be used with any other product canisters, and actuator from other products should not be used with albuterol sulfate inhalation aerosolcanister. The correct amount of medication in each canister cannot be assured after 200 actuations, and when the dose indicator display window shows zero, 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. Albuterol sulfate inhalation aerosol does not contain chlorofluorocarbons (CFCs) as the propellant. Manufactured by Aeropharm GmbH D-07407 Rudolstadt, Germany Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 The brands listed are the registered trademarks of their respective owners and are not trademarks of Sandoz Inc. Rev. July 2021 46293491 Relabeled By: Preferred Pharmaceuticals Inc.

INSTRUCTIONS FOR USE Albuterol Sulfate Inhalation Aerosol With Dose Indicator (al bue’ter ol sul’fate) Read this Instructions for Use before you start using albuterol sulfate inhalation aerosol and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or treatment. Your doctor should show you how your child should use albuterol sulfate inhalation aerosol. Important Information: • Albuterol sulfate inhalation aerosol is for oral inhalation use only. • Take albuterol sulfate inhalation aerosol exactly as your doctor tells you to. Albuterol sulfate inhalation aerosol comes as a canister with a dose indicator. The dose indicator is located on the top of the canister that fits into an actuator ( See Figure A ). The dose indicator display window will show you how many puffs of medicine you have left. A puff of medicine is released each time you press the center of the dose indicator. • Do not use the Albuterol Sulfate Inhalation Aerosol actuator with a canister of medicine from any other inhaler. • Do not use the Albuterol Sulfate Inhalation Aerosol canister with an actuator from any other inhaler. Figure A Before you use albuterol sulfate inhalation aerosol for the first time make sure that the pointer on the dose indicator is pointing to the right of the “200” inhalation mark in the dose indicator display window ( See Figure A ). Each canister of albuterol sulfate inhalation aerosol contains 200 puffs of medicine. This does not include the sprays of medicine used for priming your inhaler. • The dose indicator display window will continue to move after every 10 puffs. • The number in the dose indicator display window will continue to change after every 20 puffs. • The color in the dose indicator display window will change to red, as shown in the shaded area, when there are only 20 puffs of medicine left in your inhaler ( See Figure B ). This is when you need to refill your prescription or ask your doctor if you need another prescription for albuterol sulfate inhalation aerosol. Figure B Priming your albuterol sulfate inhalation aerosol inhaler: Before you use albuterol sulfate inhalation aerosol for the first time, you should prime your inhaler. If you do not use your albuterol sulfate inhalation aerosol for more than 2 weeks, you should re-prime it before use. • Remove the cap from the mouthpiece ( See Figure C ). Check inside the mouthpiece for objects before use. • Make sure the canister is fully inserted into the actuator. • Hold the inhaler in an upright position away from your face and shake the inhaler well . • Press down fully on the center of the dose indicator to release a spray of medicine. You may hear a soft click from the dose indicator as it counts down during use. • Repeat the priming step 3 more times to release a total of 4 sprays of medicine. Shake the inhaler well before each priming spray. • After the 4 priming sprays, the dose indicator should be pointing to 200. There are now 200 puffs of medicine left in the canister. • Your inhaler is now ready to use. Using your albuterol sulfate inhalation aerosol inhaler: Step 1: Shake the inhaler well before each use. Remove the cap from the mouthpiece ( see Figure C ). Check inside the mouthpiece for objects before use. Make sure the canister is fully inserted into the actuator. Figure C Step 2: Breathe out as fully as you comfortably can through your mouth.

nhalation aerosol inhaler: Step 1: Shake the inhaler well before each use. Remove the cap from the mouthpiece ( see Figure C ). Check inside the mouthpiece for objects before use. Make sure the canister is fully inserted into the actuator. Figure C Step 2: Breathe out as fully as you comfortably can through your mouth. Hold the inhaler in the upright position with the mouthpiece pointing towards you and place the mouthpiece fully into the mouth ( SeeFigure D ). Close your lips around the mouthpiece. Figure D Step 3: While breathing in deeply and slowly, press down on the center of the dose indicator with your index finger until the canister stops moving in the actuator and a puff of medicine has been released ( SeeFigure D ). Then stop pressing the dose indicator. Step 4: Hold your breath as long as you comfortably can, up to 10 seconds. Remove the inhaler from your mouth, and then breathe out. Step 5:If your doctor has prescribed additional puffs of albuterol sulfate inhalation aerosol , wait 1 minute, then shake the inhaler well. Repeat steps 3 through 5 in the section “Using your albuterol sulfate inhalation aerosol inhaler”. Step 6: Replace the cap right away after use. Cleaning your albuterol sulfate inhalation aerosol inhaler: It is very important that you keep the mouthpiece clean so that medicine will not build up and block the spray through the mouthpiece. Clean the mouthpiece 1 time each week or if your mouthpiece becomes blocked ( See Figure F ). Step 1: Remove the canister from the actuator and take the cap off the mouthpiece. Do not clean the metal canister or let it get wet. Step 2: Wash the mouthpiece through the top and bottom with warm running water for 30 seconds ( See Figure E ). Figure E Step 3: Shake off as much water from the mouthpiece as you can. Step 4: Look in the mouthpiece to make sure any medicine buildup has been completely washed away. If the mouthpiece is blocked with buildup, little to no medicine will come out of the mouthpiece ( See FigureF ). If there is any buildup, repeat Steps 2 through 4 in the section “Cleaning your albuterol sulfate inhalation aerosol inhaler” . Figure F Step 5: Let the mouthpiece air-dry such as overnight ( See Figure G ). Do not put the canister back into the actuator if it is still wet. Figure G Step 6: When the mouthpiece is dry, put the canister back in the actuator and put the cap on the mouthpiece. Note: If you need to use your albuterol sulfate inhalation aerosol inhaler before it is completely dry, put the canister back in the actuator and shake the inhaler well. Press down on the center of the dose indicator 2 times to release a total of 2 sprays into the air, away from your face. Take your dose as prescribed then clean and air-dry your inhaler as described in the section “Cleaning your albuterol sulfate inhalation aerosol inhaler” . How should I store albuterol sulfate inhalation aerosol? • Store albuterol sulfate inhalation aerosol at room temperature between 20° to 25°C (68° to 77°F). • Store with the mouthpiece down. • Avoid exposing albuterol sulfate inhalation aerosol to extreme heat and cold. • Do not puncture or burn the canister. • Keep your albuterol sulfate inhalation aerosol inhaler and all medicines out of the reach of children. Manufactured by Aeropharm GmbH D-07407 Rudolstadt, Germany This Instructions for Use has been approved by the U.S. Food and Drug Administration. Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Rev. July 2021 46293491 Relabeled By: Preferred Pharmaceuticals Inc. Fig-A Fig-B Fig-C Fig-D Fig-E Fig-F Fig-G

1 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.

2 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 )].

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 )].

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 )].

3 DOSAGE FORMS AND STRENGTHS Inhalation Powder: multi-dose breath-actuated dry powder inhaler that delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouth piece per actuation. Each inhaler is supplied for 200 or 30 inhalations. [see How Supplied/Storage and Handling ( 16 )] . Inhalation powder: dry powder inhaler 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) from the mouthpiece per actuation. The inhaler is supplied for 200 or 30 inhalation doses. ProAir Digihaler includes a built-in electronic module. ( 3 )

4 CONTRAINDICATIONS ProAir Digihaler is contraindicated in patients with a history of hypersensitivity to albuterol and/or severe hypersensitivity to milk proteins. Rare cases of hypersensitivity reactions, including urticaria, angioedema, and rash have been reported after the use of albuterol sulfate. There have been reports of anaphylactic reactions in patients using inhalation therapies containing lactose [see Warnings and Precautions ( 5.6 )] . Patients with hypersensitivity to albuterol. ( 4 ) Patients with severe hypersensitivity to milk proteins. ( 4 )

5 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).

pharyngeal 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.

5.2 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.

5.5 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.

