Symbicort (Budesonide and Formoterol Fumarate Dihydrate): Side Effects, Uses, Dosage, Interactions, Warnings (2024)

Description for Symbicort

SYMBICORT 80/4.5 and SYMBICORT 160/4.5 each contain micronized budesonide and micronized formoterol fumarate dihydrate for oral inhalation only.

Each SYMBICORT 80/4.5 and SYMBICORT 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 either 60 or 120 actuations [see Dosage Forms And Strengths and HOW SUPPLIED/Storage And Handling]. After priming, each actuation meters either 91/5.1 mcg or 181/5.1 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. SYMBICORT also contains povidone K25 USP as a suspending agent and polyethylene glycol 1000 NF as a lubricant.

SYMBICORT 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 SYMBICORT is budesonide, 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 C₂₅H₃₄O₆ and its molecular weight is 430.5. Its structural formula is:

Budesonide 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 10³.

The other active component of SYMBICORT is formoterol fumarate dihydrate, a selective beta2-agonist designated chemically as (R*,R*)-(±)-N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1methylethyl]amino]ethyl]phenyl]formamide, (E)-2-butendioate(2:1), dihydrate. The empirical formula of formoterol is C₄₂H₅₆N₄O₁₄ and its molecular weight is 840.9. Its structural formula is:

Formoterol fumarate dihydrate 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.

Uses for Symbicort

Treatment Of Asthma

SYMBICORT is indicated for thetreatment of asthma in patients 6 years of age and older.

SYMBICORT should be used forpatients not adequately controlled on a long-term asthma-control medicationsuch as an inhaled corticosteroid (ICS) or whose disease warrants initiation oftreatment with both an inhaled corticosteroid and long-acting beta2-adrenergicagonist (LABA).

Important Limitations Of Use

• SYMBICORT is NOT indicated for the relief of acute bronchospasm.

Maintenance Treatment Of Chronic Obstructive Pulmonary Disease

SYMBICORT 160/4.5 is indicatedfor the maintenance treatment of airflow obstruction in patients with chronicobstructive pulmonary disease (COPD) including chronic bronchitis and/oremphysema. SYMBICORT 160/4.5 is also indicated to reduce exacerbations of COPD.SYMBICORT 160/4.5 is the only strength indicated for the treatment of COPD.

Important Limitations Of Use

• SYMBICORT is NOT indicated for the relief of acute bronchospasm.

Dosage for Symbicort

Administration Information

SYMBICORT should be administered as 2 inhalations twicedaily (morning and evening, approximately 12 hours apart), every day by theorally inhaled route only. After inhalation, the patient should rinse the mouthwith water without swallowing.

Prime SYMBICORT before using for the first time byreleasing two test sprays into the air away from the face, shaking well for 5seconds before each spray. In cases where the inhaler has not been used formore than 7 days or when it has been dropped, prime the inhaler again byshaking well before each spray and releasing two test sprays into the air awayfrom the face.

More frequent administration or a higher number ofinhalations (more than 2 inhalations twice daily) of the prescribed strength ofSYMBICORT is not recommended as some patients are more likely to experienceadverse effects with higher doses of formoterol. Patients using SYMBICORTshould not use additional LABA for any reason [see WARNINGS AND PRECAUTIONS].

Asthma

If asthma symptoms arise in the period between doses, aninhaled, short-acting beta2-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 2inhalations of SYMBICORT 80/4.5 or SYMBICORT 160/4.5 twice daily.

The recommended starting dosages for SYMBICORT forpatients 12 years of age and older are based upon patients' asthma severity orlevel of control of asthma symptoms, and risk of exacerbations on currentinhaled corticosteroids.

The maximum recommended dosage in adult and adolescentpatients 12 years and older is SYMBICORT 160/4.5, two inhalations twice daily.

Improvement in asthma control following inhaledadministration of SYMBICORT can occur within 15 minutes of beginning treatment,although maximum benefit may not be achieved for 2 weeks or longer afterbeginning treatment. Individual patients will experience a variable time to onsetand degree of symptom relief.

For patients who do not respond adequately to thestarting dose after 1-2 weeks of therapy with SYMBICORT 80/4.5, replacementwith SYMBICORT 160/4.5 may provide additional asthma control.

If a previously effective dosage regimen of SYMBICORTfails to provide adequate control of asthma, the therapeutic regimen should bere-evaluated and additional therapeutic options, (e.g., replacing the lowerstrength of SYMBICORT 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 dosageis 2 inhalations of SYMBICORT 80/4.5 twice daily.

Chronic Obstructive Pulmonary Disease

For patients with COPD the recommended dose is SYMBICORT160/4.5, two inhalations twice daily.

If shortness of breath occurs in the period betweendoses, an inhaled, short-acting beta2-agonist should be taken for immediaterelief.

HOW SUPPLIED

Dosage Forms And Strengths

SYMBICORT is available as a metered-dose inhalercontaining a combination of budesonide (80 or 160 mcg) and formoterol (4.5 mcg)as an inhalation aerosol in the following two strengths: 80/4.5 and 160/4.5.Each dosage strength contains 60 or 120 actuations per/canister. Each strengthof SYMBICORT is supplied with a red plastic actuator with a gray dust cap.

Storage And Handling

SYMBICORT is available in twostrengths and is supplied in the following package sizes:

Dosage Forms And Strengths

Each strength is supplied as apressurized aluminum canister with an attached counting device, a red plasticactuator body with a white mouthpiece, and attached gray dust cap. Each 120inhalation canister has a net fill weight of 10.2 grams and each 60 inhalationcanister has a net fill weight of 6.9 grams (SYMBICORT 80/4.5) or 6 grams(SYMBICORT 160/4.5). Each canister is packaged in a foil overwrap pouch withdesiccant sachet and placed into a carton. Each carton contains one canisterand a Patient Information leaflet.

The SYMBICORT canister shouldonly be used with the SYMBICORT actuator, and the SYMBICORT actuator should notbe used with any other inhalation drug product.

The correct amount ofmedication in each inhalation cannot be ensured after the labeled number ofinhalations from the canister have been used, even though the inhaler may notfeel completely empty and may continue to operate. The inhaler should bediscarded when the labeled number of inhalations have been used or within 3months after removal from the foil pouch. Never immerse the canister into waterto determine the amount remaining in the canister (“float test”).

Store at controlled room temperature 20°C to 25°C (68°Fto 77°F) [see USP]. Store the inhaler with the mouthpiece down.

For best results, the canister should be at roomtemperature before use. Shake well for 5 seconds before using.

Keep out of the reach of children. Avoid spraying ineyes.

CONTENTS UNDER PRESSURE.

Do not puncture or incinerate. Do not store near heat oropen flame. Exposure to temperatures over 120°F may cause bursting. Never throwcontainer into fire or incinerator.

Manufactured for: AstraZeneca Pharmaceuticals LP,Wilmington, DE 19850 By: AstraZeneca Dunkerque Production, Dunkerque, France. Revised:Dec 2017

Side Effects for Symbicort

LABA use may result in the following:

• Serious asthma-related events – hospitalizations, intubations, death [see WARNINGS AND PRECAUTIONS].
• Cardiovascular and central nervous system effects [see WARNINGS AND PRECAUTIONS].

Systemic and inhaled corticosteroid use may result in thefollowing:

• Candida albicans infection [see WARNINGS AND PRECAUTIONS]
• Pneumonia or lower respiratory tract infections in patients with COPD [see WARNINGS AND PRECAUTIONS]
• Immunosuppression [see WARNINGS AND PRECAUTIONS]
• Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS]
• Growth effects in pediatric patients [see WARNINGS AND PRECAUTIONS]
• Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]

Because clinical trials are conducted under widelyvarying conditions, adverse reaction rates observed in the clinical trials of adrug cannot be directly compared to rates in the clinical trials of anotherdrug and may not reflect the rates observed in practice.

Clinical Trials Experience In Asthma

Adult And Adolescent Patients 12 Years Of Age And Older

The overall safety data in adults and adolescents arebased upon 10 active-and placebo-controlled clinical trials in which 3393patients ages 12 years and older (2052 females and 1341 males) with asthma ofvarying severity were treated with SYMBICORT 80/4.5 or 160/4.5 taken 2inhalations once or twice daily for 12 to 52 weeks. In these trials, thepatients on SYMBICORT had a mean age of 38 years and were predominantlyCaucasian (82%).

