Airsupra

1 INDICATIONS AND USAGE AIRSUPRA is indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years of age and older. AIRSUPRA is a combination of albuterol, a beta 2 -adrenergic agonist and budesonide, a corticosteroid, indicated for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION • Recommended Dosage: AIRSUPRA 180 mcg/160 mcg (administered as 2 actuations of albuterol/budesonide 90 mcg/80 mcg) by oral inhalation as needed for asthma symptoms. ( 2.1 ) • Do not take more than 6 doses (12 inhalations) in a 24-hour period. ( 2.1 ) • Prime inhaler prior to first use. Re-prime when inhaler has not been used for more than 7 days, is dropped, or after cleaning. ( 2.2 ) • Discard when the dose counter displays 0. ( 2.3 ) 2.1 Recommended Dosage and Administration The recommended dosage of AIRSUPRA is albuterol 180 mcg and budesonide 160 mcg (administered as 2 actuations of AIRSUPRA [albuterol/budesonide 90 mcg/80 mcg]) as needed for asthma symptoms by oral inhalation. Do not take more than 6 doses (12 inhalations) in a 24-hour period [see Warnings and Precautions (5.4) ] . 2.2 Priming Before Use • Priming AIRSUPRA is essential to ensure appropriate drug content in each actuation. Prime AIRSUPRA before using for the first time. To prime AIRSUPRA, release 4 sprays into the air away from the face, shaking well before each spray. • AIRSUPRA must be re-primed when the inhaler has not been used for more than 7 days, is dropped, or after cleaning. To re-prime AIRSUPRA, release 2 sprays into the air away from the face, shaking well before each spray. 2.3 Dose Counter The canister has an attached dose indicator (also known as puff indicator) which indicates how many inhalations (puffs) remain. The dose indicator pointer will move after every actuation. The pointer will show the number of inhalations remaining in the canister. When nearing the end of the usable inhalations, the color behind the number in the dose indicator display window changes to yellow. AIRSUPRA should be discarded when the pointer reaches zero.

3 DOSAGE FORMS AND STRENGTHS Inhalation aerosol: a pressurized metered dose inhaler (a pressurized canister with an attached dose indicator, supplied with a white plastic actuator with a frosted clear plastic dust cap) that delivers a combination of albuterol 90 mcg and budesonide 80 mcg per actuation. Inhalation aerosol: Pressurized metered dose inhaler that delivers a combination of albuterol 90 mcg and budesonide 80 mcg per actuation. ( 3 )

4 CONTRAINDICATIONS AIRSUPRA is contraindicated in patients with a history of hypersensitivity to albuterol, budesonide, or any of the excipients [see Warnings and Precautions (5.5) , Description (11) ] . Hypersensitivity to albuterol, budesonide, or to any of the excipients. ( 4 )