6 ADVERSE REACTIONS Use of ProAir Digihaler may be associated with the following: Paradoxical bronchospasm [see Warnings and Precautions ( 5.1 )] Cardiovascular Effects [see Warnings and Precautions ( 5.4 )] Immediate hypersensitivity reactions [see Warnings and Precautions ( 5.6 )] Hypokalemia [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (≥1% and >placebo) are back pain, pain, gastroenteritis viral, sinus headache, urinary tract infection, nasopharyngitis, oropharyngeal pain and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Respiratory, LLC at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience A total of 1289 subjects were treated with albuterol sulfate inhalation powder (ProAir RespiClick hereafter referred to as albuterol sulfate MDPI) during the clinical development program. The most common adverse reactions (≥1% and >placebo) were back pain, pain, gastroenteritis viral, sinus headache, and urinary tract infection. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults and Adolescents 12 years of Age and Older: The adverse reaction information presented in Table 1 below concerning albuterol sulfate MDPI is derived from the 12-week blinded treatment period of three studies which compared albuterol sulfate MDPI 180 mcg four times daily with a double-blinded matched placebo in 653 asthmatic patients 12 to 76 years of age. Table 1: Adverse Reactions Experienced by Greater Than or Equal to 1.0% of Adult and Adolescent Patients in the Albuterol sulfate MDPI Group and Greater Than Placebo in three 12-Week Clinical Trials 1 Preferred Term Number (%) of patients Albuterol sulfate MDPI 180 mcg QID N=321 Placebo N=333 Back pain 6 (2%) 4 (1%) Pain 5 (2%) 2 (<1%) Gastroenteritis viral 4 (1%) 3 (<1%) Sinus headache 4 (1%) 3 (<1%) Urinary tract infection 4 (1%) 3 (<1%) This table includes all adverse events (whether considered by the investigator drug related or unrelated to drug) which occurred at an incidence rate of greater than or equal to 1.0% in the albuterol sulfate MDPI group and greater than placebo. In a long-term study of 168 patients treated with albuterol sulfate MDPI for up to 52 weeks (including a 12-week double-blind period), the most commonly reported adverse events greater than or equal to 5% were upper respiratory infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia. In a small cumulative dose study, tremor, palpitations, and headache were the most frequently occurring (≥5%) adverse events. Pediatric Patients 4 to 11 Years of Age: The adverse reaction information presented in Table 2 below concerning albuterol sulfate MDPI is derived from a 3‑week pediatric clinical trial which compared albuterol sulfate MDPI 180 mcg four times daily with a double‑blinded matched placebo in 185 asthmatic patients 4 to 11 years of age.

ients 4 to 11 Years of Age: The adverse reaction information presented in Table 2 below concerning albuterol sulfate MDPI is derived from a 3‑week pediatric clinical trial which compared albuterol sulfate MDPI 180 mcg four times daily with a double‑blinded matched placebo in 185 asthmatic patients 4 to 11 years of age. Table 2: Adverse Reactions Experienced by Greater Than or Equal to 2.0% of Patients 4 to 11 Years of Age in the Albuterol sulfate MDPI Group and Greater Than Placebo in the 3 Week Trial Preferred Term Number (%) of patients Albuterol sulfate MDPI 180 mcg QID N=93 Placebo N=92 Nasopharyngitis 2 (2%) 1 (1%) Oropharyngeal pain 2 (2%) 1 (1%) Vomiting 3 (3%) 1 (1%) 6.2 Postmarketing Experience In addition to the adverse reactions reported from clinical trials with albuterol sulfate MDPI, the following adverse events have been reported during use of other inhaled albuterol sulfate products: Urticaria, angioedema, rash, bronchospasm, hoarseness, oropharyngeal edema, and arrhythmias (including atrial fibrillation, supraventricular tachycardia, extrasystoles), rare cases of aggravated bronchospasm, lack of efficacy, asthma exacerbation (potentially fatal), muscle cramps, and various oropharyngeal side-effects such as throat irritation, altered taste, glossitis, tongue ulceration, and gagging. 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. In addition, albuterol, like other sympathomimetic agents, can cause adverse reactions such as: angina, hypertension or hypotension, palpitations, central nervous system stimulation, insomnia, headache, nervousness, tremor, muscle cramps, drying or irritation of the oropharynx, hypokalemia, hyperglycemia, and metabolic acidosis.

<table width="498px" cellspacing="0" cellpadding="0" border="0"><col width="99.5pt"/><col width="196.25pt"/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" rowspan="2">Preferred Term </th><th styleCode=" Botrule Toprule Lrule Rrule" colspan="2"> Number (%) of patients</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule">Albuterol sulfate MDPI 180 mcg QID N=321</th><th styleCode=" Botrule Toprule Lrule Rrule">Placebo N=333</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Back pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>6 (2%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>5 (2%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Gastroenteritis viral</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Sinus headache</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr></tbody></table>

raph>3 (&lt;1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Urinary tract infection</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4 (1%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (&lt;1%)</paragraph></td></tr></tbody></table> <table cellspacing="0" cellpadding="0"><col width="99.5pt"/><col width="196.25pt"/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" rowspan="2">Preferred Term</th><th styleCode=" Botrule Toprule Lrule Rrule" colspan="2"> Number (%) of patients</th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule">Albuterol sulfate MDPI 180 mcg QID N=93</th><th styleCode=" Botrule Toprule Lrule Rrule">Placebo N=92</th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Nasopharyngitis</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (2%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Oropharyngeal pain</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2 (2%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1%)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Vomiting</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>3 (3%)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1 (1%)</paragraph></td></tr></tbody></table>

7 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.

ion 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are clinical considerations with use of albuterol in pregnant women [see Clinical Considerations] . In animal reproduction studies, when albuterol sulfate was administered subcutaneously to pregnant mice there was evidence of cleft palate at less than and up to 9 times the maximum recommended human daily inhalation dose (MRHDID) [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control. Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of ProAir Digihaler for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. ProAir Digihaler has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure nine-tenths the maximum recommended human dose (MRHDID) for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Similar effects were not observed at approximately one-eleventh the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg) . 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. 8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production.

rats were dosed with radiolabeled albuterol sulfate demonstrated that drug-related material is transferred from the maternal circulation to the fetus. 8.2 Lactation Risk Summary There are no available data on the presence of albuterol in human milk, the effects on the breastfed child, or the effects on milk production. However, plasma levels of albuterol after inhaled therapeutic doses are low in humans, and if present in breast milk, albuterol has a low oral bioavailability [see Clinical Pharmacology ( 12.3 )] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ProAir Digihaler and any potential adverse effects on the breastfed child from albuterol or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of ProAir Digihaler for the treatment or prevention of bronchospasm with reversible obstructive airway disease have been established in pediatric patients 12 to 17 years of age. Use of ProAir Digihaler for this indication is supported by evidence from two 12-week clinical trials in 318 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, one long-term safety study in children 12 years of age and older, and one single-dose crossover study comparing doses of 90 and 180 mcg with albuterol sulfate inhalation aerosol (ProAir ® HFA) in 71 patients [see Clinical Studies ( 14.1 )]. The safety and effectiveness of ProAir Digihaler for treatment of exercise-induced bronchospasm have been established in children 12 years of age and older. Use of ProAir Digihaler for this indication is supported from one single-dose crossover study in 38 patients age 16 and older with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies ( 14.2 )] . The safety profile for patients ages 12 to 17 was consistent with the overall safety profile seen in these studies. The safety of ProAir Digihaler in children 4 to 11 years of age is based on two single-dose, controlled, crossover studies: one with 61 patients comparing doses of 90 and 180 mcg with matched placebo and albuterol HFA MDI and one with 15 patients comparing a dose of 180 mcg with matched albuterol HFA MDI; and one 3‑week clinical trial in 185 patients 4 to 11 years of age with asthma comparing a dose of 180 mcg four times daily with matched albuterol HFA MDI. The effectiveness of albuterol sulfate MDPI in children 4 to 11 years with exercise-induced bronchospasm is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of albuterol sulfate MDPI 90 mcg and 180 mcg with placebo in 61 patients with asthma, and data from a 3‑week clinical trial in 185 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol 4 times daily with placebo [see Clinical Studies ( 14.1 )] . The safety and effectiveness of ProAir Digihaler in pediatric patients below the age of 4 years have not been established. 8.5 Geriatric Use Clinical studies of albuterol sulfate MDPI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions ( 5.4 , 5.7 )].