The incidence of common adverse events in Table 2 belowis based upon pooled data from three 12-week, double-blind, placebo-controlledclinical studies in which 401 adult and adolescent patients (148 males and 253females) age 12 years and older were treated with 2 inhalations of SYMBICORT80/4.5 or SYMBICORT 160/4.5 twice daily. The SYMBICORT group was composed ofmostly Caucasian (84%) patients with a mean age of 38 years, and a mean percentpredicted FEV₁ at baseline of 76 and 68 for the 80/4.5 mcg and 160/4.5 mcgtreatment groups, respectively. Control arms for comparison included 2inhalations of budesonide HFA metered dose inhaler (MDI) 80 or 160 mcg,formoterol dry powder inhaler (DPI) 4.5 mcg, or placebo (MDI and DPI) twicedaily. Table 2 includes all adverse events that occurred at an incidence of >3%in any one SYMBICORT group and more commonly than in the placebo group withtwice-daily dosing. In considering these data, the increased average durationof patient exposure for SYMBICORT patients should be taken into account, asincidences are not adjusted for an imbalance of treatment duration.

Table 2 : Adverse reactions occurring at an incidenceof ≥ 3% and more commonly than placebo in the SYMBICORT groups: pooleddata from three 12-week, double-blind, placebo-controlled clinical asthmatrials in patients 12 years and older

Long-Term Safety -Asthma Clinical Trials In Patients 12 Years And Older

Long-term safety studies inadolescent and adult patients 12 years of age and older, treated for up to 1year at doses up to 1280/36 mcg/day (640/18 mcg twice daily), revealed neitherclinically important changes in the incidence nor new types of adverse eventsemerging after longer periods of treatment. Similarly, no significant orunexpected patterns of abnormalities were observed for up to 1 year in safetymeasures including chemistry, hematology, ECG, Holter monitor, and HPA-axisassessments.

Pediatric Patients 6 To Less Than 12 Years Of Age

The safety data for pediatric patientsaged 6 to less than 12 years is based on 1 trial of 12 weeks treatmentduration. Patients (79 female and 105 male) receiving inhaled corticosteroid attrial entry were randomized to SYMBICORT 80/4.5 (n=92) or budesonide pMDI 80mcg (n=92), 2 inhalations twice daily. The overall safety profile of thesepatients was similar to that observed in patients 12 years of age and older whor*ceived SYMBICORT 80/4.5 twice daily in studies of similar design. Commonadverse reactions that occurred in patients treated with SYMBICORT 80/4.5 witha frequency of ≥3% and more frequently than patients treated only withbudesonide pMDI 80 mcg included upper respiratory tract infection, pharyngitis,headache, and rhinitis.

Clinical Trials Experience In Chronic Obstructive Pulmonary Disease

The safety data described belowreflect exposure to SYMBICORT 160/4.5 in 1783 patients. SYMBICORT 160/4.5 wasstudied in two placebo-controlled lung function studies (6 and 12 months in duration),and two active-controlled exacerbation studies (6 and 12 months in duration) inpatients with COPD.

The incidence of common adverseevents in Table 3 below is based upon pooled data from two double-blind,placebo-controlled lung function clinical studies (6 and 12 months in duration)in which 771 adult COPD patients (496 males and 275 females) 40 years of ageand older were treated with SYMBICORT 160/4.5, two inhalations twice daily. Ofthese patients 651 were treated for 6 months and 366 were treated for 12months. The SYMBICORT group was composed of mostly Caucasian (93%) patientswith a mean age of 63 years, and a mean percent predicted FEV₁ at baseline of33%. Control arms for comparison included 2 inhalations of budesonide HFA (MDI)160 mcg, formoterol (DPI) 4.5 mcg or placebo (MDI and DPI) twice daily.Table 3 includes all adverse events that occurred at an incidence of ≥3%in the SYMBICORT group and more commonly than in the placebo group. Inconsidering these data, the increased average duration of patient exposure toSYMBICORT should be taken into account, as incidences are not adjusted for animbalance of treatment duration.

Table 3 : Adverse reactions occurring at an incidenceof ≥ 3% and more commonly than placebo in the SYMBICORT group: pooleddata from two double-blind, placebo-controlled clinical COPD trials

Lung infections other thanpneumonia (mostly bronchitis) occurred in a greater percentage of subjectstreated with SYMBICORT 160/4.5 compared with placebo (7.9% vs. 5.1%, respectively).There were no clinically important or unexpected patterns of abnormalitiesobserved for up to 1 year in chemistry, hematology, ECG, ECG (Holter)monitoring, HPA-axis, bone mineral density and ophthalmology assessments.

The safety findings from thetwo double-blind, active-controlled exacerbations studies (6 and 12 months induration) in which 1012 adult COPD patients (616 males and 396 females) 40years of age and older were treated with SYMBICORT 160/4.5, two inhalationstwice daily were consistent with the lung function studies.

Postmarketing Experience

The following adverse reactionshave been identified during post-approval use of SYMBICORT. Because thesereactions are reported voluntarily from a population of uncertain size, it isnot always possible to reliably estimate their frequency or establish a causalrelationship to drug exposure. Some of these adverse reactions may also havebeen observed in clinical studies with SYMBICORT.

Cardiac disorders: angina pectoris,tachycardia, atrial and ventricular tachyarrhythmias, atrial fibrillation,extrasystoles, palpitations

Endocrine disorders: hypercorticism, growthvelocity reduction in pediatric patients

Eye disorders: cataract, glaucoma,increased intraocular pressure

Gastrointestinal disorders: oropharyngealcandidiasis, nausea

Immune system disorders: immediate and delayedhypersensitivity reactions, such as anaphylactic reaction, angioedema,bronchospasm, urticaria, exanthema, dermatitis, pruritus

Metabolic and nutritiondisorders: hyperglycemia,hypokalemia

Musculoskeletal, connectivetissue, and bone disorders: muscle cramps

Nervous system disorders: tremor, dizziness

Psychiatric disorders: behavior disturbances,sleep disturbances, nervousness, agitation, depression, restlessness

Respiratory, thoracic, and mediastinal disorders: dysphonia,cough, throat irritation

Skin and subcutaneous tissue disorders: skinbruising

Vascular disorders: hypotension, hypertension

Drug Interactions for Symbicort

In clinical studies, concurrent administration ofSYMBICORT and other drugs, such as short-acting beta2agonists, intranasalcorticosteroids, and antihistamines/decongestants has not resulted in anincreased frequency of adverse reactions. No formal drug interaction studieshave been performed with SYMBICORT.

Inhibitors Of Cytochrome P4503A4

The main route of metabolism of corticosteroids,including budesonide, a component of SYMBICORT, is via cytochrome P450 (CYP)isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a stronginhibitor of CYP3A4, the mean plasma concentration of orally administeredbudesonide increased. Concomitant administration of CYP3A4 may inhibit themetabolism of, and increase the systemic exposure to, budesonide. Cautionshould be exercised when considering the coadministration of SYMBICORT withlong-term ketoconazole and other known strong CYP3A4 inhibitors (e.g.,ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone,nelfinavir, saquinavir, telithromycin) [see WARNINGS AND PRECAUTIONS].

Monoamine Oxidase Inhibitors And Tricyclic Antidepressants

SYMBICORT should be administered with caution to patientsbeing treated with monoamine oxidase inhibitors or tricyclic antidepressants,or within 2 weeks of discontinuation of such agents, because the action offormoterol, a component of SYMBICORT, on the vascular system may be potentiatedby these agents. In clinical trials with SYMBICORT, a limited number of COPDand asthma patients received tricyclic antidepressants, and, therefore, noclinically meaningful conclusions on adverse events can be made.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers (including eye drops) may not only blockthe pulmonary effect of beta-agonists, such as formoterol, a component ofSYMBICORT, but may produce severe bronchospasm in patients with asthma.Therefore, patients with asthma should not normally be treated withbeta-blockers. However, under certain circ*mstances, there may be no acceptablealternatives to the use of beta-adrenergic blocking agents in patients withasthma. In this setting, cardioselective beta-blockers could be considered,although they should be administered with caution.

Diuretics

The ECG changes and/or hypokalemia that may result fromthe administration of non-potassium-sparing diuretics (such as loop or thiazidediuretics) can be acutely worsened by beta-agonists, especially when therecommended dose of the beta-agonist is exceeded. Although the clinicalsignificance of these effects is not known, caution is advised in thecoadministration of SYMBICORT with non-potassium-sparing diuretics.

.

Warnings for Symbicort

Included as part of the PRECAUTIONS section.

Precautions for Symbicort

Serious Asthma-Related Events – Hospitalizations, Intubations And Death

Use of LABA as monotherapy (without ICS) for asthma isassociated with an increased risk of asthma-related death [see SalmeterolMulticenter Asthma Research Trial (SMART)]. Available data from controlledclinical trials also suggest that use of LABA as monotherapy increases the riskof asthma-related hospitalization in pediatric and adolescent patients. Thesefindings are considered a class effect of LABA. When LABA are used infixed-dose combination with ICS, data from large clinical trials do not show asignificant increase in the risk of serious asthma-related events(hospitalizations, intubations, death) compared to ICS alone (see SeriousAsthma-Related Events with ICS/LABA).

