AIRSUPRA

AIRSUPRA (albuterol and budesonide) Inhalation Aerosol is a pressurized metered dose inhaler containing a combination of micronized albuterol sulfate, a relatively selective, short-acting beta 2 -adrenergic agonist and micronized budesonide, a corticosteroid, for oral inhalation. Albuterol sulfate is the official generic name in the United States. The World Health Organization recommended name for the drug is salbutamol sulfate. Albuterol sulfate has the following chemical name: USP racemic α 1 [( tert- Butylamino)methyl]-4-hydroxy- m -xylene-α,α'-diol sulfate (2:1) (salt). The empirical formula is (C 13 H 21 NO 3 ) 2 •H 2 SO 4 , and the molecular weight is 576.7. Its structural formula is: Albuterol sulfate is a white to off-white powder that is freely soluble in water, slightly soluble in alcohol and in ether, and practically insoluble in chloroform. It has a LogP of 0.44 at physiological pH. Albuterol has one chiral center and exists as a 1:1 racemic mixture. Budesonide is a corticosteroid designated chemically as (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide is provided as a mixture of two epimers (22R and 22S). The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide is a white to off-white powder that is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform. Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 10 3 . AIRSUPRA is formulated as a hydrofluoroalkane (HFA-134a) propelled pressurized metered dose inhaler containing 120 inhalations. The canister has an attached dose indicator and is supplied with a white plastic actuator with a frosted clear plastic dust cap tethered to it. After priming, each actuation of AIRSUPRA 90 mcg/80 mcg meters 99 mcg of albuterol and 88 mcg of budesonide from the valve which delivers 90 mcg of albuterol (equivalent to 108 mcg of albuterol sulfate) and 80 mcg of budesonide from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inhalation through the delivery system. AIRSUPRA also contains porous particles that form a co-suspension with the drug crystals. The porous particles are comprised of the phospholipid 1,2-distearoyl- sn -glycero-3-phosphocholine (DSPC) and calcium chloride. Porous particles and HFA-134a are excipients in the formulation. Albuterol structural formula Budesonide structural formula

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 )

• 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.

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 )

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

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 ) 7.1 Inhibitors 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) ] . 7.2 Use 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. 7.3 Beta-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. 7.4 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 AIRSUPRA with non-potassium-sparing diuretics. Consider monitoring potassium levels. 7.5 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 AIRSUPRA. 7.6 Monoamine 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.