8.1 Pregnancy Risk Summary There are no randomized clinical studies of use of albuterol during pregnancy. Available data from published epidemiological studies and postmarketing case reports of pregnancy outcomes following inhaled albuterol use do not consistently demonstrate a risk of major birth defects or miscarriage. There are clinical considerations with use of albuterol in pregnant women [see Clinical Considerations] . In animal reproduction studies, when albuterol sulfate was administered subcutaneously to pregnant mice there was evidence of cleft palate at less than and up to 9 times the maximum recommended human daily inhalation dose (MRHDID) [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk In women with poorly or moderately controlled asthma, there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women should be closely monitored and medication adjusted as necessary to maintain optimal control. Labor or Delivery Because of the potential for beta-agonist interference with uterine contractility, use of ProAir Digihaler for relief of bronchospasm during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. ProAir Digihaler has not been approved for the management of pre-term labor. Serious adverse reactions, including pulmonary edema, have been reported during or following treatment of premature labor with beta 2 -agonists, including albuterol. Data Animal Data In a mouse reproduction study, subcutaneously administered albuterol sulfate produced cleft palate formation in 5 of 111 (4.5%) fetuses at an exposure nine-tenths the maximum recommended human dose (MRHDID) for adults (on a mg/m 2 basis at a maternal dose of 0.25 mg/kg) and in 10 of 108 (9.3%) fetuses at approximately 9 times the MRHDID (on a mg/m 2 basis at a maternal dose of 2.5 mg/kg). Similar effects were not observed at approximately one-eleventh the MRHDID for adults (on a mg/m 2 basis at a maternal dose of 0.025 mg/kg). Cleft palate also occurred in 22 of 72 (30.5%) fetuses from females treated subcutaneously with isoproterenol (positive control). In a rabbit reproduction study, orally administered albuterol sulfate induced cranioschisis in 7 of 19 fetuses (37%) at approximately 750 times the MRHDID (on a mg/m 2 basis at a maternal dose of 50 mg/kg). In a rat reproduction study, an albuterol sulfate/HFA-134a formulation administered by inhalation did not produce any teratogenic effects at exposures approximately 80 times the MRHDID (on a mg/m 2 basis at a maternal dose of 10.5 mg/kg) . 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.

8.4 Pediatric Use The safety and effectiveness of ProAir Digihaler for the treatment or prevention of bronchospasm with reversible obstructive airway disease have been established in pediatric patients 12 to 17 years of age. Use of ProAir Digihaler for this indication is supported by evidence from two 12-week clinical trials in 318 patients 12 years of age and older with asthma comparing doses of 180 mcg four times daily with placebo, one long-term safety study in children 12 years of age and older, and one single-dose crossover study comparing doses of 90 and 180 mcg with albuterol sulfate inhalation aerosol (ProAir ® HFA) in 71 patients [see Clinical Studies ( 14.1 )]. The safety and effectiveness of ProAir Digihaler for treatment of exercise-induced bronchospasm have been established in children 12 years of age and older. Use of ProAir Digihaler for this indication is supported from one single-dose crossover study in 38 patients age 16 and older with exercise-induced bronchospasm comparing doses of 180 mcg with placebo [see Clinical Studies ( 14.2 )] . The safety profile for patients ages 12 to 17 was consistent with the overall safety profile seen in these studies. The safety of ProAir Digihaler in children 4 to 11 years of age is based on two single-dose, controlled, crossover studies: one with 61 patients comparing doses of 90 and 180 mcg with matched placebo and albuterol HFA MDI and one with 15 patients comparing a dose of 180 mcg with matched albuterol HFA MDI; and one 3‑week clinical trial in 185 patients 4 to 11 years of age with asthma comparing a dose of 180 mcg four times daily with matched albuterol HFA MDI. The effectiveness of albuterol sulfate MDPI in children 4 to 11 years with exercise-induced bronchospasm is extrapolated from clinical trials in patients 12 years of age and older with asthma and exercise-induced bronchospasm, based on data from a single-dose study comparing the bronchodilatory effect of albuterol sulfate MDPI 90 mcg and 180 mcg with placebo in 61 patients with asthma, and data from a 3‑week clinical trial in 185 asthmatic children 4 to 11 years of age comparing a dose of 180 mcg albuterol 4 times daily with placebo [see Clinical Studies ( 14.1 )] . The safety and effectiveness of ProAir Digihaler in pediatric patients below the age of 4 years have not been established.

8.5 Geriatric Use Clinical studies of albuterol sulfate MDPI did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Warnings and Precautions ( 5.4 , 5.7 )]. All beta 2 -adrenergic agonists, including albuterol, are known to be substantially excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

10 OVERDOSAGE 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 ProAir Digihaler. Treatment consists of discontinuation of ProAir Digihaler 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 ProAir Digihaler.

11 DESCRIPTION The active ingredient of ProAir Digihaler inhalation powder is albuterol sulfate, a racemic salt of albuterol. Albuterol sulfate is a beta 2 -adrenergic agonist. It has the chemical name α 1 -[( tert -butylamino) methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1) (salt), and the following chemical structure: The molecular weight of albuterol sulfate is 576.7, and the empirical formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 . Albuterol sulfate is a white to off-white crystalline powder. It is soluble in water and slightly soluble in ethanol. Albuterol sulfate is the official U.S. Adopted Name in the United States, and salbutamol sulfate is the recommended World Health Organization international nonproprietary name. ProAir Digihaler is inhalation-driven, multi-dose inhalation powder (dry powder inhaler) for oral inhalation only. It contains a formulation blend of albuterol sulfate with alpha-lactose monohydrate. Each actuation provides a metered dose of 2.6 mg of the formulation containing 117 mcg of albuterol sulfate (equivalent to 97 mcg of albuterol base) and lactose from the device reservoir. Under standardized in vitro test conditions with fixed flow rates ranging from 58 to 71 L/min, and with a total air volume of 2 L, ProAir Digihaler inhaler delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) with lactose from the mouthpiece. The actual amount of drug delivered to the lung will depend on patient factors, such as inspiratory flow profile. In a study that investigated the peak inspiratory flow rate (PIFR) in asthma (n=27, ages 12 to 17 years old and n=50, ages 18 to 45 years old) and COPD (n=50, over 50 years old) patients, the mean PIFR achieved by subjects was >60 L/min (range = 31 to 110 L/min.), indicating that patients would be able to achieve the required inspiratory flow to operate the MDPI device correctly. The inhaler is provided for 200 or 30 actuations (inhalations). ProAir Digihaler contains a QR code on the electronic module which is built-in to the top of the inhaler and automatically detects, records and stores data on inhaler events, including peak inspiratory flow rate (L/min). ProAir Digihaler may pair with and transmit data to the mobile App where inhaler events are categorized. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Albuterol sulfate is a beta 2 -adrenergic agonist. The pharmacologic effects of albuterol sulfate are attributable to activation of beta 2 -adrenergic receptors on airway smooth muscle. Activation of beta 2 -adrenergic receptors 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 is associated with the activation of protein kinase A, which in turn inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in muscle relaxation. Albuterol relaxes the smooth muscle 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. While it is recognized that beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% of which are cardiac beta 2 -adrenergic receptors. The precise function of these receptors has not been established [see Warnings and Precautions ( 5.4 )] . 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. However, 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 [ see Warnings and Precautions ( 5.4 )]. 12.2 Pharmacodynamics In a pharmacodynamic (PD) trial conducted in 47 patients, the PD and safety profiles were similar for albuterol sulfate MDPI and ProAir HFA. Comparable changes from baseline in the PD measures (serum glucose and potassium concentrations, QTcB, QTcF, heart rate, systolic blood pressure, and diastolic blood pressure) were observed following cumulative dose administration up to 1440 mcg of both albuterol sulfate MDPI and ProAir HFA. The overall safety, efficacy and PD profile of albuterol sulfate MDPI and ProAir HFA were comparable. Following 90 or 180 mcg single-dose inhalation, the bronchodilatory effect of albuterol sulfate MDPI was significantly greater than placebo and comparable to that of ProAir HFA in patients 12 years of age and older (N=71) and pediatric patients 4 to 11 years of age (N=61) with persistent asthma. Cardiac Electrophysiology As with other beta 2 -adrenergic agonists, albuterol sulfate MDPI prolonged QT intervals following a 1440 mcg cumulative dose. The prolongation was comparable to that of ProAir HFA. 12.3 Pharmacokinetics Absorption Albuterol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hour following single- or multiple-dose oral inhalation(s) of albuterol sulfate MDPI. In a cumulative dose study, the AUC 0-t was comparable between albuterol sulfate MDPI group and ProAir HFA group; C max value was approximately one-third higher in albuterol sulfate MDPI group than ProAir HFA group. Distribution The volume of distribution has not been determined for albuterol sulfate MDPI.