Serious Asthma-Related Events With ICS/LABA

Four large, 26-week, randomized, blinded,active-controlled clinical safety trials were conducted to evaluate the risk ofserious asthma-related events when LABA were used in fixed-dose combinationwith ICS compared to ICS alone in patients with asthma. Three trials includedadult and adolescent patients aged ≥12 years: one trial comparedbudesonide/formoterol (SYMBICORT) to budesonide [see Clinical Studies];one trial compared fluticasone propionate/salmeterol inhalation powder tofluticasone propionate inhalation powder; and one trial compared mometasonefuroate/formoterol to mometasone furoate. The fourth trial included pediatricpatients 4 to 11 years of age and compared fluticasone propionate/salmeterolinhalation powder to fluticasone propionate inhalation powder. The primarysafety endpoint for all four trials was serious asthma-related events(hospitalizations, intubations and death). A blinded adjudication committeedetermined whether events were asthma-related.

The three adult and adolescent trials were designed torule out a risk margin of 2.0, and the pediatric trial was designed to rule outa risk of 2.7. Each individual trial met its pre-specified objective anddemonstrated non-inferiority of ICS/LABA to ICS alone. A meta-analysis of thethree adult and adolescent trials did not show a significant increase in riskof a serious asthma-related event with ICS/LABA fixed-dose combination comparedwith ICS alone (Table 1). These trials were not designed to rule out all riskfor serious asthma-related events with ICS/LABA compared with ICS.

Table 1: Meta-analysis of Serious Asthma-RelatedEvents in Patients with Asthma Aged 12 Years and Older

The pediatric safety trial included 6208 pediatricpatients 4 to 11 years of age who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalationpowder). In this trial, 27/3107 (0.9%) patients randomized to ICS/LABA and21/3101 (0.7%) patients randomized to ICS experienced a serious asthma-relatedevent. There were no asthma-related deaths or intubations. ICS/LABA did notshow a significantly increased risk of a serious asthma-related event comparedto ICS based on the pre-specified risk margin (2.7), with an estimated hazardratio of time to first event of 1.29 (95% CI: 0.73, 2.27).

Salmeterol Multicenter Asthma Research Trial (SMART)

A 28-week, placebo-controlled U.S. trial that comparedthe safety of salmeterol with placebo, each added to usual asthma therapy,showed an increase in asthma-related deaths in patients receiving salmeterol(13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treatedwith placebo; relative risk: 4.37 [95% CI 1.25, 15.34]). Use of background ICSwas not required in SMART. The increased risk of asthma-related death isconsidered a class effect of LABA monotherapy.

Formoterol Monotherapy Studies

Clinical studies with formoterol used as monotherapysuggested a higher incidence of serious asthma exacerbation in patients whor*ceived formoterol than in those who received placebo. The sizes of thesestudies were not adequate to precisely quantify the difference in seriousasthma exacerbations between treatment groups.

Deterioration Of Disease And Acute Episodes

SYMBICORT should not be initiated in patients duringrapidly deteriorating or potentially life-threatening episodes of asthma or COPD.SYMBICORT has not been studied in patients with acutely deteriorating asthma orCOPD. The initiation of SYMBICORT in this setting is not appropriate.

Increasing use of inhaled, short-acting beta2-agonists isa marker of deteriorating asthma. In this situation, the patient requiresimmediate re-evaluation with reassessment of the treatment regimen, givingspecial consideration to the possible need for replacing the current strengthof SYMBICORT with a higher strength, adding additional inhaled corticosteroid,or initiating systemic corticosteroids. Patients should not use more than 2inhalations twice daily (morning and evening) of SYMBICORT.

SYMBICORT should not be used for the relief of acutesymptoms, i.e., as rescue therapy for the treatment of acute episodes ofbronchospasm. An inhaled, short-acting beta2-agonist, not SYMBICORT, should beused to relieve acute symptoms such as shortness of breath.

When beginning treatment with SYMBICORT, patients whohave been taking oral or inhaled, short-acting beta2-agonists on a regularbasis (e.g., 4 times a day) should be instructed to discontinue the regular useof these drugs.

Excessive Use Of SYMBICORT And Use With Other Long-Acting Beta2-Agonists

As with other inhaled drugs containing beta2-adrenergicagents, SYMBICORT should not be used more often than recommended, at higherdoses than recommended, or in conjunction with other medications containingLABA, as an overdose may result. Clinically significant cardiovascular effectsand fatalities have been reported in association with excessive use of inhaledsympathomimetic drugs. Patients using SYMBICORT should not use an additionalLABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for anyreason, including prevention of exercise-induced bronchospasm (EIB) or thetreatment of asthma or COPD.

Local Effects

In clinical studies, the development of localizedinfections of the mouth and pharynx with Candida albicans has occurredin patients treated with SYMBICORT. When such an infection develops, it shouldbe treated with appropriate local or systemic (i.e., oral antifungal) therapywhile treatment with SYMBICORT continues, but at times therapy with SYMBICORTmay need to be interrupted. Advise the patient to rinse his/her mouth withwater without swallowing following inhalation to help reduce the risk oforopharyngeal candidiasis.

Pneumonia And Other Lower Respiratory Tract Infections

Physicians should remain vigilant for the possibledevelopment of pneumonia in patients with COPD as the clinical features ofpneumonia and exacerbations frequently overlap. Lower respiratory tractinfections, including pneumonia, have been reported following the inhaledadministration of corticosteroids.

In a 6-month lung function study of 1704 patients withCOPD, there was a higher incidence of lung infections other than pneumonia(e.g., bronchitis, viral lower respiratory tract infections, etc.) in patientsreceiving SYMBICORT 160/4.5 (7.6%) than in those receiving SYMBICORT 80/4.5(3.2%), formoterol 4.5 mcg (4.6%) or placebo (3.3%). Pneumonia did not occurwith greater incidence in the SYMBICORT 160/4.5 group (1.1 %) compared withplacebo (1.3%). In a 12-month lung function study of 1964 patients with COPD,there was also a higher incidence of lung infections other than pneumonia inpatients receiving SYMBICORT 160/4.5 (8.1%) than in those receiving SYMBICORT80/4.5 (6.9%), formoterol 4.5 mcg (7.1%) or placebo (6.2%). Similar to the6-month study, pneumonia did not occur with greater incidence in the SYMBICORT160/4.5 group (4.0%) compared with placebo (5.0%).

Immunosuppression

Patients who are on drugs that suppress the immune systemare more susceptible to infection than healthy individuals. Chicken pox andmeasles, for example, can have a more serious or even fatal course insusceptible children or adults using corticosteroids. In such children oradults who have not had these diseases or been properly immunized, particularcare should be taken to avoid exposure. How the dose, route, and duration ofcorticosteroid administration affects the risk of developing a disseminated infectionis not known. The contribution of the underlying disease and/or priorcorticosteroid treatment to the risk is also not known. If exposed, therapywith varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin(IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxiswith pooled intramuscular immunoglobulin (IG) may be indicated (see therespective package inserts for complete VZIG and IG prescribing information).If chicken pox develops, treatment with antiviral agents may be considered. Theimmune responsiveness to varicella vaccine was evaluated in pediatric patientswith asthma ages 12 months to 8 years with budesonide inhalation suspension.

An open-label, nonrandomized clinical study examined theimmune responsiveness to varicella vaccine in 243 asthma patients 12 months to8 years of age who were treated with budesonide inhalation suspension 0.25 mgto 1 mg daily (n=151) or noncorticosteroid asthma therapy (n=92) (i.e., beta2-agonists,leukotriene receptor antagonists, cromones). The percentage of patientsdeveloping a seroprotective antibody titer of >5.0 (gpELISA value) inresponse to the vaccination was similar in patients treated with budesonideinhalation suspension (85%), compared to patients treated withnoncorticosteroid asthma therapy (90%). No patient treated with budesonideinhalation suspension developed chicken pox as a result of vaccination.

Inhaled corticosteroids should be used with caution, ifat all, in patients with active or quiescent tuberculosis infections of therespiratory tract; untreated systemic fungal, bacterial, viral, or parasiticinfections; or ocular herpes simplex.

Transferring Patients From Systemic Corticosteroid Therapy

Particular care is needed for patients who have beentransferred from systemically active corticosteroids to inhaled corticosteroidsbecause deaths due to adrenal insufficiency have occurred in patients withasthma during and after transfer from systemic corticosteroids to lesssystemically available inhaled corticosteroids. After withdrawal from systemiccorticosteroids, a number of months are required for recovery ofhypothalamic-pituitary-adrenal (HPA) function.