5 WARNINGS AND PRECAUTIONS • If symptoms continue after using AIRSUPRA, this may be a marker of destabilization of asthma and requires reevaluation of treatment. ( 5.1 ) • If paradoxical bronchospasm occurs, discontinue AIRSUPRA immediately and institute alternative therapy. ( 5.2 ) • Cardiovascular effects may occur. Use with caution in patients sensitive to sympathomimetic drugs and patients with cardiovascular disorders. ( 5.3 ) • Excessive use may be fatal. Do not exceed maximum recommended dosage. ( 5.4 ) • Hypersensitivity reactions may occur. Discontinue AIRSUPRA immediately. ( 5.5 ) • Use with caution in patients with convulsive disorders, hyperthyroidism, diabetes mellitus, and ketoacidosis. ( 5.6 ) • Hypokalemia may occur. ( 5.7 ) • Potential worsening of infections (e.g., existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. ( 5.8 ) • Oropharyngeal candidiasis may occur. Advise patients to rinse mouth with water, if available, without swallowing after use. Monitor patients periodically. ( 5.9 ) • Hypercorticism and adrenal suppression may occur with very high dosages in susceptible individuals. If such changes occur, consider appropriate therapy. ( 5.10 ) • Monitor patients with major risk factors for decreased bone mineral content. ( 5.11 ) • Glaucoma and cataracts may occur. Consider referral to an ophthalmologist in patients who develop ocular symptoms. ( 5.12 ) 5.1 Deterioration of Asthma Asthma may deteriorate acutely over a period of hours or chronically over several days or longer. If the patient continues to experience symptoms after using AIRSUPRA or requires more doses of AIRSUPRA than usual, this may be a marker of destabilization of asthma and requires evaluation of the patient and their treatment regimen. 5.2 Paradoxical Bronchospasm AIRSUPRA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with AIRSUPRA, 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. 5.3 Cardiovascular Effects AIRSUPRA, like other drugs containing beta 2 -adrenergic agonists, can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, blood pressure, and/or other symptoms. If such effects occur, AIRSUPRA 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, AIRSUPRA, like all sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. 5.4 Do Not Exceed Recommended Dosage As with other inhaled drugs containing beta-adrenergic agents, AIRSUPRA should not be used more than the maximum daily dose [see Dosage and Administration (2.1) ] , as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.5 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions can occur after administration of albuterol sulfate and budesonide, components of AIRSUPRA, as demonstrated by cases of anaphylaxis, angioedema, bronchospasm, oropharyngeal edema, rash, and urticaria. Discontinue AIRSUPRA if such reactions occur [see Contraindications (4) ] . 5.6 Risk of Sympathomimetic Amines with Certain Coexisting Conditions AIRSUPRA, like all therapies containing 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. 5.7 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 Warnings and Precautions (5.3) , Clinical Pharmacology (12.1) ] . The decrease in serum potassium is usually transient, not requiring supplementation. 5.8 Immunosuppression and Risk of Infections Patients who are using drugs that suppress the immune system are more susceptible to infection. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients using corticosteroids. In patients who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affects the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective Prescribing Information for VZIG and IG). If chicken pox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract; untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.9 Oropharyngeal Candidiasis AIRSUPRA contains budesonide, an inhaled corticosteroid (ICS). Localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with ICS agents. Monitor patients periodically. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with AIRSUPRA continues. In some cases, therapy with AIRSUPRA may need to be interrupted. Advise the patient to rinse his/her mouth with water, if available, without swallowing following administration of AIRSUPRA to help reduce the risk of oropharyngeal candidiasis. 5.10 Hypercorticism and Adrenal Suppression Budesonide, a component of AIRSUPRA, will often help control asthma symptoms with less suppression of hypothalamic-pituitary-adrenal (HPA) function than therapeutically equivalent oral doses of prednisone. Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of AIRSUPRA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded. Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing AIRSUPRA. Because of the possibility of systemic absorption of ICS, patients treated with AIRSUPRA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, appropriate therapy should be initiated as needed. 5.11 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing ICS. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post-menopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. 5.12 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of ICS, including budesonide, a component of AIRSUPRA. Consider referral to an ophthalmologist in patients who develop ocular symptoms. 5.13 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the co-administration of AIRSUPRA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to budesonide may occur [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . 5.14 Effects on Growth in Pediatric Patients Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of AIRSUPRA have not been established in pediatric patients, and AIRSUPRA is not indicated for use in this population [see Use in Specific Populations (8.4) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Deterioration of Asthma [see Warnings and Precautions (5.1) ] • Paradoxical Bronchospasm [see Warnings and Precautions (5.2) ] • Cardiovascular Effects [see Warnings and Precautions (5.3) ] • Hypersensitivity Reactions, including Anaphylaxis [see Warnings and Precautions (5.5) ] • Hypokalemia [see Warnings and Precautions (5.7) ] • Immunosuppression and Risk of Infections [see Warnings and Precautions (5.8) ] • Oropharyngeal Candidiasis [see Warnings and Precautions (5.9) ] • Hypercorticism and Adrenal Suppression [see Warnings and Precautions (5.10) ] • Reduction in Bone Mineral Density [see Warnings and Precautions (5.11) ] • Glaucoma and Cataracts [see Warnings and Precautions (5.12) ] • Effects on Growth in Pediatric Patients [see Warnings and Precautions (5.14) ] Most common adverse reactions (incidence ≥ 1%) are headache, oral candidiasis, cough, dysphonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of AIRSUPRA is based on data from 3 trials: MANDALA, DENALI and BATURA [see Clinical Studies (14) ] . All reported safety data is based on patients who received AIRSUPRA 180 mcg/160 mcg. While patients 12 to 17 years of age were included in these trials, AIRSUPRA is not approved in this age group [see Use in Specific Populations (8.4) ] . In MANDALA, AIRSUPRA 180 mcg/160 mcg was administered as needed in patients with asthma who were receiving medium to high dose ICS or low to high dose ICS/LABA, with or without another controller medicine as maintenance therapy. A total of 1015 patients 12 to 84 years of age (mean age: 51 years) received at least one dose of AIRSUPRA and participated in the study for a mean duration of 310 days. Of these, 905 patients were exposed for at least 24 weeks and 323 patients had exposure for at least 1 year. The mean daily use was 2.6 actuations. On the majority of study days, patients used 2 or less actuations; more than 8 actuations were used on less than 2% of study days. The incidence of common adverse reactions in MANDALA is described in Table 1. Table 1 Summary of Adverse Reactions with AIRSUPRA Reported in ≥ 1% of Patients (MANDALA) Adverse Reaction AIRSUPRA 180 mcg/160 mcg N = 1015 (%) AS MDI 1 180 mcg N = 1015 (%) Headache 44 (4.3) 50 (4.9) Oral candidiasis 2 13 (1.3) 5 (0.5) Cough 10 (1.0) 11 (1.1) 1 Albuterol Metered Dose Inhaler = AS MDI 2 Oral candidiasis also includes those reactions reported under the preferred term oropharyngeal candidiasis. The safety profile of AIRSUPRA in MANDALA was similar to that observed with AS MDI, irrespective of background ICS dose. In DENALI, AIRSUPRA 180 mcg/160 mcg was administered 4 times a day for 12 weeks in patients with asthma who were previously treated with as-needed short-acting beta 2 -agonists (SABA) alone or with low-dose ICS maintenance therapy plus as-needed SABA. A total of 197 patients 13 to 81 years of age (mean age: 50 years) received at least one dose of AIRSUPRA. The adverse reactions profile was similar to MANDALA except for the following adverse reactions for AIRSUPRA with an incidence ≥ 1.0% that exceeded the incidence in MANDALA: headache (5.1%), dysphonia (2.0%), and oral/oropharyngeal candidiasis (1.5%), compared to headache (7.1%), dysphonia (0%), and oral/oropharyngeal candidiasis (0%) in the placebo arm. In BATURA, AIRSUPRA 180 mcg/160 mcg was administered as needed for 12 to 52 weeks in patients with asthma who were previously treated with as-needed SABA alone, or as-needed SABA plus background maintenance of either low-dose ICS or leukotriene receptor antagonist (LTRA). The 26% of patients on background ICS or LTRA were instructed to continue these treatments throughout the study period. A total of 1209 patients 12 to 95 years of age (mean age: 43 years) received at least one dose of AIRSUPRA and participated in the study for a mean duration of 259 days. Of them, 1109 patients were exposed for at least 12 weeks and 258 patients were exposed for at least 1 year. The mean daily use was 1.5 actuations for AIRSUPRA and 1.8 actuations for AS MDI 180 mcg. On the majority of study days, patients used 2 or less actuations of AIRSUPRA or AS MDI 180 mcg; more than 8 actuations were used on 2% of study days for patients on AIRSUPRA and 4% of study days for patients on AS MDI 180 mcg. The safety profile of AIRSUPRA in BATURA was similar to that in MANDALA. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of budesonide or albuterol. 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. Cardiovascular disorders : myocardial ischemia, tremor, tachycardia, palpitations, extrasystoles, arrhythmias (including atrial fibrillation, supraventricular tachycardia), syncope, hypertension, peripheral vasodilatation Endocrine disorders : signs or symptoms of systemic glucocorticosteroid effect (including hypofunction of the adrenal gland and reduction of growth rate) Eye disorders : cataracts, glaucoma, increased intraocular pressure Immune system disorders : immediate and delayed hypersensitivity reactions (including anaphylactic reaction, angioedema, bronchospasm, rash, contact dermatitis and urticaria) General disorders : fever, weight gain, taste perversion, flu syndrome Gastrointestinal disorders : nausea, vomiting, dyspepsia, diarrhea Infections : sinusitis, pharyngitis, respiratory tract infection, nasopharyngitis, gastroenteritis, otitis media, laryngitis Metabolic disorders : hypokalemia, metabolic acidosis Musculoskeletal disorders : hypertonia, musculoskeletal pain, myalgia, asthenia, arthralgia, muscle cramps, fracture Neurological or psychiatric system disorders : migraine, dizziness, central nervous system stimulation, insomnia, hyperactivity, psychiatric symptoms (including psychosis, depression, aggressive reactions, irritability, nervousness, restlessness, behavioral disturbances and anxiety) Respiratory, thoracic, and mediastinal disorders : rhinitis, nasal congestion, throat irritation, oropharyngeal edema, upper respiratory inflammation, drying or irritation of the oropharynx Skin and subcutaneous tissue disorders : skin bruising, ecchymosis