ulfate MDPI. In a cumulative dose study, the AUC 0-t was comparable between albuterol sulfate MDPI group and ProAir HFA group; C max value was approximately one-third higher in albuterol sulfate MDPI group than ProAir HFA group. Distribution The volume of distribution has not been determined for albuterol sulfate MDPI. Published literature suggests that albuterol exhibits low in vitro plasma protein binding (10%). Elimination The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-life was approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-dose administration. Metabolism Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. Excretion The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Specific Populations No pharmacokinetic studies for ProAir Digihaler have been conducted in neonates or elderly subjects. The systemic exposure in children 6 to 11 years of age is similar to that of adults following 180 mcg single dose inhalation of albuterol sulfate MDPI. The influence of gender or race on the pharmacokinetics of ProAir Digihaler has not been studied. Patients with Renal Impairment : The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of ProAir Digihaler to patients with renal impairment [see Use in Specific Populations ( 8.5 )] . Patients with Hepatic Impairment : The effect of hepatic impairment on the pharmacokinetics of ProAir Digihaler has not been evaluated. Drug Interaction Studies : In vitro and in vivo drug interaction studies have not been conducted with ProAir Digihaler. Known clinically significant drug interactions are outlined in Drug Interactions ( 7 ).

12.2 Pharmacodynamics In a pharmacodynamic (PD) trial conducted in 47 patients, the PD and safety profiles were similar for albuterol sulfate MDPI and ProAir HFA. Comparable changes from baseline in the PD measures (serum glucose and potassium concentrations, QTcB, QTcF, heart rate, systolic blood pressure, and diastolic blood pressure) were observed following cumulative dose administration up to 1440 mcg of both albuterol sulfate MDPI and ProAir HFA. The overall safety, efficacy and PD profile of albuterol sulfate MDPI and ProAir HFA were comparable. Following 90 or 180 mcg single-dose inhalation, the bronchodilatory effect of albuterol sulfate MDPI was significantly greater than placebo and comparable to that of ProAir HFA in patients 12 years of age and older (N=71) and pediatric patients 4 to 11 years of age (N=61) with persistent asthma. Cardiac Electrophysiology As with other beta 2 -adrenergic agonists, albuterol sulfate MDPI prolonged QT intervals following a 1440 mcg cumulative dose. The prolongation was comparable to that of ProAir HFA.

12.3 Pharmacokinetics Absorption Albuterol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hour following single- or multiple-dose oral inhalation(s) of albuterol sulfate MDPI. In a cumulative dose study, the AUC 0-t was comparable between albuterol sulfate MDPI group and ProAir HFA group; C max value was approximately one-third higher in albuterol sulfate MDPI group than ProAir HFA group. Distribution The volume of distribution has not been determined for albuterol sulfate MDPI. Published literature suggests that albuterol exhibits low in vitro plasma protein binding (10%). Elimination The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-life was approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-dose administration. Metabolism Information available in the published literature suggests that the primary enzyme responsible for the metabolism of albuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or via inhalation after oral charcoal administration, there was a 3- to 4-fold difference in the area under the concentration-time curves between the (R)- and (S)-albuterol enantiomers, with (S)-albuterol concentrations being consistently higher. However, without charcoal pretreatment, after either oral or inhalation administration the differences were 8- to 24-fold, suggesting that the (R)-albuterol is preferentially metabolized in the gastrointestinal tract, presumably by SULTIA3. Excretion The primary route of elimination of albuterol is through renal excretion (80% to 100%) of either the parent compound or the primary metabolite. Less than 20% of the drug is detected in the feces. Following intravenous administration of racemic albuterol, between 25% and 46% of the (R)-albuterol fraction of the dose was excreted as unchanged (R)-albuterol in the urine. Specific Populations No pharmacokinetic studies for ProAir Digihaler have been conducted in neonates or elderly subjects. The systemic exposure in children 6 to 11 years of age is similar to that of adults following 180 mcg single dose inhalation of albuterol sulfate MDPI. The influence of gender or race on the pharmacokinetics of ProAir Digihaler has not been studied. Patients with Renal Impairment : The effect of renal impairment on the pharmacokinetics of albuterol was evaluated in 5 subjects with creatinine clearance of 7 to 53 mL/min, and the results were compared with those from healthy volunteers. Renal disease had no effect on the half-life, but there was a 67% decline in albuterol clearance. Caution should be used when administering high doses of ProAir Digihaler to patients with renal impairment [see Use in Specific Populations ( 8.5 )] . Patients with Hepatic Impairment : The effect of hepatic impairment on the pharmacokinetics of ProAir Digihaler has not been evaluated. Drug Interaction Studies : In vitro and in vivo drug interaction studies have not been conducted with ProAir Digihaler. Known clinically significant drug interactions are outlined in Drug Interactions ( 7 ).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximum recommended daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m 2 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 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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 380 times the MRHDID for adults on a mg/m 2 basis). 13.2 Animal Toxicology and/or Pharmacology 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 β‑agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

13.1 Carcinogenesis, Mutagenesis, 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 and above dietary doses of 2 mg/kg (approximately 15 times and 6 times the maximum recommended daily inhalation dose (MRHDID) for adults and children, respectively, on a mg/m 2 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 1,900 times and 740 times the MRHDID for adults and children, respectively, on a mg/m 2 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 250 times and 100 times the MRHDID for adults and children, respectively, on a mg/m 2 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 380 times the MRHDID for adults on a mg/m 2 basis).

14 CLINICAL STUDIES 14.1 Overview of Clinical Studies The safety and effectiveness of ProAir Digihaler has been established in the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease and in the prevention of exercise-induced bronchospasm in patients 4 years of age and older. The use of ProAir Digihaler for these indications is supported by adequate and well-controlled studies in adults and pediatric patients of albuterol sulfate inhalation powder (ProAir RespiClick hereafter referred to as albuterol sulfate MDPI) [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.2 , 14.3 )]. 14.2 Bronchospasm Associated with Asthma Adult and Adolescent Patients 12 Years of Age and Older In two 12-week, randomized, double-blind, placebo-controlled studies of identical design (Study 1 and Study 2), albuterol sulfate MDPI (153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. Patients were maintained on inhaled corticosteroid treatment. Serial FEV 1 measurements, shown below in Figure 1 as average of the mean changes from test-day baseline at Day 1 and Day 85, demonstrated that two inhalations of albuterol sulfate MDPI produced significantly greater improvement in FEV 1 AUC 0‑6hr over the pre-treatment value than placebo in Study 1. Consistent results were observed in Study 2. Figure 1: FEV 1 as Mean Change from Test-Day, Pre-Dose Baseline in a 12-Week Clinical Trial (Study 1) In Study 1, 44 of 78 patients treated with albuterol sulfate MDPI achieved a 15% increase in FEV 1 within 30 minutes post‑dose on Day 1. The median time to onset was 5.7 minutes, and median duration of effect as measured by a 15% increase was approximately 2 hours. Consistent results were observed in Study 2. In a double‑blind, randomized, placebo–controlled, single‑dose crossover study evaluating albuterol sulfate MDPI and ProAir HFA in 71 adult and adolescent subjects ages 12 and older with persistent asthma, ProAir RespiClick had bronchodilator efficacy that was significantly greater than placebo at administered doses of 90 and 180 mcg. Pediatric Patients 4 to 11 Years of Age In a 3‑week, randomized, double‑blind, placebo-controlled trial, albuterol sulfate MDPI (92 patients) was compared to a matched placebo (92 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily. Serial FEV 1 measurements, expressed as the baseline-adjusted percent-predicted FEV 1 AUC 0‑6h over the 3‑week treatment period, demonstrated that 2 inhalations of albuterol sulfate MDPI produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo. In this study, 48 of 92 patients treated with albuterol sulfate MDPI achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1. The median time to onset was 5.9 minutes, and the median duration of effect as measured by a 15% increase was approximately 1 hour. In a placebo-controlled, single-dose, crossover study in 61 patients 4 to 11 years of age, albuterol sulfate MDPI, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo and with albuterol HFA MDI.

