Budesonide and formoterol fumarate dihydrate

1 INDICATIONS AND USAGE Budesonide and formoterol fumarate dihydrate inhalation aerosol is a combination product containing a corticosteroid and a long-acting beta 2 -adrenergic agonist indicated for: Treatment of asthma in patients 6 years of age and older. ( 1.1 ) Maintenance treatment of airflow obstruction and reducing exacerbations in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. ( 1.2 ) Important limitations: Not indicated for the relief of acute bronchospasm. ( 1.1 , 1.2 ) 1.1 Treatment of Asthma Budesonide and formoterol fumarate dihydrate inhalation aerosol is indicated for the treatment of asthma in patients 6 years of age and older. Budesonide and formoterol fumarate dihydrate inhalation aerosol should be used for patients not adequately controlled on a long-term asthma-control medication such as an inhaled corticosteroid (ICS) or whose disease warrants initiation of treatment with both an inhaled corticosteroid and long-acting beta 2 -adrenergic agonist (LABA). Important Limitations of Use: Budesonide and formoterol fumarate dihydrate inhalation aerosol is NOT indicated for the relief of acute bronchospasm. 1.2 Maintenance Treatment of Chronic Obstructive Pulmonary Disease Budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. Budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 is also indicated to reduce exacerbations of COPD. Budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 is the only strength indicated for the treatment of COPD. Important Limitations of Use: Budesonide and formoterol fumarate dihydrate inhalation aerosol is NOT indicated for the relief of acute bronchospasm.

2 DOSAGE AND ADMINISTRATION For oral inhalation only. Treatment of asthma in patients 12 years and older: 2 inhalations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 or 160/4.5 twice daily. Starting dosage is based on asthma severity. ( 2.2 ) Treatment of asthma in patients aged 6 to less than 12 years: 2 inhalations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 twice daily. ( 2.2 ) Maintenance treatment in COPD: 2 inhalations of budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 twice daily. ( 2.3 ) 2.1 Administration Information Budesonide and formoterol fumarate dihydrate inhalation aerosol should be administered as 2 inhalations twice daily (morning and evening, approximately 12 hours apart), every day by the orally inhaled route only. After inhalation, the patient should rinse the mouth with water without swallowing. Prime budesonide and formoterol fumarate dihydrate inhalation aerosol before using for the first time by releasing two test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well before each spray and releasing two test sprays into the air away from the face. More frequent administration or a higher number of inhalations (more than 2 inhalations twice daily) of the prescribed strength of budesonide and formoterol fumarate dihydrate inhalation aerosol is not recommended as some patients are more likely to experience adverse effects with higher doses of formoterol. Patients using budesonide and formoterol fumarate dihydrate inhalation aerosol should not use additional LABA for any reason [see Warnings and Precautions ( 5.3 , 5.12 )] . 2.2 Asthma If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief. Adult and Adolescent Patients 12 Years of Age and Older For patients 12 years of age and older, the dosage is 2 inhalations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 or budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 twice daily. The recommended starting dosages for budesonide and formoterol fumarate dihydrate inhalation aerosol for patients 12 years of age and older are based upon patients' asthma severity or level of control of asthma symptoms, and risk of exacerbations on current inhaled corticosteroids. The maximum recommended dosage in adult and adolescent patients 12 years and older is budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5, two inhalations twice daily. Improvement in asthma control following inhaled administration of budesonide and formoterol fumarate dihydrate inhalation aerosol can occur within 15 minutes of beginning treatment, although maximum benefit may not be achieved for 2 weeks or longer after beginning treatment. Individual patients will experience a variable time to onset and degree of symptom relief. For patients who do not respond adequately to the starting dose after 1 to 2 weeks of therapy with budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5, replacement with budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 may provide additional asthma control. If a previously effective dosage regimen of budesonide and formoterol fumarate dihydrate inhalation aerosol fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, (e.g., replacing the lower strength of budesonide and formoterol fumarate dihydrate inhalation aerosol with the higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids) should be considered. Pediatric Patients Aged 6 to Less than 12 Years For patients 6 to less than 12 years of age, the dosage is 2 inhalations of budesonide and formotero …

