DailyMed Label: ProAir Digihaler

DailyMed Label: ProAir Digihaler

2022

DailyMed Prescription

ProAir Digihaler

Albuterol Sulfate

Teva Respiratory, LLC

NDC: 59310-540

NDC: 59310-540

NDC: 59310-117

NDC: 59310-117

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

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 ) ProAir ® Digihaler ® is indicated for the treatment or prevention of bronchospasm in patients 4 years of age and older with reversible obstructive airway disease. ProAir Digihaler is indicated for the prevention of exercise-induced bronchospasm in patients 4 years of age and older.

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 ) 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. The recommended dosage is 2 inhalations 15 to 30 minutes before exercise by oral inhalation. 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. 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 )]. 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 )].

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 )

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 )

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 ) 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. 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. 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. 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. 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. 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. 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. 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.

Use of ProAir Digihaler may be associated with the following:

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 ) 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. 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. 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. 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.

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. 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. 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. 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.

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.

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 )]. 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. 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 ).

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). 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.

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 )]. 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 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.

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. 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. Food and Drug Administration.       Revised: 06/2022 Teva logo

PC5719 Pro Air Digi outer carton PC5719 ProAir Digi inner carton NDC 59310-117-20 Rx Only ProAir digihaler (albuterol sulfate) Inhalation Powder 200 metered inhalations 0.65g  net contents Refer to enclosed Patient Leaflet and Instructions for Use for detailed information on product use and handling. For more information visit www.ProAirDigihaler.com or call 1-800-603-0788 CONTENTS : Each metered dose contains 117 mcg of albuterol sulfate (equivalent to 97 mcg of albuterol base) from the device reservoir and delivers 108 mcg of albuterol sulfate (equivalent to 90 mcg of albuterol base) with lactose from the mouthpiece. Usual Dosage : See package insert for full prescribing information. IMPORTANT SAFETY INFORMATION If recommended dosage does not provide relief of symptoms or symptoms become worse, seek medical attention immediately. While taking ProAir ® digihaler TM  other inhaled medicines should be used only as prescribed by your physician. NEVER WASH OR PUT ANY PART OF YOUR INHALER IN WATER. IMPORTANT Discard inhaler when dose counter displays 0, or after the expiration date on the product, whichever comes first. Store inhaler at controlled room temperature between 15°C and 25°C (59°F and 77°F). Avoid exposure to extreme heat, cold, or humidity. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 MANUFACTURED IN IRELAND ©2022 Teva Respiratory, LLC FCC ID: 2AJVSPDR0000401 For California Only : This product uses batteries containing Perchlorate Material – special handling may apply. See  www .dtsc.ca.gov/hazardouswaste/perchlorate [22 CCR 67384.4(a)]. Rev. 01/2022 Rev 01/2022 Rev 01/2022