and the median duration of effect as measured by a 15% increase was approximately 1 hour. In a placebo-controlled, single-dose, crossover study in 61 patients 4 to 11 years of age, albuterol sulfate MDPI, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo and with albuterol HFA MDI. Albuterol sulfate MDPI provided similar bronchodilation when administered as one or two inhalations (baseline-adjusted percent-predicted serial FEV 1 observed over 6 hours post-dose), whereas two inhalations from albuterol HFA MDI provided significantly greater bronchodilation compared to a single inhalation. Figure 1 14.3 Exercise-Induced Bronchospasm In a randomized, single-dose, crossover study in 38 adult and adolescent patients with exercise-induced bronchospasm (EIB), two inhalations of albuterol sulfate MDPI taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as the maintenance of FEV 1 within 80% of post-dose, pre-exercise baseline values) in 97% (37 of 38) of patients as compared to 42% (16 of 38) of patients when they received placebo. Patients who participated in these clinical trials were allowed to use concomitant steroid therapy. 14.1 Overview of Clinical Studies The safety and effectiveness of ProAir Digihaler has been established in the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease and in the prevention of exercise-induced bronchospasm in patients 4 years of age and older. The use of ProAir Digihaler for these indications is supported by adequate and well-controlled studies in adults and pediatric patients of albuterol sulfate inhalation powder (ProAir RespiClick hereafter referred to as albuterol sulfate MDPI) [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.2 , 14.3 )].

The use of ProAir Digihaler for these indications is supported by adequate and well-controlled studies in adults and pediatric patients of albuterol sulfate inhalation powder (ProAir RespiClick hereafter referred to as albuterol sulfate MDPI) [see Use in Specific Populations ( 8.4 ), Clinical Studies ( 14.2 , 14.3 )]. 14.2 Bronchospasm Associated with Asthma Adult and Adolescent Patients 12 Years of Age and Older In two 12-week, randomized, double-blind, placebo-controlled studies of identical design (Study 1 and Study 2), albuterol sulfate MDPI (153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic patients 12 to 76 years of age at a dose of 180 mcg albuterol four times daily. Patients were maintained on inhaled corticosteroid treatment. Serial FEV 1 measurements, shown below in Figure 1 as average of the mean changes from test-day baseline at Day 1 and Day 85, demonstrated that two inhalations of albuterol sulfate MDPI produced significantly greater improvement in FEV 1 AUC 0‑6hr over the pre-treatment value than placebo in Study 1. Consistent results were observed in Study 2. Figure 1: FEV 1 as Mean Change from Test-Day, Pre-Dose Baseline in a 12-Week Clinical Trial (Study 1) In Study 1, 44 of 78 patients treated with albuterol sulfate MDPI achieved a 15% increase in FEV 1 within 30 minutes post‑dose on Day 1. The median time to onset was 5.7 minutes, and median duration of effect as measured by a 15% increase was approximately 2 hours. Consistent results were observed in Study 2. In a double‑blind, randomized, placebo–controlled, single‑dose crossover study evaluating albuterol sulfate MDPI and ProAir HFA in 71 adult and adolescent subjects ages 12 and older with persistent asthma, ProAir RespiClick had bronchodilator efficacy that was significantly greater than placebo at administered doses of 90 and 180 mcg. Pediatric Patients 4 to 11 Years of Age In a 3‑week, randomized, double‑blind, placebo-controlled trial, albuterol sulfate MDPI (92 patients) was compared to a matched placebo (92 patients) in asthmatic children 4 to 11 years of age at a dose of 180 mcg albuterol four times daily. Serial FEV 1 measurements, expressed as the baseline-adjusted percent-predicted FEV 1 AUC 0‑6h over the 3‑week treatment period, demonstrated that 2 inhalations of albuterol sulfate MDPI produced significantly greater improvement in FEV 1 over the pre-treatment value than the matched placebo. In this study, 48 of 92 patients treated with albuterol sulfate MDPI achieved a 15% increase in FEV 1 within 30 minutes post-dose on Day 1. The median time to onset was 5.9 minutes, and the median duration of effect as measured by a 15% increase was approximately 1 hour. In a placebo-controlled, single-dose, crossover study in 61 patients 4 to 11 years of age, albuterol sulfate MDPI, administered at albuterol doses of 90 and 180 mcg, was compared with a matched placebo and with albuterol HFA MDI. Albuterol sulfate MDPI provided similar bronchodilation when administered as one or two inhalations (baseline-adjusted percent-predicted serial FEV 1 observed over 6 hours post-dose), whereas two inhalations from albuterol HFA MDI provided significantly greater bronchodilation compared to a single inhalation. Figure 1

Albuterol sulfate MDPI provided similar bronchodilation when administered as one or two inhalations (baseline-adjusted percent-predicted serial FEV 1 observed over 6 hours post-dose), whereas two inhalations from albuterol HFA MDI provided significantly greater bronchodilation compared to a single inhalation. Figure 1 14.3 Exercise-Induced Bronchospasm In a randomized, single-dose, crossover study in 38 adult and adolescent patients with exercise-induced bronchospasm (EIB), two inhalations of albuterol sulfate MDPI taken 30 minutes before exercise prevented EIB for the hour following exercise (defined as the maintenance of FEV 1 within 80% of post-dose, pre-exercise baseline values) in 97% (37 of 38) of patients as compared to 42% (16 of 38) of patients when they received placebo. Patients who participated in these clinical trials were allowed to use concomitant steroid therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING ProAir Digihaler inhalation powder is supplied as a white inhaler with a red cap, in a sealed foil pouch, one pouch per carton. Actuations Net Contents NDC 200 0.65 g 59310-117-20 30 0.30 g 59310-540-30 Store at room temperature (between 15°C and 25°C; 59°F and 77°F). Avoid exposure to extreme heat, cold, or humidity. Keep out of reach of children. ProAir Digihaler inhaler has a dose counter. Patients should never try to alter the numbers for the dose counter. Discard the inhaler 13 months after opening the foil pouch, when the counter displays 0, or after the expiration date on the product, whichever comes first. The labeled amount of medication in each actuation cannot be assured after the counter displays 0, even though the inhaler is not completely empty and will continue to operate [see Dosage and Administration ( 2.4 ), Patient Counseling Information ( 1 7 )]. ProAir Digihaler contains a QR code and a built-in electronic module which automatically detects, records, and stores data on inhaler events, including peak inspiratory flow rate (L/min). ProAir Digihaler may pair with and transmit data to the mobile App via Bluetooth ® wireless technology where inhaler events are categorized. ProAir Digihaler contains a lithium-manganese dioxide battery and should be disposed of in accordance with state and local regulations.