Patients who have been previously maintained on 20 mg or moreper day of prednisone (or its equivalent) may be most susceptible, particularlywhen their systemic corticosteroids have been almost completely withdrawn.During this period of HPA suppression, patients may exhibit signs and symptomsof adrenal insufficiency when exposed to trauma, surgery, or infection(particularly gastroenteritis) or other conditions associated with severeelectrolyte loss. Although SYMBICORT may provide control of asthma symptomsduring these episodes, in recommended doses it supplies less than normalphysiological amounts of glucocorticoid systemically and does NOT provide themineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress, a severe asthma attack or asevere COPD exacerbation, patients who have been withdrawn from systemiccorticosteroids should be instructed to resume oral corticosteroids (in largedoses) immediately and to contact their physicians for further instruction.These patients should also be instructed to carry a warning card indicatingthat they may need supplementary systemic corticosteroids during periods ofstress, a severe asthma attack, or a severe COPD exacerbation.

Patients requiring oral corticosteroids should be weanedslowly from systemic corticosteroid use after transferring to SYMBICORT.Prednisone reduction can be accomplished by reducing the daily prednisone doseby 2.5 mg on a weekly basis during therapy with SYMBICORT. Lung function (meanforced expiratory volume in 1 second [FEV₁] or morning peak expiratory flow[PEF]), beta-agonist use, and asthma or COPD symptoms should be carefullymonitored during withdrawal of oral corticosteroids. In addition, patientsshould be observed for signs and symptoms of adrenal insufficiency, such asfatigue, lassitude, weakness, nausea and vomiting, and hypotension.

Transfer of patients from systemic corticosteroid therapyto inhaled corticosteroids or SYMBICORT may unmask conditions previouslysuppressed by the systemic corticosteroid therapy (e.g., rhinitis,conjunctivitis, eczema, arthritis, eosinophilic conditions). Some patients mayexperience symptoms of systemically active corticosteroid withdrawal (e.g.,joint and/or muscular pain, lassitude, depression) despite maintenance or evenimprovement of respiratory function.

Hypercorticism And Adrenal Suppression

Budesonide, a component of SYMBICORT, will often helpcontrol asthma and COPD symptoms with less suppression of HPA function thantherapeutically equivalent oral doses of prednisone. Since budesonide isabsorbed into the circulation and can be systemically active at higher doses,the beneficial effects of SYMBICORT in minimizing HPA dysfunction may beexpected only when recommended dosages are not exceeded and individual patientsare titrated to the lowest effective dose.

Because of the possibility of systemic absorption ofinhaled corticosteroids, patients treated with SYMBICORT should be observedcarefully for any evidence of systemic corticosteroid effects. Particular careshould be taken in observing patients postoperatively or during periods ofstress for evidence of inadequate adrenal response.

It is possible that systemic corticosteroid effects suchas hypercorticism and adrenal suppression (including adrenal crisis) may appearin a small number of patients, particularly when budesonide is administered athigher than recommended doses over prolonged periods of time. If such effectsoccur, the dosage of SYMBICORT should be reduced slowly, consistent withaccepted procedures for reducing systemic corticosteroids and for management ofasthma symptoms.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering thecoadministration of SYMBICORT with ketoconazole, and other known strong CYP3A4inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir,itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) becauseadverse effects related to increased systemic exposure to budesonide may occur [seeDRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

Paradoxical Bronchospasm And Upper Airway Symptoms

As with other inhaled medications, SYMBICORT can produceparadoxical bronchospasm, which may be life threatening. If paradoxicalbronchospasm occurs following dosing with SYMBICORT, it should be treatedimmediately with an inhaled, short-acting bronchodilator, SYMBICORT should bediscontinued immediately, and alternative therapy should be instituted.

Immediate Hypersensitivity Reactions

Immediate hypersensitivity reactions may occur afteradministration of SYMBICORT, as demonstrated by cases of urticaria, angioedema,rash, and bronchospasm.

Cardiovascular And Central Nervous System Effects

Excessive beta-adrenergic stimulation has been associatedwith seizures, angina, hypertension or hypotension, tachycardia with rates upto 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation,nausea, dizziness, fatigue, malaise, and insomnia [see OVERDOSAGE ].Therefore, SYMBICORT, like all products containing sympathomimetic amines,should be used with caution in patients with cardiovascular disorders,especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Formoterol, a component of SYMBICORT, can produce aclinically significant cardiovascular effect in some patients as measured bypulse rate, blood pressure, and/or symptoms. Although such effects are uncommonafter administration of formoterol at recommended doses, if they occur, thedrug may need to be discontinued. In addition, beta-agonists have been reportedto produce ECG changes, such as flattening of the T wave, prolongation of theQTc interval, and ST segment depression. The clinical significance of thesefindings is unknown. Fatalities have been reported in association withexcessive use of inhaled sympathomimetic drugs.

Reduction In Bone Mineral Density

Decreases in bone mineral density (BMD) have beenobserved with long-term administration of products containing inhaledcorticosteroids. The clinical significance of small changes in BMD with regardto long-term consequences such as fracture is unknown. Patients with major riskfactors for decreased bone mineral content, such as prolonged immobilization,family history of osteoporosis, postmenopausal status, tobacco use, advancedage, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g.,anticonvulsants, oral corticosteroids) should be monitored and treated withestablished standards of care. Since patients with COPD often have multiplerisk factors for reduced BMD, assessment of BMD is recommended prior toinitiating SYMBICORT and periodically thereafter. If significant reductions inBMD are seen and SYMBICORT is still considered medically important for thatpatient's COPD therapy, use of medication to treat or prevent osteoporosisshould be strongly considered.

Effects of treatment with SYMBICORT 160/4.5, SYMBICORT80/4.5, formoterol 4.5 mcg, or placebo on BMD was evaluated in a subset of 326patients (females and males 41 to 88 years of age) with COPD in the 12-monthlung function study. BMD evaluations of the hip and lumbar spine regions wereconducted at baseline and 52 weeks using dual energy x-ray absorptiometry (DEXA)scans. Mean changes in BMD from baseline to end of treatment were small (meanchanges ranged from -0.01 -0.01 g/cm²). ANCOVA results for total spine andtotal hip BMD based on the end of treatment time point showed that allgeometric LS Mean ratios for the pairwise treatment group comparisons wereclose to 1, indicating that overall, BMD for total hip and total spine regionsfor the 12-month time point were stable over the entire treatment period.

Effect On Growth

Orally inhaled corticosteroids may cause a reduction ingrowth velocity when administered to pediatric patients. Monitor the growth ofpediatric patients receiving SYMBICORT routinely (e.g., via stadiometry). Tominimize the systemic effects of orally inhaled corticosteroids, including SYMBICORT,titrate each patient's dose to the lowest dosage that effectively controlshis/her symptoms [see DOSAGE AND ADMINISTRATION and Use In SpecificPopulations].

Glaucoma And Cataracts

Glaucoma, increased intraocular pressure, and cataractshave been reported in patients with asthma and COPD following the long-termadministration of inhaled corticosteroids, including budesonide, a component ofSYMBICORT. Therefore, close monitoring is warranted in patients with a changein vision or with history of increased intraocular pressure, glaucoma, and/orcataracts.

Effects of treatment with SYMBICORT 160/4.5, SYMBICORT80/4.5, formoterol 4.5 mcg, or placebo on development of cataracts or glaucomawere evaluated in a subset of 461 patients with COPD in the 12-month lungfunction study. Ophthalmic examinations were conducted at baseline, 24 weeks,and 52 weeks. There were 26 subjects (6%) with an increase in posteriorsubcapsular score from baseline to maximum value (>0.7) during therandomized treatment period. Changes in posterior subcapsular scores of >0.7from baseline to treatment maximum occurred in 11 patients (9.0%) in theSYMBICORT 160/4.5 group, 4 patients (3.8%) in the SYMBICORT 80/4.5 group, 5patients (4.2%) in the formoterol group, and 6 patients (5.2%) in the placebogroup.

Eosinophilic Conditions And Churg-Strauss Syndrome

In rare cases, patients on inhaled corticosteroids maypresent with systemic eosinophilic conditions. Some of these patients haveclinical features of vasculitis consistent with Churg-Strauss syndrome, acondition that is often treated with systemic corticosteroid therapy. Theseevents usually, but not always, have been associated with the reduction and/orwithdrawal of oral corticosteroid therapy following the introduction of inhaledcorticosteroids. Physicians should be alert to eosinophilia, vasculitic rash,worsening pulmonary symptoms, cardiac complications, and/or neuropathy presentingin their patients. A causal relationship between budesonide and theseunderlying conditions has not been established.

Coexisting Conditions

SYMBICORT, like all medications containingsympathomimetic amines, should be used with caution in patients with convulsivedisorders or thyrotoxicosis and in those who are unusually responsive tosympathomimetic amines. Doses of the related beta2-adrenoceptor agonistalbuterol, when administered intravenously, have been reported to aggravatepreexisting diabetes mellitus and ketoacidosis.