3 DOSAGE FORMS AND STRENGTHS Budesonide and formoterol fumarate dihydrate inhalation aerosol is available as a metered-dose inhaler containing a combination of budesonide, USP (80 or 160 mcg) and formoterol, USP (4.5 mcg) as an inhalation aerosol in the following two strengths: 80/4.5 and 160/4.5. Each dosage strength contains 120 actuations per/canister. Each strength of budesonide and formoterol fumarate dihydrate inhalation aerosol is supplied with a white plastic actuator with a red cap. Metered-dose inhaler containing a combination of budesonide (80 or 160 mcg) and formoterol (4.5 mcg) as an inhalation aerosol. ( 3 )

4 CONTRAINDICATIONS The use of budesonide and formoterol fumarate dihydrate inhalation aerosol is contraindicated in the following conditions: Primary treatment of status asthmaticus or other acute episodes of asthma or COPD where intensive measures are required. Hypersensitivity to any of the ingredients in budesonide and formoterol fumarate dihydrate inhalation aerosol. Primary treatment of status asthmaticus or acute episodes of asthma or COPD requiring intensive measures ( 4 ) Hypersensitivity to any of the ingredients in budesonide and formoterol fumarate dihydrate inhalation aerosol ( 4 )

6 ADVERSE REACTIONS LABA use may result in the following: Serious asthma-related events – hospitalizations, intubations, death [see Warnings and Precautions ( 5.1 )] . Cardiovascular and central nervous system effects [see Warnings and Precautions ( 5.12 )] . Systemic and inhaled corticosteroid use may result in the following: Candida albicans infection [see Warnings and Precautions ( 5.4 )] Pneumonia or lower respiratory tract infections in patients with COPD [see Warnings and Precautions ( 5.5 )] Immunosuppression [see Warnings and Precautions ( 5.6) ] Hypercorticism and adrenal suppression [see Warnings and Precautions ( 5.8 ) ] Growth effects in pediatric patients [see Warnings and Precautions ( 5.14 ) ] Glaucoma and cataracts [see Warnings and Precautions ( 5.15 )] 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. Most common adverse reactions (incidence ≥3%) are: Asthma: nasopharyngitis, headache, upper respiratory tract infection, pharyngolaryngeal pain, sinusitis, influenza, back pain, nasal congestion, stomach discomfort, vomiting, and oral candidiasis. ( 6.1 ) COPD: nasopharyngitis, oral candidiasis, bronchitis, sinusitis, upper respiratory tract infections. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience in Asthma Adult and Adolescent Patients 12 Years of Age and Older The overall safety data in adults and adolescents are based upon 10 active- and placebo-controlled clinical trials in which 3393 patients ages 12 years and older (2052 females and 1341 males) with asthma of varying severity were treated with budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 or 160/4.5 taken 2 inhalations once or twice daily for 12 to 52 weeks. In these trials, the patients on budesonide and formoterol fumarate dihydrate inhalation aerosol had a mean age of 38 years and were predominantly Caucasian (82%). The incidence of common adverse events in Table 2 below is based upon pooled data from three 12-week, double-blind, placebo-controlled clinical studies in which 401 adult and adolescent patients (148 males and 253 females) age 12 years and older were treated with 2 inhalations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 or budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 twice daily. The budesonide and formoterol fumarate dihydrate inhalation aerosol group was composed of mostly Caucasian (84%) patients with a mean age of 38 years, and a mean percent predicted FEV 1 at baseline of 76 and 68 for the 80/4.5 mcg and 160/4.5 mcg treatment groups, respectively. Control arms for comparison included 2 inhalations of budesonide HFA metered dose inhaler (MDI) 80 or 160 mcg, formoterol dry powder inhaler (DPI) 4.5 mcg, or placebo (MDI and DPI) twice daily. Table 2 includes all adverse events that occurred at an incidence of ≥3% in any one budesonide and formoterol fumarate dihydrate inhalation aerosol group and more commonly than in the placebo group with twice-daily dosing. In considering these data, the increased average duration of patient exposure for budesonide and formoterol fumarate dihydrate inhalation aerosol patients should be taken into account, as incidences are not adjusted for an imbalance of treatment duration. Table 2: Adverse Reactions Occurring at an Incidence of ≥3% and More Commonly than Placebo in the Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Groups: Pooled Data from Three 12-week, Double-Blind, Placebo-Controlled Clinical Asthma trials in Patients 12 Years and Older Treatment 1 Bude sonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Budesonide Formoterol Placebo Adverse Event 80/4.5 mcg 160/4.5 mcg 8 …