<table cellspacing="0" cellpadding="0" border="1"><col width="1px1pt1pt"/><col width="2.55in"/><col width="2.55in"/><tbody><tr><td styleCode=" Toprule"><paragraph><content styleCode="bold">Actuations</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Net Contents</content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">NDC</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>200</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.65 g</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>59310-117-20</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>30</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule">0.30 g</td><td styleCode=" Botrule Toprule Lrule Rrule">59310-540-30</td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Patients should be given the following information: Frequency of Use The action of ProAir Digihaler should last for 4 to 6 hours. Instruct patients to not use ProAir Digihaler more frequently than recommended. Instruct patients to not increase the dose or frequency of doses of ProAir Digihaler without consulting the physician. If patients find that treatment with ProAir Digihaler becomes less effective for symptomatic relief, symptoms become worse, and/or they need to use the product more frequently than usual, they should seek medical attention immediately [see Warnings and Precautions ( 5.2 )] . Use of ProAir Digihaler Electronic Module and Mobile App Direct the patient to the Instructions for Use (IFU) on how to download the App and use the inhaler. Advise the patient that pairing of the inhaler to the App, having Bluetooth turned on, or being near their smartphone is not required for delivery of the medication from the inhaler or for normal use of the product [see Dosage and Administration ( 2.5 )] . Caring for and Storing the Inhaler Instruct patients to not open their inhaler unless they are taking a dose. Repeated opening and closing the cover without taking medication will waste medication and may damage the inhaler. Advise patients to keep their inhaler dry and clean at all times. Never wash or put any part of the inhaler in water. Patient should replace inhaler if washed or placed in water. Routine maintenance is not required. If the mouthpiece needs cleaning, instruct patients to gently wipe the mouthpiece with a dry cloth or tissue as needed. Instruct patients to store the inhaler at room temperature and to avoid exposure to extreme heat, cold, or humidity. Instruct patients to never take the inhaler apart. Inform patients that ProAir Digihaler has a dose counter. When the patient receives the inhaler, the number 200 will be displayed for the 200 dose canister; and 30 will be displayed for the 30 dose canister. The dose counter will count down each time the mouthpiece cap is opened and closed. The dose counter window displays the number of actuations left in the inhaler in units of two (e.g., 200, 198, 196, etc.). When the counter displays 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. Inform patients to discard ProAir Digihaler when the dose counter displays 0 or after the expiration date on the product, whichever comes first [see Dosage and Administration ( 2.3 ), ( 2.4 )] . Paradoxical Bronchospasm Inform patients that ProAir Digihaler can produce paradoxical bronchospasm. Instruct patients to discontinue ProAir Digihaler if paradoxical bronchospasm occurs [see Warnings and Precautions ( 5.1 )] . Concomitant Drug Use Inform patients that, while they are taking ProAir Digihaler, they should take other inhaled drugs and asthma medications only as directed by a physician [see Drug Interactions ( 7 )] . Common Adverse Events Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, and nervousness.

hile they are taking ProAir Digihaler, they should take other inhaled drugs and asthma medications only as directed by a physician [see Drug Interactions ( 7 )] . Common Adverse Events Common adverse effects of treatment with inhaled albuterol include palpitations, chest pain, rapid heart rate, tremor, and nervousness. Pregnancy Inform patients who are pregnant or nursing that they should contact their physician about the use of ProAir Digihaler [see Use in Specific Populations ( 8.1 )] . General Information on Use Effective and safe use of ProAir Digihaler includes an understanding of the way that it should be administered. Do not use a spacer or volume holding chamber with ProAir Digihaler. Patients should be instructed on the proper use of the inhaler. See the FDA-approved Patient Information and Patient Instructions for Use. 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. In general, the technique for administering ProAir Digihaler to children is similar to that for adults. Children should use ProAir Digihaler under adult supervision, as instructed by the patient’s physician. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 © Teva Respiratory, LLC. All rights reserved. The Bluetooth® word mark and logos are registered trademarks owned by the Bluetooth SIG, Inc. and any use of such marks by Teva Respiratory, LLC is under license. United States Patent Nos. 6701917, 6718972, 6748947, 6871646, 7540282, 8006690, 8651103, 8978966, 9216260, 9463288, 9731087, 9782550, 9782551, 10022510, 10124131 PRORDH-003 Rev. 06/2022 Teva Logo

PATIENT INFORMATION ProAir ® Digihaler ® (prō´ār di´ji haye´´ ler) (albuterol sulfate) inhalation powder What is ProAir Digihaler? ProAir Digihaler is a prescription medicine used in people 4 years of age and older to: treat or prevent bronchospasm in people who have reversible obstructive airway disease prevent exercise-induced bronchospasm ProAir Digihaler contains a built-in electronic module that records and stores information about inhaler events. The ProAir Digihaler may be used with, and transmits information to, an App through Bluetooth ® wireless technology. ProAir Digihaler does not need to be connected to the App in order for you to take your medicine. The electronic module does not control or interfere with delivery of the medicine through the inhaler. It is not known if ProAir Digihaler is safe and effective in children under 4 years of age. Do not use ProAir Digihaler if you are allergic to albuterol sulfate, lactose, milk proteins, or any of the ingredients in ProAir Digihaler. See the end of this leaflet for a complete list of ingredients in ProAir Digihaler. Before using ProAir Digihaler, tell your doctor about all of your medical conditions, including if you: have heart problems have high blood pressure (hypertension) have convulsions (seizures) have thyroid problems have diabetes have low potassium levels in your blood are pregnant or plan to become pregnant. It is not known if ProAir Digihaler will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant. are breastfeeding or plan to breastfeed. It is not known if ProAir Digihaler passes into your breast milk. Talk to your doctor about the best way to feed your baby if you are using ProAir Digihaler. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ProAir Digihaler and other medicines may affect each other and cause side effects. ProAir Digihaler may affect the way other medicines work, and other medicines may affect the way ProAir Digihaler works. Especially tell your doctor if you take: • other inhaled medicines or asthma medicines • digoxin • beta blocker medicines • monoamine oxidase inhibitors • diuretics • tricyclic antidepressants Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I use ProAir Digihaler? For detailed instructions on how to use the inhaler, see “Instructions for Use” at the end of this Patient Information. For detailed instructions on how to set up the App, go to www.ProAirDigihaler.com or call Teva at 1-888-603-0788. Connection to the App, having your Bluetooth turned on, or being near your smartphone is not required for your ProAir Digihaler to work and for you to get your medicine. The electronic module does not control or interfere with delivery of the medicine through the inhaler. Use ProAir Digihaler exactly as your doctor tells you to use it. If your child needs to use ProAir Digihaler, watch your child closely to make sure your child uses the inhaler correctly. Your doctor will show you how your child should use ProAir Digihaler. Each dose of ProAir Digihaler should last up to 4 hours to 6 hours. Do not increase your dose or take extra doses of ProAir Digihaler without first talking to your doctor.

, watch your child closely to make sure your child uses the inhaler correctly. Your doctor will show you how your child should use ProAir Digihaler. Each dose of ProAir Digihaler should last up to 4 hours to 6 hours. Do not increase your dose or take extra doses of ProAir Digihaler without first talking to your doctor. Do not use a spacer or volume holding chamber with ProAir Digihaler. ProAir Digihaler does not need priming. Get medical help right away if ProAir Digihaler no longer helps your symptoms. Get medical help right away if your symptoms get worse or if you need to use your inhaler more often. While you are using ProAir Digihaler, do not use other inhaled rescue medicines and asthma medicines unless your doctor tells you to do so. Call your doctor if your asthma symptoms, like wheezing and trouble breathing, become worse over a few hours or days. Your doctor may need to give you another medicine (for example, corticosteroids) to treat your symptoms. What are the possible side effects of ProAir Digihaler? ProAir Digihaler may cause serious side effects, including: worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm). If this happens stop using ProAir Digihaler and call your doctor or get emergency help right away. heart problems, including faster heart rate and higher blood pressure possible death in people with asthma who use too much ProAir Digihaler allergic reactions. Call your doctor right away if you have the following symptoms of an allergic reaction: ○ itchy skin ○ rash ○ swelling beneath your skin or in your throat ○ worsening trouble breathing worsening of other medical problems in people who also use ProAir Digihaler including increases in blood sugar low potassium levels in your blood The most common side effects of ProAir Digihaler include: • back pain • fast heart rate • pain • shakiness • upset stomach • nervousness • sinus headache • headache • urinary tract infection • dizziness • your heart feels like it is pounding or racing (palpitations) • sore throat • chest pain • runny nose • vomiting These are not all of the possible side effects of ProAir Digihaler. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store ProAir Digihaler? Store ProAir Digihaler at room temperature between 59ºF and 77ºF (15ºC and 25ºC). Avoid exposure to extreme heat, cold, or humidity. Keep the cap on the inhaler closed during storage. Keep your ProAir Digihaler inhaler dry and clean at all times. Do not wash or put any part of your ProAir Digihaler i nhaler in water. Replace your inhaler if washed or placed in water. Keep ProAir Digihaler and all medicines out of the reach of children. General information about the safe and effective use of ProAir Digihaler. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ProAir Digihaler for a condition for which it was not prescribed. Do not give ProAir Digihaler to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or doctor for information about ProAir Digihaler that was written for health professionals. What are the ingredients in ProAir Digihaler? Active ingredient: albuterol sulfate Inactive ingredients: lactose (may contain milk proteins) For more information about ProAir Digihaler, call 1-888-603-0788, or go to www.ProAirDigihaler.com The Bluetooth® word mark and logos are registered trademarks owned by the Bluetooth SIG, Inc. and any use of such marks by Teva Respiratory, LLC is under license. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2022 Teva Respiratory, LLC. All rights reserved. PRODHPL-003 This Patient Information has been approved by the U.S.