Hypokalemia And Hyperglycemia

Beta-adrenergic agonist medications may producesignificant hypokalemia in some patients, possibly through intracellularshunting, which has the potential to produce adverse cardiovascular effects [seeCLINICAL PHARMACOLOGY]. The decrease in serum potassium is usuallytransient, not requiring supplementation. Clinically significant changes inblood glucose and/or serum potassium were seen infrequently during clinicalstudies with SYMBICORT at recommended doses.

Patient Counseling Information

Advise the patient to read the FDA-approved patientlabeling (PATIENT INFORMATION and Instructions for Use).

Serious Asthma-Related Events

Inform patients with asthma that LABA when used aloneincreases the risk of asthma-related hospitalization or asthma-related death.Available data show that when ICS and LABA are used together, such as withSYMBICORT, there is not a significant increase in risk of these events.

Not For Acute Symptoms

Inform patients that SYMBICORT is not meant to relieveacute symptoms of asthma or COPD and extra doses should not be used for thatpurpose. Advise patients to treat acute symptoms with an inhaled, short-actingbeta2-agonist such as albuterol. Provide patients with such medication andinstruct the patient in how it should be used.

Instruct patients to seek medical attention immediatelyif they experience any of the following:

• Decreasing effectiveness of inhaled, short-acting beta2-agonists
• Need for more inhalations than usual of inhaled, short-acting beta2-agonists
• Significant decrease in lung function as outlined by the physician

Tell patients they should not stop therapy with SYMBICORTwithout physician/provider guidance since symptoms may recur afterdiscontinuation.

Do Not Use Additional Long-Acting Beta2-Agonists

Instruct patients not to use other LABA for asthma andCOPD.

Local Effects

Inform patients that localized infections with Candidaalbicans occurred in the mouth and pharynx in some patients. Iforopharyngeal candidiasis develops, it should be treated with appropriate localor systemic (i.e., oral) antifungal therapy while still continuing therapy withSYMBICORT, but at times therapy with SYMBICORT may need to be temporarilyinterrupted under close medical supervision. Rinsing the mouth with waterwithout swallowing after inhalation is advised to reduce the risk of thrush.

Pneumonia

Patients with COPD have a higher risk of pneumonia;instruct them to contact their healthcare provider if they develop symptoms ofpneumonia.

Immunosuppression

Warn patients who are on immunosuppressant doses ofcorticosteroids to avoid exposure to chicken pox or measles and, if exposed, toconsult their physician without delay. Inform patients of potential worseningof existing tuberculosis, fungal, bacterial, viral, or parasitic infections, orocular herpes simplex.

Hypercorticism And Adrenal Suppression

Advise patients that SYMBICORT may cause systemiccorticosteroid effects of hypercorticism and adrenal suppression. Additionally,inform patients that deaths due to adrenal insufficiency have occurred duringand after transfer from systemic corticosteroids. Patients should taper slowlyfrom systemic corticosteroids if transferring to SYMBICORT.

Reduction In Bone Mineral Density

Advise patients who are at an increased risk fordecreased BMD that the use of corticosteroids may pose an additional risk.

Reduced Growth Velocity

Inform patients that orally inhaled corticosteroids, acomponent of SYMBICORT, may cause a reduction in growth velocity whenadministered to pediatric patients. Physicians should closely follow the growthof children and adolescents taking corticosteroids by any route.

Ocular Effects

Long-term use of inhaled corticosteroids may increase therisk of some eye problems (cataracts or glaucoma); consider regular eyeexaminations.

Risks Associated With Beta-Agonist Therapy

Inform patients of adverse effects associated with beta2agonists,such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Budesonide

Long-term studies were conducted in rats and mice usingoral administration to evaluate the carcinogenic potential of budesonide.

In a 2-year study in Sprague-Dawley rats, budesonidecaused a statistically significant increase in the incidence of gliomas in malerats at an oral dose of 50 mcg/kg (approximately equivalent to the MRHDID inadults and children on a mcg/m² basis). No tumorigenicity was seen in male andfemale rats at respective oral doses up to 25 and 50 mcg/kg (approximatelyequivalent to the MRHDID in adults and children on a mcg/m² basis). In twoadditional 2-year studies in male Fischer and Sprague-Dawley rats, budesonidecaused no gliomas at an oral dose of 50 mcg/kg (approximately equivalent to theMRHDID in adults and children on a mcg/m² basis). However, in the maleSprague-Dawley rats, budesonide caused a statistically significant increase inthe incidence of hepatocellular tumors at an oral dose of 50 mcg/kg(approximately equivalent to the MRHDID in adults and children on a mcg/m² basis).The concurrent reference corticosteroids (prednisolone and triamcinoloneacetonide) in these two studies showed similar findings.

In a 91-week study in mice, budesonide caused notreatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately2 times the MRHDID in adults and children on a mcg/m² basis).

Budesonide was not mutagenic or clastogenic in sixdifferent test systems: Ames Salmonella/microsome plate test, mousemicronucleus test, mouse lymphoma test, chromosome aberration test in humanlymphocytes, sex-linked recessive lethal test in Drosophila melanogaster, andDNA repair analysis in rat hepatocyte culture.

Fertility and reproductive performance were unaffected inrats at subcutaneous doses up to 80 mcg/kg (approximately equal to the MRHDIDon a mcg/m² basis). However, it caused a decrease in prenatal viability andviability in the pups at birth and during lactation, along with a decrease inmaternal bodyweight gain, at subcutaneous doses of 20 mcg/kg and above (lessthan the MRHDID on a mcg/m² basis). No such effects were noted at 5 mcg/kg(less than the MRHDID on a mcg/m² basis).

Formoterol

Long-term studies were conducted in mice using oraladministration and rats using inhalation administration to evaluate thecarcinogenic potential of formoterol fumarate.

In a 24-month carcinogenicity study in CD-1 mice,formoterol at oral doses of 100 mcg/kg and above (approximately 30 and 15 timesthe MRHDID in adults and children, respectively, on a mcg/m² basis) caused adose-related increase in the incidence of uterine leiomyomas.

In a 24-month carcinogenicity study in Sprague-Dawleyrats, an increased incidence of mesovarian leiomyoma and uterine leiomyosarcomawere observed at the inhaled dose of 130 mcg/kg (approximately 70 and 35 timesthe MRHDID in adults and children, respectively, on a mcg/m² basis). No tumorswere seen at 22 mcg/kg (approximately 12 and 6 times the MRHDID in adults andchildren, respectively, on a mcg/m² basis).

Other beta-agonist drugs have similarly demonstratedincreases in leiomyomas of the genital tract in female rodents. The relevanceof these findings to human use is unknown.

Formoterol was not mutagenic or clastogenic in Ames Salmonella/microsomeplate test, mouse lymphoma test, chromosome aberration test in humanlymphocytes, and rat micronucleus test.

A reduction in fertility and/or reproductive performancewas identified in male rats treated with formoterol at an oral dose of 15,000mcg/kg (approximately 2200 times the MRHDID on an AUC basis). No such effectwas seen at 3000 mcg/kg (approximately 1600 times the MRHDID on a mcg/m² basis).In a separate study with male rats treated with an oral dose of 15,000 mcg/kg(approximately 8000 times the MRHDID on a mcg/m² basis), there were findings oftesticular tubular atrophy and spermatic debris in the testes and oligospermiain the epididymides. No effect on fertility was detected in female rats atdoses up to 15,000 mcg/kg (approximately 1100 times the MRHDID on an AUC basis).

Use In Specific Populations

Pregnancy

Risk Summary

There are no adequate and well-controlled studies ofSYMBICORT or one of its individual components, formoterol fumarate, in pregnantwomen; however studies are available for the other component budesonide. Inanimal reproduction studies, SYMBICORT, administered by the inhalation route,was teratogenic, embryocidal, and reduced fetal weights in rats at less thanthe maximum recommended human daily inhalation dose (MRHDID) on a mcg/m² basis.Budesonide alone, administered by the subcutaneous route, was teratogenic,embryocidal, and reduced fetal weights in rats and rabbits at less than theMRHDID, but these effects were not seen in rats that received inhaled doses upto 4 times the MRHDID. Studies of pregnant women have not shown that inhaledbudesonide alone increases the risk of abnormalities when administered duringpregnancy. Experience with oral corticosteroids suggests that rodents are moreprone to teratogenic effects from corticosteroid exposure than humans.Formoterol fumarate alone, administered by the oral route, was teratogenic inrats and rabbits at 1600 and 65,000 times the MRHDID, respectively. Formoterolfumarate was also embryocidal, increased pup loss at birth and duringlactation, and decreased pup weight in rats at 110 times the MRHDID. Theseadverse effects generally occurred at large multiples of the MRHDID whenformoterol fumarate was administered by the oral route to achieve high systemicexposures. No teratogenic, embryocidal, or developmental effects were seen inrats that received inhalation doses up to 375 times the MRHDID.

