AIRSUPRA Albuterol sulfate and budesonide 90 ug; 80 ug Aerosol, Metered — NDC 0310-9080-28 (Billing 00310-9080-28)

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 )

5.1Deterioration 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.

5.2Paradoxical 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.

5.3Cardiovascular 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.

5.4Do 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.

5.5Hypersensitivity 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) ] .

5.6Risk of Sympathomimetic Amines with Certain Coexisting Conditions AIRSUPRA, like all therapies containing sympathomimetic amines, should be used wi…

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.

6.1Clinical 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-…

7 DRUG INTERACTIONS No formal drug interaction studies have been performed with AIRSUPRA. • Strong cytochrome P450 3A4 inhibitors (e.g. ritonavir): Use with caution. May cause systemic corticosteroid effects. ( 7.1 ) • Other short-acting bronchodilators: Use judiciously with other short-acting beta agonists.

( 7.2 ) • Beta blockers: May decrease effectiveness of AIRSUPRA and produce severe bronchospasm. When there are no acceptable alternatives to the use of beta-adrenergic-blocking agents, consider cardioselective beta-blockers and use with caution. ( 7.3 ) • Diuretics, or non-potassium-sparing diuretics: May potentiate hypokalemia or ECG changes.

Consider monitoring potassium levels with concomitant use. ( 7.4 ) • Digoxin: May decrease serum digoxin levels. Carefully evaluate digoxin levels with concomitant use.

( 7.5 ) • Monoamine oxidase inhibitors (MAOI) and tricyclic antidepressants: Use AIRSUPRA with extreme caution with concomitant use. ( 7.6 )

7.1Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including budesonide, a component of AIRSUPRA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. Concomitant administration of a CYP3A4 inhibitor may inhibit the metabolism of, and increase the systemic exposure to, budesonide.

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) [see Warnings and Precautions (5.11) ] .

7.2Use with Other Short-Acting Bronchodilators AIRSUPRA contains the short-acting beta-agonist, albuterol. Therefore, concomitant use of additional beta-agonists with AIRSUPRA should be used judiciously to prevent beta-agonist overdose.

7.3Beta-Blockers Beta-adrenergic receptor blocking agents not only block the pulmonary effect of beta-agonists, such as albuterol, a component of AIRSUPRA, 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, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-adrenergic-blocking agents in these patients.

In this setting, consider cardioselective beta-blockers, although they should be administered with caution.

7.4Diuretics 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 AIRSUPRA with non-potassium-sparing diuretics. Consider monitoring potassium levels.

7.5Digoxin 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 AIRSUPRA.

7.6Monoamine Oxidase Inhibitors or Tricyclic Antidepressants AIRSUPRA 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.