d logos are registered trademarks owned by the Bluetooth SIG, Inc. and any use of such marks by Teva Respiratory, LLC is under license. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2022 Teva Respiratory, LLC. All rights reserved. PRODHPL-003 This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2022 Teva logo

<table width="684px"><col/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">ProAir^&#xAE; Digihaler^&#xAE;(pr&#x14D;&#xB4;&#x101;r </content><content styleCode="bold">di&#xB4;ji haye&#xB4;&#xB4; ler)</content></paragraph><paragraph><content styleCode="bold">(albuterol sulfate)</content></paragraph><content styleCode="bold">inhalation powder</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What is </content><content styleCode="bold">ProAir </content><content styleCode="bold">Digihaler?</content></paragraph><paragraph>ProAir Digihaler is a prescription medicine used in people 4 years of age and older to:</paragraph><list listType="unordered" styleCode="Disc"><item>treat or prevent bronchospasm in people who have reversible obstructive airway disease</item><item>prevent exercise-induced bronchospasm</item></list><paragraph>ProAir Digihaler contains a built-in electronic module that records and stores information about inhaler events. The ProAir Digihaler may be used with, and transmits information to, an App through Bluetooth^&#xAE;wireless technology.</paragraph><paragraph><content styleCode="bold">ProAir Digihaler does not need to be connected to the App in order for you to take your medicine. </content>The electronic module does not control or interfere with delivery of the medicine through the inhaler.</paragraph> It is not known if ProAir Digihaler is safe and effective in children under 4 years of age.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><content styleCode="bold"><content styleCode="bold">Do not use ProAir Digihaler if you </content>are </content>allergic to albuterol sulfate, lactose, milk proteins, or any of the ingredients in ProAir Digihaler. See the end of this leaflet for a complete list of ingredients in ProAir Digihaler.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Before using </content><content styleCode="bold">ProAir</content><content styleCode="bold"> Digihaler, tell your doctor about all of your medical conditions, including if you:</content></paragraph><list listType="unordered" styleCode="Disc"><item>have heart problems</item><item>have high blood pressure (hypertension)</item><item>have convulsions (seizures)</item><item>have thyroid problems</item><item>have diabetes</item><item>have low potassium levels in your blood</item><item>are pregnant or plan to become pregnant. It is not known if ProAir Digihaler will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.</item><item>are breastfeeding or plan to breastfeed. It is not known if ProAir Digihaler passes into your breast milk. Talk to your doctor about the best way to feed your baby if you are using ProAir Digihaler.</item></list><paragraph><content styleCode="bold">Tell your doctor about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>ProAir Digihaler and other medicines may affect each other and cause side effects.

oAir Digihaler.</item></list><paragraph><content styleCode="bold">Tell your doctor about all the medicines you take,</content> including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>ProAir Digihaler and other medicines may affect each other and cause side effects. ProAir Digihaler may affect the way other medicines work, and other medicines may affect the way ProAir Digihaler works.</paragraph><paragraph>Especially tell your doctor if you take:</paragraph><paragraph>&#x2022; other inhaled medicines or asthma medicines &#x2022; digoxin</paragraph><paragraph>&#x2022; beta blocker medicines &#x2022; monoamine oxidase inhibitors</paragraph><paragraph> &#x2022; diuretics &#x2022; tricyclic antidepressants</paragraph><paragraph>Ask your doctor or pharmacist for a list of these medicines if you are not sure. </paragraph> Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">How should I use </content><content styleCode="bold">ProAir Digihaler?</content><list listType="unordered" styleCode="Disc"><item>For detailed instructions on how to use the inhaler, see<content styleCode="bold"> &#x201C;Instructions for Use&#x201D;</content> at the end of this Patient Information.</item><item>For detailed instructions on how to set up the App, go to www.ProAirDigihaler.com or call Teva at 1-888-603-0788.</item><item>Connection to the App, having your Bluetooth turned on, or being near your smartphone is not required for your ProAir Digihaler to work and for you to get your medicine.</item><item>The electronic module does not control or interfere with delivery of the medicine through the inhaler.</item><item>Use ProAir Digihaler exactly as your doctor tells you to use it.</item><item>If your child needs to use ProAir Digihaler, watch your child closely to make sure your child uses the inhaler correctly. Your doctor will show you how your child should use ProAir Digihaler.</item><item>Each dose of ProAir Digihaler should last up to 4 hours to 6 hours.</item><item><content styleCode="bold">Do not</content> increase your dose or take extra doses of ProAir Digihaler without first talking to your doctor.</item><item>Do not use a spacer or volume holding chamber with ProAir Digihaler.</item><item>ProAir Digihaler does not need priming.</item><item>Get medical help right away if ProAir Digihaler no longer helps your symptoms.</item><item>Get medical help right away if your symptoms get worse or if you need to use your inhaler more often.</item><item>While you are using ProAir Digihaler, <content styleCode="bold">do not</content> use other inhaled rescue medicines and asthma medicines unless your doctor tells you to do so.</item></list> Call your doctor if your asthma symptoms, like wheezing and trouble breathing, become worse over a few hours or days. Your doctor may need to give you another medicine (for example, corticosteroids) to treat your symptoms.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">What are the possible side effects of </content><content styleCode="bold">ProAir Digihaler?</content><paragraph><content styleCode="bold">ProAir Digihaler</content><content styleCode="bold"> may cause serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm). </content>If this happens stop using ProAir Digihaler and call your doctor or get emergency help right away.

se serious side effects, including:</content></paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">worsening trouble breathing, coughing and wheezing (paradoxical bronchospasm). </content>If this happens stop using ProAir Digihaler and call your doctor or get emergency help right away. </item><item><content styleCode="bold">heart problems, including faster heart rate and higher blood pressure</content></item><item><content styleCode="bold">possible death in people with asthma who use too much </content><content styleCode="bold">ProAir </content><content styleCode="bold">Digihaler</content></item><item><content styleCode="bold">allergic reactions. </content>Call your doctor right away if you have the following symptoms of an allergic reaction:</item></list><paragraph>&#x25CB; itchy skin &#x25CB; rash</paragraph><paragraph> &#x25CB; swelling beneath your skin or in your throat &#x25CB; worsening trouble breathing</paragraph><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">worsening of other medical problems in people who also use </content><content styleCode="bold">ProAir</content><content styleCode="bold"> Digihaler including increases in blood sugar</content></item><item><content styleCode="bold">low potassium levels in your blood</content></item></list><paragraph>The most common side effects of ProAir Digihaler include:</paragraph><paragraph>&#x2022; back pain &#x2022; fast heart rate</paragraph><paragraph>&#x2022; pain &#x2022; shakiness</paragraph><paragraph>&#x2022; upset stomach &#x2022; nervousness</paragraph><paragraph>&#x2022; sinus headache &#x2022; headache</paragraph><paragraph>&#x2022; urinary tract infection &#x2022; dizziness</paragraph><paragraph>&#x2022; your heart feels like it is pounding or racing (palpitations) &#x2022; sore throat</paragraph><paragraph>&#x2022; chest pain &#x2022; runny nose</paragraph><paragraph> &#x2022; vomiting </paragraph><paragraph>These are not all of the possible side effects of ProAir Digihaler.</paragraph> Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"> <content styleCode="bold">How should I store </content><content styleCode="bold">ProAir Digihaler?</content><list listType="unordered" styleCode="Disc"><item>Store ProAir Digihaler at room temperature between 59&#xBA;F and 77&#xBA;F (15&#xBA;C and 25&#xBA;C).</item><item>Avoid exposure to extreme heat, cold, or humidity.</item><item>Keep the cap on the inhaler closed during storage. </item><item>Keep your ProAir Digihaler inhaler dry and clean at all times. </item><item><content styleCode="bold">Do not wash or put any part of your </content><content styleCode="bold">ProAir Digihaler i</content><content styleCode="bold">nhaler in water. </content>Replace your inhaler if washed or placed in water.</item></list><content styleCode="bold">Keep </content><content styleCode="bold">ProAir Digihaler and all medicines out of the reach of children.</content></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">General information about the safe and effective use of </content><content styleCode="bold">ProAir Digihaler.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ProAir Digihaler for a condition for which it was not prescribed. Do not give ProAir Digihaler to other people, even if they have the same symptoms that you have.