The estimated background risk of major birth defects andmiscarriage of the indicated populations is unknown. In the U.S. generalpopulation, the estimated background risk of major birth defects andmiscarriage 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 aspreeclampsia in the mother and prematurity, low birth weight, and small forgestational age in the neonate. Pregnant women with asthma should be closelymonitored and medication adjusted as necessary to maintain optimal asthmacontrol.

Labor Or Delivery

There are no well-controlled human studies that haveinvestigated the effects of SYMBICORT during labor and delivery. Because of thepotential for beta-agonist interference with uterine contractility, use ofSYMBICORT during labor should be restricted to those patients in whom thebenefits clearly outweigh the risk.

Data

Human Data

Studies of pregnant women have not shown that inhaledbudesonide increases the risk of abnormalities when administered duringpregnancy. The results from a large population-based prospective cohort epidemiologicalstudy reviewing data from three Swedish registries covering approximately 99%of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry;Registry of Congenital Malformations; Child Cardiology Registry) indicate noincreased risk for congenital malformations from the use of inhaled budesonideduring early pregnancy. Congenital malformations were studied in 2014 infantsborn to mothers reporting the use of inhaled budesonide for asthma in earlypregnancy (usually 10-12 weeks after the last menstrual period), the periodwhen most major organ malformations occur. The rate of recorded congenitalmalformations was similar compared to the general population rate (3.8% vs.3.5%, respectively). In addition, after exposure to inhaled budesonide, thenumber of infants born with orofacial clefts was similar to the expected numberin the normal population (4 children vs. 3.3, respectively).

These same data were utilized in a second study bringingthe total to 2534 infants whose mothers were exposed to inhaled budesonide. Inthis study, the rate of congenital malformations among infants whose motherswere exposed to inhaled budesonide during early pregnancy was not differentfrom the rate for all newborn babies during the same period (3.6%).

Animal Data

SYMBICORT

In an embryo-fetal development study in pregnant ratsdosed during the period of organogenesis from gestation days 6-16, SYMBICORTproduced umbilical hernia in fetuses at doses less than the MRHDID (on a mcg/m²basis at maternal inhaled doses of 12/0.66 mcg/kg/day and above). Fetal weightswere reduced at approximately 5 and 3 times the MRHDID, respectively (on an AUCbasis at a maternal inhaled dose of 80/4.4 mcg/kg (budesonide/formoterol)). Noteratogenic or embryocidal effects were detected at doses less than the MRHDID(on a mcg/m² basis at a maternal inhaled dose of 2.5/0.14 mcg/kg/day).

Budesonide

In a fertility and reproduction study, male rats weresubcutaneously dosed for 9 weeks and females for 2 weeks prior to pairing andthroughout the mating period. Females were dosed up until weaning of theiroffspring. Budesonide caused a decrease in prenatal viability and viability inthe pups at birth and during lactation, along with a decrease in maternalbody-weight gain, at doses less than the MRHDID (on a mcg/m² basis at maternalsubcutaneous doses of 20 mcg/kg/day and above). No such effects were noted at adose less than the MRHDID (on a mcg/m² basis at a maternal subcutaneous dose of5 mcg/kg/day).

In an embryo-fetal development study in pregnant rabbitsdosed during the period of organogenesis from gestation days 6-18, budesonideproduced fetal loss, decreased fetal weight, and skeletal abnormalities atdoses less than the MRHDID (on a mcg/m² basis at a maternal subcutaneous doseof 25 mcg/kg/day). In an embryo-fetal development study in pregnant rats dosedduring the period of organogenesis from gestation days 6-15, budesonideproduced similar adverse fetal effects at doses approximately 8 times theMRHDID (on a mcg/m² basis at a maternal subcutaneous dose of 500 mcg/kg/day).In another embryo-fetal development study in pregnant rats, no teratogenic orembryocidal effects were seen at doses up to 4 times the MRHDID (on a mcg/m² basisat maternal inhalation doses up to 250 mcg/kg/day).

In a peri-and post-natal development study, rats dosedfrom gestation day 15 to postpartum day 21, budesonide had no effects ondelivery, but did have an effect on growth and development of offspring.Offspring survival was reduced and surviving offspring had decreased mean bodyweights at birth and during lactation at doses less than the MRHDID and higher(on a mcg/m² basis at maternal subcutaneous doses of 20 mcg/kg/day and higher).These findings occurred in the presence of maternal toxicity.

Formoterol

In a fertility and reproduction study, male rats wereorally dosed for 9 weeks and females for 2 weeks prior to pairing andthroughout the mating period. Females were either dosed up to gestation day 19or up until weaning of their offspring. Males were dosed up to 25 weeks.Umbilical hernia was observed in rat fetuses at oral doses 1600 times andgreater than the MRHDID (on a mcg/m² basis at maternal oral doses of 3000mcg/kg/day and higher). Brachygnathia was observed in rat fetuses at a dose8000 times the MRHDID (on a mcg/m² basis at a maternal oral dose of 15,000mcg/kg/day). Pregnancy was prolonged at a dose 8000 times the MRHDID (on amcg/m² basis at a maternal oral dose of 15,000 mcg/kg/day). Fetal and pupdeaths occurred at doses approximately 1600 times the MRHDID and higher (on amcg/m² basis at oral doses of 3000 mcg/kg/day and higher) during gestation.

In an embryo-fetal development study in pregnant ratsdosed during the period of organogenesis from gestation days 6-15, noteratogenic, embryocidal or developmental effects were seen at doses up to 375times the MRHDID (on a mcg/m² basis with maternal inhalation doses up to 690mcg/kg/day).

In an embryo-fetal development study in pregnant rabbitsdosed during the period of organogenesis from gestation days 6-18, subcapsularcysts on the liver were observed in the fetuses at a dose 65,000 times theMRHDID (on a mcg/m² basis with a maternal oral dose of 60,000 mcg/kg/day). Noteratogenic effects were observed at doses up to 3800 times the MRHDID (on amcg/m² basis at maternal oral doses up to 3500 mcg/kg/day).

In a pre-and post-natal development study, pregnantfemale rats received formoterol at oral doses of 0, 210, 840, and 3400mcg/kg/day from gestation day 6 through the lactation period. Pup survival wasdecreased from birth to postpartum day 26 at doses 110 times the MRHDID andhigher (on a mcg/m² basis at maternal oral doses of 210 mcg/kg/day and higher),although there was no evidence of a dose-response relationship. There were notreatment-related effects on the physical, functional, and behavioral developmentof rat pups.

Lactation

Risk Summary

There are no available data on the effects of SYMBICORT,budesonide or formoterol fumarate on the breastfed child or on milk production.Budesonide, like other inhaled corticosteroids, is present in human milk [see Data].There are no available data on the presence of formoterol fumarate in humanmilk. Formoterol fumarate is present in rat milk [see Data]. Thedevelopmental and health benefits of breastfeeding should be considered alongwith the mother's clinical need for SYMBICORT and any potential adverse effectson the breastfed infant from SYMBICORT or from the underlying maternalcondition.

Data

Human data with budesonide delivered via dry powderinhaler indicates that the total daily oral dose of budesonide available inbreast milk to the infant is approximately 0.3% to 1% of the dose inhaled bythe mother [see CLINICAL PHARMACOLOGY]. For SYMBICORT, the dose ofbudesonide available to the infant in breast milk, as a percentage of thematernal dose, would be expected to be similar.

In the fertility and reproduction study in rats, plasmalevels of formoterol were measured in pups on post-natal day 15 [see Use In SpecificPopulations]. It was estimated that the maximum plasma concentration thatthe pups received from the maternal animal, at the highest dose of 15 mg/kg,after nursing was 4.4% (0.24 nmol/L for a litter vs. 5.5 nmol/L for themother).

Pediatric Use

Safety and effectiveness of SYMBICORT in asthma patients12 years of age and older have been established in studies up to 12 months. Inthe two 12-week, double-blind, placebo-controlled US pivotal studies 25patients 12 to 17 years of age were treated with SYMBICORT twice daily [see ClinicalStudies]. Efficacy results in this age group were similar to those observedin patients 18 years and older. There were no obvious differences in the typeor frequency of adverse events reported in this age group compared withpatients 18 years of age and older.

The safety and effectiveness of SYMBICORT 80/4.5 inasthma patients 6 to less than 12 years of age have been established in studiesof up to 12-week duration [see Clinical Studies]. The safety profile inthese patients was consistent to that observed in patients 12 years of age andolder who also received SYMBICORT [see ADVERSE REACTIONS].