16 HOW SUPPLIED/STORAGE AND HANDLING AIRSUPRA Inhalation Aerosol is supplied as a pressurized aluminum canister with an attached dose indicator and a white plastic actuator, with a frosted clear plastic dust cap tethered to it. Each canister is packaged in a foil overwrap pouch with a desiccant sachet and placed into a carton. Each carton contains one canister and a Patient Information leaflet. Each 120-inhalation canister has a net fill weight of 10.7 grams. AIRSUPRA is available in the following package size as presented in Table 4: Table 4 Package Information for AIRSUPRA Package Size Strength albuterol/budesonide Number of Inhalations per Canister NDC AIRSUPRA 90 mcg/80 mcg 120 0310-9080-12 The AIRSUPRA canister should only be used with the AIRSUPRA actuator, and the AIRSUPRA actuator should not be used with any other inhalation drug product. Counter The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, when the dose indicator pointer reaches zero, even though the canister may not feel completely empty. AIRSUPRA should be discarded when the dose indicator pointer reaches zero, or 12 months after removal of the foil pouch, whichever comes first. Never immerse the canister in water to determine the amount remaining in the canister (“float test”). Storage Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [ see USP ] . Keep in a dry place away from heat and sunlight. For best results, the canister should be at room temperature before use. Shake well before using. Keep out of reach of children. Contents under pressure. Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 49°C (120°F) may cause bursting. Never throw canister into fire or incinerator. Avoid spraying in eyes.