7 DRUG INTERACTIONS In clinical studies, concurrent administration of budesonide and formoterol fumarate dihydrate inhalation aerosol and other drugs, such as short-acting beta 2 -agonists, intranasal corticosteroids, and antihistamines/decongestants has not resulted in an increased frequency of adverse reactions. No formal drug interaction studies have been performed with budesonide and formoterol fumarate dihydrate inhalation aerosol. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects.( 7.1 ) Monoamine oxidase inhibitors and tricyclic antidepressants: Use with extreme caution. May potentiate effect of formoterol on vascular system. ( 7.2 ) Beta-blockers: Use with caution. May block bronchodilatory effects of beta-agonists and produce severe bronchospasm. ( 7.3 ) Diuretics: Use with caution. Electrocardiographic changes and/or hypokalemia associated with non-potassium-sparing diuretics may worsen with concomitant beta-agonists. ( 7.4 ) 7.1 Inhibitors of Cytochrome P4503A4 The main route of metabolism of corticosteroids, including budesonide, a component of budesonide and formoterol fumarate dihydrate inhalation aerosol, 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 CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide. Caution should be exercised when considering the coadministration of budesonide and formoterol fumarate dihydrate inhalation aerosol 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 ( 5.9 )] . 7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Budesonide and formoterol fumarate dihydrate inhalation aerosol should be administered with 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 formoterol, a component of budesonide and formoterol fumarate dihydrate inhalation aerosol, on the vascular system may be potentiated by these agents. In clinical trials with budesonide and formoterol fumarate dihydrate inhalation aerosol, a limited number of COPD and asthma patients received tricyclic antidepressants, and, therefore, no clinically meaningful conclusions on adverse events can be made. 7.3 Beta-Adrenergic Receptor Blocking Agents Beta-blockers (including eye drops) may not only block the pulmonary effect of beta-agonists, such as formoterol, a component of budesonide and formoterol fumarate dihydrate inhalation aerosol, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. 7.4 Diuretics The ECG changes and/or hypokalemia that 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 budesonide and formoterol fumarate dihydrate inhalation aerosol with non-potassium-sparing diuretics.

8 USE IN SPECIFIC POPULATIONS Hepatic impairment: Monitor patients for signs of increased drug exposure. ( 8.6 ) 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of budesonide and formoterol fumarate dihydrate inhalation aerosol or one of its individual components, formoterol fumarate, in pregnant women; however studies are available for the other component budesonide. In animal reproduction studies, budesonide and formoterol fumarate dihydrate, administered by the inhalation route, was teratogenic, embryocidal, and reduced fetal weights in rats at less than the maximum recommended human daily inhalation dose (MRHDID) on a mcg/m 2 basis. Budesonide alone, administered by the subcutaneous route, was teratogenic, embryocidal, and reduced fetal weights in rats and rabbits at less than the MRHDID, but these effects were not seen in rats that received inhaled doses up to 4 times the MRHDID. Studies of pregnant women have not shown that inhaled budesonide alone increases the risk of abnormalities when administered during pregnancy. Experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. Formoterol fumarate alone, administered by the oral route, was teratogenic in rats and rabbits at 1600 and 65,000 times the MRHDID, respectively. Formoterol fumarate was also embryocidal, increased pup loss at birth and during lactation, and decreased pup weight in rats at 110 times the MRHDID. These adverse effects generally occurred at large multiples of the MRHDID when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No teratogenic, embryocidal, or developmental effects were seen in rats that received inhalation doses up to 375 times the MRHDID. The estimated background risk of major birth defects and miscarriage of the indicated populations is unknown. In the U.S. general population, the estimated background 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 several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or Delivery There are no well-controlled human studies that have investigated the effects of budesonide and formoterol fumarate dihydrate inhalation aerosol during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of budesonide and formoterol fumarate dihydrate inhalation aerosol during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Data Human Data Studies of pregnant women have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy. The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995 to 1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy. Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10 to 12 weeks after the last menstrual period), the period when most major organ malformations occur. The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs. 3.5%, respectively). In addition, after exposure to inhaled budesonide, the number of infants bo …