The safety and effectiveness of SYMBICORT in asthmapatients less than 6 years of age have not been established.

Controlled clinical studies have shown that orallyinhaled corticosteroids including budesonide, a component of SYMBICORT, maycause a reduction in growth velocity in pediatric patients. This effect hasbeen observed in the absence of laboratory evidence of HPA-axis suppression,suggesting that growth velocity is a more sensitive indicator of systemiccorticosteroid exposure in pediatric patients than some commonly used tests ofHPA-axis function. The long-term effect of this reduction in growth velocityassociated with orally inhaled corticosteroids, including the impact on finalheight are unknown. The potential for “catch-up” growth followingdiscontinuation of treatment with orally inhaled corticosteroids has not beenadequately studied.

In a study of asthmatic children 5 to 12 years of age,those treated with budesonide DPI 200 mcg twice daily (n=311) had a 1.1centimeter reduction in growth compared with those receiving placebo (n=418) atthe end of one year; the difference between these two treatment groups did notincrease further over three years of additional treatment. By the end of 4years, children treated with budesonide DPI and children treated with placebohad similar growth velocities. Conclusions drawn from this study may beconfounded by the unequal use of corticosteroids in the treatment groups andinclusion of data from patients attaining puberty during the course of thestudy.

The growth of pediatric patients receiving orally inhaledcorticosteroids, including SYMBICORT, should be monitored. If a child oradolescent on any corticosteroid appears to have growth suppression, thepossibility that he/she is particularly sensitive to this effect should beconsidered. The potential growth effects of prolonged treatment should beweighed against the clinical benefits obtained. To minimize the systemiceffects of orally inhaled corticosteroids, including SYMBICORT, each patientshould be titrated to the lowest strength that effectively controls his/herasthma [see DOSAGE AND ADMINISTRATION].

Geriatric Use

Of the total number of asthma patients treated withSYMBICORT twice daily in two 12-week studies and a 26-week postmarketing study,791 were 65 years of age or older, of whom 141 were 75 years of age or older.

In the COPD studies of 6 to 12 months duration, 810patients treated with SYMBICORT 160/4.5, two inhalations twice daily were 65years old and above and of those, 177 patients were 75 years of age and older.No overall differences in safety or effectiveness were observed between thesepatients and younger patients, and other reported clinical experience has notidentified differences in responses between the elderly and younger patients.

As with other products containing beta2-agonists, specialcaution should be observed when using SYMBICORT in geriatric patients who haveconcomitant cardiovascular disease that could be adversely affected by beta2-agonists.

Based on available data for SYMBICORT or its activecomponents, no adjustment of dosage of SYMBICORT in geriatric patients iswarranted.

Hepatic Impairment

Formal pharmaco*kinetic studies using SYMBICORT have notbeen conducted in patients with hepatic impairment. However, since bothbudesonide and formoterol fumarate are predominantly cleared by hepaticmetabolism, impairment of liver function may lead to accumulation of budesonideand formoterol fumarate in plasma. Therefore, patients with hepatic diseaseshould be closely monitored.

Renal Impairment

Formal pharmaco*kinetic studies using SYMBICORT have notbeen conducted in patients with renal impairment.

Overdose Information for Symbicort

SYMBICORT

SYMBICORT contains both budesonide and formoterol;therefore, the risks associated with overdosage for the individual componentsdescribed below apply to SYMBICORT. In pharmaco*kinetic studies, single doses of960/54 mcg (12 actuations of SYMBICORT 80/4.5) and 1280/36 mcg (8 actuations of160/4.5), were administered to patients with COPD. A total of 1920/54 mcg (12actuations of SYMBICORT 160/4.5) was administered as a single dose to bothhealthy subjects and patients with asthma. In a long-term active-controlledsafety study in adolescent and adult asthma patients 12 years of age and older,SYMBICORT 160/4.5 was administered for up to 12 months at doses up to twice thehighest recommended daily dose. There were no clinically significant adversereactions observed in any of these studies.

Budesonide

The potential for acute toxic effects following overdoseof budesonide is low. If used at excessive doses for prolonged periods,systemic corticosteroid effects such as hypercorticism may occur [see WARNINGSAND PRECAUTIONS]. Budesonide at five times the highest recommended dose(3200 mcg daily) administered to humans for 6 weeks caused a significantreduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTHcompared with placebo (+1%). The corresponding effect of 10 mg prednisone dailywas a 35% reduction in the plasma cortisol response to ACTH.

Formoterol

An overdose of formoterol would likely lead to anexaggeration of effects that are typical for beta2agonists: 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 allsympathomimetic medications, cardiac arrest and even death may be associatedwith abuse of formoterol. No clinically significant adverse reactions were seenwhen formoterol was delivered to adult patients with acute bronchoconstrictionat a dose of 90 mcg/day over 3 hours or to stable asthmatics 3 times a day at atotal dose of 54 mcg/day for 3 days.

Treatment of formoterol overdosage consists ofdiscontinuation of the medication together with institution of appropriatesymptomatic and/or supportive therapy. The judicious use of a cardioselectivebeta-receptor blocker may be considered, bearing in mind that such medicationcan produce bronchospasm. There is insufficient evidence to determine ifdialysis is beneficial for overdosage of formoterol. Cardiac monitoring isrecommended in cases of overdosage.

Contraindications for Symbicort

The use of SYMBICORT is contraindicated in the followingconditions:

• 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 SYMBICORT.

Clinical Pharmacology for Symbicort

Mechanism Of Action

SYMBICORT

SYMBICORT contains bothbudesonide and formoterol; therefore, the mechanisms of action described belowfor the individual components apply to SYMBICORT. These drugs represent twoclasses of medications (a synthetic corticosteroid and a long-acting selectivebeta2-adrenoceptor agonist) that have different effects on clinical,physiological, and inflammatory indices of COPD and asthma.

Budesonide

Budesonide is ananti-inflammatory corticosteroid that exhibits potent glucocorticoid activityand weak mineralocorticoid activity. In standard in vitro and animal models,budesonide has approximately a 200fold higher affinity for the glucocorticoidreceptor and a 1000-fold higher topical anti-inflammatory potency than cortisol(rat croton oil ear edema assay). As a measure of systemic activity, budesonideis 40 times more potent than cortisol when administered subcutaneously and 25times more potent when administered orally in the rat thymus involution assay.

In glucocorticoid receptoraffinity studies, the 22R form of budesonide was two times as active as the 22Sepimer. In vitro studies indicated that the two forms of budesonide do notinterconvert.

Inflammation is an important component in thepathogenesis of COPD and asthma. Corticosteroids have a wide range ofinhibitory 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 andnon–allergic-mediated inflammation. These anti-inflammatory actions ofcorticosteroids may contribute to their efficacy in COPD and asthma.

Studies in asthmatic patients have shown a favorableratio between topical anti-inflammatory activity and systemic corticosteroideffects over a wide range of doses of budesonide. This is explained by acombination of a relatively high local anti-inflammatory effect, extensivefirst pass hepatic degradation of orally absorbed drug (85%-95%), and the lowpotency of formed metabolites.

Formoterol

Formoterol fumarate is a long-acting selective beta2-adrenergicagonist (beta2-agonist) with a rapid onset of action. Inhaled formoterolfumarate acts locally in the lung as a bronchodilator. In vitro studies haveshown that formoterol has more than 200-fold greater agonist activity at beta2-receptorsthan at beta1receptors. The in vitro binding selectivity to beta2-over beta1-adrenoceptorsis higher for formoterol than for albuterol (5 times), whereas salmeterol has ahigher (3 times) beta2-selectivity ratio than formoterol.

Although beta2-receptors are the predominant adrenergicreceptors in bronchial smooth muscle and beta1receptors are the predominantreceptors in the heart, there are also beta2-receptors in the human heartcomprising 10% to 50% of the total beta-adrenergic receptors. The precisefunction of these receptors has not been established, but they raise the possibilitythat even highly selective beta2-agonists may have cardiac effects.

The pharmacologic effects of beta2-adrenoceptor agonistdrugs, including formoterol, are at least in part attributable to stimulationof intracellular adenyl cyclase, the enzyme that catalyzes the conversion ofadenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclicAMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscleand inhibition of release of mediators of immediate hypersensitivity fromcells, especially from mast cells.

In vitro tests show that formoterol is an inhibitor ofthe release of mast cell mediators, such as histamine and leukotrienes, fromthe human lung. Formoterol also inhibits histamine-induced plasma albuminextravasation in anesthetized guinea pigs and inhibits allergen-inducedeosinophil influx in dogs with airway hyper-responsiveness. The relevance ofthese in vitro and animal findings to humans is unknown.

