FDA label 6d6a3e12-ee60-4cec-9f1b-df00c47b769f

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). 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.

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. 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>

<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>