12.1 Mechanism of Action Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Budesonide and formoterol fumarate dihydrate inhalation aerosol contains both budesonide and formoterol; therefore, the mechanisms of action described below for the individual components apply to budesonide and formoterol fumarate dihydrate inhalation aerosol. These drugs represent two classes of medications (a synthetic corticosteroid and a long-acting selective beta 2 -adrenoceptor agonist) that have different effects on clinical, physiological, and inflammatory indices of COPD and asthma. Budesonide Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay). As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay. In glucocorticoid receptor affinity studies, the 22R form of budesonide was two times as active as the 22S epimer. In vitro studies indicated that the two forms of budesonide do not interconvert. Inflammation is an important component in the pathogenesis of COPD and asthma. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non–allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in COPD and asthma. Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of budesonide. This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85% to 95%), and the low potency of formed metabolites. Formoterol Formoterol fumarate is a long-acting selective beta 2 -adrenergic agonist (beta 2 -agonist) with a rapid onset of action. Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta 2 -receptors than at beta 1 -receptors. The in vitro binding selectivity to beta 2 - over beta 1 -adrenoceptors is higher for formoterol than for albuterol (5 times), whereas salmeterol has a higher (3 times) beta 2 -selectivity ratio than formoterol. Although beta 2 -receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta 1 -receptors are the predominant receptors in the heart, there are also beta 2 -receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta 2 -agonists may have cardiac effects. The pharmacologic effects of beta 2 -adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil i …

11 DESCRIPTION Budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 mcg and 160/4.5 mcg each contain micronized budesonide, USP and micronized formoterol fumarate dihydrate, USP for oral inhalation only. Each budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5 and budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 canister is formulated as a hydrofluoroalkane (HFA 227; 1,1,1,2,3,3,3-heptafluoropropane)-propelled pressurized metered dose inhaler containing 120 actuations [see Dosage Forms and Strengths ( 3 ) and How Supplied/Storage and Handling ( 16 ) ] . After priming, each actuation meters either 89/5.0 mcg or 177/5.0 mcg from the valve and delivers either 80/4.5 mcg, or 160/4.5 mcg (budesonide micronized/formoterol fumarate dihydrate micronized) 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 inspiration through the delivery system. Budesonide and formoterol fumarate dihydrate inhalation aerosol also contains povidone K25 as a suspending agent and polyethylene glycol 1000 as a lubricant. Budesonide and formoterol fumarate dihydrate inhalation aerosol should be primed before using for the first time by releasing two test sprays into the air away from the face, shaking well for 5 seconds before each spray. In cases where the inhaler has not been used for more than 7 days or when it has been dropped, prime the inhaler again by shaking well for 5 seconds before each spray and releasing two test sprays into the air away from the face. One active component of budesonide and formoterol fumarate dihydrate inhalation aerosol is budesonide USP, a corticosteroid designated chemically as (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde. Budesonide, USP is provided as a mixture of two epimers (22R and 22S). The molecular formula of budesonide, USP is C 25 H 34 O 6 and its molecular weight is 430.5. Its structural formula is: Budesonide, USP is a white to off-white, tasteless, odorless powder which 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 . The other active component of budesonide and formoterol fumarate dihydrate inhalation aerosol is formoterol fumarate dihydrate USP, a selective beta 2 -agonist designated chemically as (R*,R*)-(±)-N-[2-hydroxy-5- [1-hydroxy-2-[[2-(4-methoxyphenyl)-1- methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate. The molecular formula of formoterol fumarate dihydrate, USP is C 42 H 56 N 4 O 14 and its molecular weight is 840.9. Its structural formula is: Formoterol fumarate dihydrate, USP is a powder which is slightly soluble in water. Its octanol-water partition coefficient at pH 7.4 is 2.6. The pKa of formoterol fumarate dihydrate at 25°C is 7.9 for the phenolic group and 9.2 for the amino group. 1 1