gihaler.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use ProAir Digihaler for a condition for which it was not prescribed. Do not give ProAir Digihaler to other people, even if they have the same symptoms that you have. It may harm them.</paragraph> You can ask your pharmacist or doctor for information about ProAir Digihaler that was written for health professionals.</td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">What are the ingredients in </content><content styleCode="bold">ProAir Digihaler?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> albuterol sulfate</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> lactose (may contain milk proteins)</paragraph><paragraph>For more information about ProAir Digihaler, call 1-888-603-0788, or go to www.ProAirDigihaler.com</paragraph><paragraph> The Bluetooth&#xAE; word mark and logos are registered trademarks owned by the Bluetooth SIG, Inc. and any use of such marks by Teva Respiratory, LLC is under license.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>Distributed by:</paragraph><paragraph>Teva Pharmaceuticals USA, Inc.</paragraph><paragraph>Parsippany, NJ 07054</paragraph><paragraph>&#xA9;2022 Teva Respiratory, LLC. All rights reserved.</paragraph><renderMultiMedia referencedObject="MM4"/><paragraph>PRODHPL-003</paragraph></td></tr></tbody></table>

INSTRUCTIONS FOR USE ProAir ® Digihaler ® (prō´ār di´ji haye´´ler) (albuterol sulfate) inhalation powder Your ProAir Digihaler Inhaler When you are ready to use ProAir Digihaler for the first time, remove the ProAir Digihaler inhaler from the foil pouch. There are 3 main parts of your ProAir Digihaler inhaler including: the white inhaler with the mouthpiece. See Figure A. the red cap that covers the mouthpiece and vent of the inhaler. See Figure A. the electronic module. See Figure A. There is an electronic module built into the top of the inhaler that records and stores information about inhaler events. The electronic module sends information through Bluetooth ® wireless technology to a mobile application (App). The electronic module does not control or interfere with delivery of the medicine through the inhaler. There is a dose counter in the back of the inhaler with a viewing window that shows you how many doses of medicine you have left. See Figure A. Figure A Your ProAir Digihaler inhaler contains 200 doses (inhalations). If you have a sample inhaler (with "SAMPLE" on the back label), your inhaler contains 30 doses (inhalations). See Figure B. The dose counter shows the number of doses left in your inhaler. When there are 20 doses left, the dose counter will change to red and you should refill your prescription or ask your doctor for another prescription. When the dose counter displays ‘0’ your inhaler is empty and you should stop using the inhaler. ProAir Digihaler contains a lithium - manganese dioxide battery and should be thrown away (disposed of) in accordance with state and local regulations. See Figure B. Figure B IMPORTANT: Always close the cap after each inhalation so your inhaler will be ready for you to take your next dose. Do not open the cap unless you are ready for your next dose. You will hear a “click” sound when the cap is opened fully. If you do not hear the “click” sound the inhaler may not be activated to give you a dose of medicine. ProAir Digihaler does not have an activation button or medicine canister. When you open the cap, a dose of ProAir Digihaler will be activated for delivery of the medicine. ProAir Digihaler does not need to be wirelessly connected to the mobile application (App) in order for it to work and for you to take your medicine. In general, the technique for administering ProAir Digihaler to children is similar to that for adults. Children should use ProAir Digihaler under adult supervision, as instructed by the patient’s physician. Do not use a spacer or volume holding chamber with ProAir Digihaler. ProAir Digihaler does not need priming. Using your ProAir Digihaler inhaler: Important: Make sure the red cap is closed before you start using your inhaler. Step 1. Open Hold the inhaler upright and open the red cap fully until you feel and hear a “click”. See Figure C . Each time you open the red cap and it “clicks”, a dose of ProAir Digihaler is ready to be inhaled. Figure C Remember: For the correct use of ProAir Digihaler, hold the inhaler upright as you open the red cap. See Figure D. Do not hold the inhaler in any other way as you open the red cap. Do not open the red cap until you are ready to take a dose of ProAir Digihaler. Figure D Step 2. Inhale Before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can. See Figure E. Do not exhale into the inhaler mouthpiece.

e inhaler in any other way as you open the red cap. Do not open the red cap until you are ready to take a dose of ProAir Digihaler. Figure D Step 2. Inhale Before you inhale, breathe out (exhale) through your mouth and push as much air from your lungs as you can. See Figure E. Do not exhale into the inhaler mouthpiece. Figure E Put the mouthpiece in your mouth and close your lips tightly around it. See Figure F. Figure F Do not block the vent above the mouthpiece with your lips or fingers. See Figure G. Figure G Breathe in quickly and deeply through your mouth, to deliver the dose of medicine to your lungs. Remove the inhaler from your mouth. Hold your breath for about 10 seconds or for as long as you comfortably can. Your ProAir Digihaler Inhaler delivers your dose of medicine as a very fine powder that you may or may not taste or feel. Do not take an extra dose from the inhaler even if you do not taste or feel the medicine. Step 3. Close Figure H Close the red cap firmly over the mouthpiece. See Figure H. Make sure you close the red cap after each inhalation so that the inhaler will be ready for your next dose. If you need another dose, close the red cap and then repeat steps 1-3. Storing your ProAir Digihaler inhaler Store ProAir Digihaler at room temperature between 59ºF and 77ºF (15ºC and 25ºC). Avoid exposure to extreme heat, cold, or humidity. Keep the red cap on the inhaler closed during storage. Keep your ProAir Digihaler inhaler dry and clean at all times. Do not wash or put any part of your ProAir Digihaler inhaler in water. Replace your inhaler if washed or placed in water. Keep your ProAir Digihaler inhaler and all medicines out of the reach of children. Cleaning your ProAir Digihaler inhaler Do not wash or put any part of your ProAir Digihaler inhaler in water. Replace your inhaler if washed or placed in water. ProAir Digihaler contains a powder and must be kept clean and dry at all times. If the mouthpiece needs cleaning, gently wipe it with a dry cloth or tissue. Replacing your ProAir Digihaler inhaler The dose counter on the back of your inhaler shows how many doses you have left. Do not try to change the numbers for the dose counter. When there are 20 doses left, the dose counter color will change to red and you should refill your prescription or ask your doctor for another prescription. When the dose counter displays ‘0’ your ProAir Digihaler inhaler is empty and you should stop using the inhaler and throw it away. Throw away your ProAir Digihaler inhaler 13 months after removing it from the foil pouch for the first time, when the dose counter displays ‘0’, or after the expiration date on the package, whichever comes first. ProAir Digihaler contains a lithium – manganese dioxide battery and should be thrown away (disposed of) in accordance with state and local regulations. Important information Do not open the red cap unless you are taking a dose. Repeatedly opening and closing the cap without inhaling a dose will waste the medicine and may damage your inhaler. Your ProAir Digihaler inhaler contains dry powder so it is important that you do not blow or breathe into it. Do not take the inhaler apart. Support For instructions on setting up the App, go to www.ProAirDigihaler.com or call Teva at 1-888-603-0788. If you have any questions about ProAir Digihaler, how to use your inhaler, go to www.ProAirDigihaler.com or call 1-888-603-0788. This device complies with part 15 of the FCC Rules. Operation is subject to the following two conditions: (1) This device may not cause harmful interference, and (2) This device must accept any interference received, including interference that may cause undesired operation. Changes or modifications not expressly approved by Teva could void the user’s authority to operate the equipment.

ect to the following two conditions: (1) This device may not cause harmful interference, and (2) This device must accept any interference received, including interference that may cause undesired operation. Changes or modifications not expressly approved by Teva could void the user’s authority to operate the equipment. This Instructions for Use has been approved by the U.S. Food and Drug Administration. The Bluetooth ® word mark and logos are registered trademarks owned by the Bluetooth SIG, Inc. and any use of such marks by Teva Respiratory, LLC is under license. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 ©2022 Teva Respiratory, LLC. All rights reserved. PRODHIFU-003 Revised June 2022 IFU Figure A New image with 30 dose counter Figure C Figure D Figure E Figure F Figure G Figure H Steps 1-3 image Teva logo