10 OVERDOSAGE Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol Budesonide and formoterol fumarate dihydrate inhalation aerosol contains both budesonide and formoterol; therefore, the risks associated with overdosage for the individual components described below apply to budesonide and formoterol fumarate dihydrate inhalation aerosol. In pharmacokinetic studies, single doses of 960/54 mcg (12 actuations of budesonide and formoterol fumarate dihydrate inhalation aerosol 80/4.5) and 1280/36 mcg (8 actuations of 160/4.5), were administered to patients with COPD. A total of 1920/54 mcg (12 actuations of budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5) was administered as a single dose to both healthy subjects and patients with asthma. In a long-term active-controlled safety study in adolescent and adult asthma patients 12 years of age and older, budesonide and formoterol fumarate dihydrate inhalation aerosol 160/4.5 was administered for up to 12 months at doses up to twice the highest recommended daily dose. There were no clinically significant adverse reactions observed in any of these studies. Budesonide The potential for acute toxic effects following overdose of budesonide is low. If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see Warnings and Precautions ( 5 )] . Budesonide at five times the highest recommended dose (3200 mcg daily) administered to humans for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%). The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH. Formoterol An overdose of formoterol would likely lead to an exaggeration of effects that are typical for beta 2 -agonists: seizures, angina, hypertension, hypotension, tachycardia, atrial and ventricular tachyarrhythmias, nervousness, headache, tremor, palpitations, muscle cramps, nausea, dizziness, sleep disturbances, metabolic acidosis, hyperglycemia, hypokalemia. As with all sympathomimetic medications, cardiac arrest and even death may be associated with abuse of formoterol. No clinically significant adverse reactions were seen when formoterol was delivered to adult patients with acute bronchoconstriction at a dose of 90 mcg/day over 3 hours or to stable asthmatics 3 times a day at a total dose of 54 mcg/day for 3 days. Treatment of formoterol overdosage consists of discontinuation of the medication together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of formoterol. Cardiac monitoring is recommended in cases of overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING Budesonide and formoterol fumarate dihydrate inhalation aerosol is available in two strengths and is supplied in the following package sizes: Strengths Actuations NDC Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol 80/4.5 mcg 120 0480-3080-31 Budesonide and Formoterol Fumarate Dihydrate Inhalation Aerosol 160/4.5 mcg 120 0480-3081-31 Each strength is supplied as a pressurized aluminum canister, a white plastic actuator body with a counting device and a white mouthpiece with removable red cap. Each 120 inhalation canister has a net fill weight of 10.2 grams. Each canister is packaged in a foil overwrap pouch with desiccant sachet and placed into a carton. Each carton contains one canister and a Patient Information leaflet. The budesonide and formoterol fumarate dihydrate inhalation aerosol canister should only be used with the budesonide and formoterol fumarate dihydrate inhalation aerosol actuator, and the budesonide and formoterol fumarate dihydrate inhalation aerosol actuator should not be used with any other inhalation drug product. The correct amount of medication in each inhalation cannot be ensured after the labeled number of inhalations from the canister have been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of inhalations have been used or within 3 months after removal from the foil pouch. Never immerse the canister into water to determine the amount remaining in the canister (“float test”). Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Store the inhaler with the mouthpiece down. For best results, the canister should be at room temperature before use. Shake well for 5 seconds before using. Keep out of the reach of children. Avoid spraying in eyes. CONTENTS UNDER PRESSURE. Do not puncture or incinerate. Do not store near heat or open flame. Exposure to temperatures over 120oF may cause bursting. Never throw container into fire or incinerator.