Pharmacodynamics

Asthma

Cardiovascular Effects

In a single-dose cross-over study involving 201 patientswith persistent asthma, single-dose treatments of 4.5, 9, and 18 mcg offormoterol in combination with 320 mcg of budesonide delivered via SYMBICORTwere compared to budesonide 320 mcg alone. Dose-ordered improvements in FEV₁ weredemonstrated when compared with budesonide. ECGs and blood samples for glucoseand potassium were obtained post-dose. For SYMBICORT, small mean increases inserum glucose and decreases in serum potassium (+0.44 mmol/L and -0.18 mmol/Lat the highest dose, respectively) were observed with increasing doses offormoterol, compared to budesonide. In ECGs, SYMBICORT produced smalldose-related mean increases in heart rate (approximately 3 bpm at the highestdose), and QTc intervals (3-6 msec) compared to budesonide alone. No subjecthad a QT or QTc value ≥500 msec.

In the United States, five 12-week, active-andplacebo-controlled studies and one 6-month active-controlled study evaluated2976 patients aged 6 years and older with asthma. Systemic pharmacodynamiceffects of formoterol (heart/pulse rate, blood pressure, QTc interval,potassium, and glucose) were similar in patients treated with SYMBICORT,compared with patients treated with formoterol dry inhalation powder 4.5 mcg, 2inhalations twice daily. No patient had a QT or QTc value ≥500 msecduring treatment.

In three placebo-controlled studies in adolescents andadults with asthma, aged 12 years and older, a total of 1232 patients (553patients in the SYMBICORT group) had evaluable continuous 24-hourelectrocardiographic monitoring. Overall, there were no important differencesin the occurrence of ventricular or supraventricular ectopy and no evidence ofincreased risk for clinically significant dysrhythmia in the SYMBICORT groupcompared to placebo.

HPA-Axis Effects

Overall, no clinically important effects on HPA-axis, asmeasured by 24-hour urinary cortisol, were observed for SYMBICORT treated adultor adolescent patients at doses up to 640/18 mcg/day compared to budesonide.

Chronic Obstructive Pulmonary Disease

Cardiovascular Effects

In two COPD lung function studies, 6 months and 12 monthsin duration including 3668 COPD patients, no clinically important differenceswere seen in pulse rate, blood pressure, potassium, and glucose betweenSYMBICORT, the individual components of SYMBICORT, and placebo [see ClinicalStudies].

ECGs recorded at multiple clinic visits on treatment inboth studies showed no clinically important differences for heart rate, PRinterval, QRS duration, heart rate, signs of cardiac ischemia or arrhythmiasbetween SYMBICORT 160/4.5 the monoproducts and placebo, all administered as 2inhalations twice daily. Based on ECGs, 6 patients treated with SYMBICORT160/4.5, 6 patients treated with formoterol 4.5 mcg, and 6 patients in theplacebo group experienced atrial fibrillation or flutter that was not presentat baseline. There were no cases of nonsustained ventricular tachycardia in theSYMBICORT 160/4.5, formoterol 4.5 mcg, or placebo groups.

In the 12-month study, 520 patients had evaluablecontinuous 24-hour ECG (Holter) monitoring prior to the first dose and afterapproximately 1 and 4 months on treatment. No clinically important differencesin ventricular or supraventricular arrhythmias, ventricular or supraventricularectopic beats, or heart rate were observed among the groups treated withSYMBICORT 160/4.5, formoterol or placebo taken as 2 inhalations twice daily. Basedon ECG (Holter) monitoring, one patient on SYMBICORT 160/4.5, no patients onformoterol 4.5 mcg, and three patients in the placebo group experienced atrialfibrillation or flutter that was not present at baseline.

HPA-axis Effects

Twenty-four hour urinary cortisol measurements werecollected in a pooled subset (n=616) of patients from two COPD lung functionstudies. The data indicated approximately 30% lower mean 24-hour urinary freecortisol values following chronic administration (> 6 months) of SYMBICORTrelative to placebo. SYMBICORT appeared to exhibit comparable cortisolsuppression to budesonide 160 mcg alone or coadministration of budesonide 160mcg and formoterol 4.5 mcg. For patients treated with SYMBICORT or placebo forup to 12 months, the percentage of patients who shifted from normal to low forthis measure were generally comparable.

Other Budesonide Products

To confirm that systemic absorption is not a significantfactor in the clinical efficacy of inhaled budesonide, a clinical study inpatients with asthma was performed comparing 400 mcg budesonide administeredvia a pressurized metered dose inhaler with a tube spacer to 1400 mcg of oralbudesonide and placebo. The study demonstrated the efficacy of inhaled budesonidebut not orally ingested budesonide, despite comparable systemic levels. Thus,the therapeutic effect of conventional doses of orally inhaled budesonide arelargely explained by its direct action on the respiratory tract.

Inhaled budesonide has been shown to decrease airwayreactivity to various challenge models, including histamine, methacholine,sodium metabisulfite, and adenosine monophosphate in patients withhyperreactive airways. The clinical relevance of these models is not certain.

Pretreatment with inhaled budesonide, 1600 mcg daily (800mcg twice daily) for 2 weeks reduced the acute (early-phase reaction) anddelayed (late-phase reaction) decrease in FEV₁ following inhaled allergenchallenge.

The systemic effects of inhaled corticosteroids arerelated to the systemic exposure to such drugs. Pharmaco*kinetic studies havedemonstrated that in both adults and children with asthma the systemic exposureto budesonide is lower with SYMBICORT compared with inhaled budesonideadministered at the same delivered dose via a dry powder inhaler [see CLINICALPHARMACOLOGY]. Therefore, the systemic effects (HPA-axis and growth) ofbudesonide delivered from SYMBICORT would be expected to be no greater thanwhat is reported for inhaled budesonide when administered at comparable dosesvia the dry powder inhaler [see Use In Specific Populations].

HPA-Axis Effects

The effects of inhaled budesonide administered via a drypowder inhaler on the HPA-axis were studied in 905 adults and 404 pediatricpatients with asthma. For most patients, the ability to increase cortisolproduction in response to stress, as assessed by cosyntropin (ACTH) stimulationtest, remained intact with budesonide treatment at recommended doses. For adultpatients treated with 100, 200, 400, or 800 mcg twice daily for 12 weeks, 4%,2%, 6%, and 13%, respectively, had an abnormal stimulated cortisol response(peak cortisol <14.5 mcg/dL assessed by liquid chromatography followingshort-cosyntropin test) as compared to 8% of patients treated with placebo.Similar results were obtained in pediatric patients. In another study inadults, doses of 400, 800, and 1600 mcg of inhaled budesonide twice daily for 6weeks were examined; 1600 mcg twice daily (twice the maximum recommended dose)resulted in a 27% reduction in stimulated cortisol (6-hour ACTH infusion) while10-mg prednisone resulted in a 35% reduction. In this study, no patient onbudesonide at doses of 400 and 800 mcg twice daily met the criterion for anabnormal stimulated-cortisol response (peak cortisol <14.5 mcg/dL assessedby liquid chromatography) following ACTH infusion. An open-label, long-termfollow-up of 1133 patients for up to 52 weeks confirmed the minimal effect onthe HPA-axis (both basal-and stimulated-plasma cortisol) of budesonide whenadministered at recommended doses. In patients who had previously beenoral-steroid-dependent, use of budesonide in recommended doses was associatedwith higher stimulated-cortisol response compared to baseline following 1 yearof therapy.

Other Formoterol Products

While the pharmacodynamic effect is via stimulation ofbeta-adrenergic receptors, excessive activation of these receptors commonlyleads to skeletal muscle tremor and cramps, insomnia, tachycardia, decreases inplasma potassium, and increases in plasma glucose. Inhaled formoterol, likeother beta2-adrenergic agonist drugs, can produce dose-related cardiovasculareffects and effects on blood glucose and/or serum potassium [see WARNINGSAND PRECAUTIONS]. For SYMBICORT, these effects are detailed in the ClinicalPharmacology, Pharmacodynamics, SYMBICORT (12.2) section.

Use of LABA drugs can result in tolerance tobronchoprotective and bronchodilatory effects.

Rebound bronchial hyperresponsiveness after cessation ofchronic long-acting beta-agonist therapy has not been observed.

Pharmaco*kinetics

SYMBICORT

Absorption

Budesonide

Healthy Subjects

Orally inhaled budesonide is rapidly absorbed in thelungs and peak concentration is typically reached within 20 minutes. After oraladministration of budesonide peak plasma concentration was achieved in about 1to 2 hours and the absolute systemic availability was 6%-13% due to extensivefirst pass metabolism. In contrast, most of the budesonide delivered to thelungs was systemically absorbed. In healthy subjects, 34% of the metered dosewas deposited in the lung (as assessed by plasma concentration method and usinga budesonide-containing dry powder inhaler) with an absolute systemicavailability of 39% of the metered dose.

Following administration of SYMBICORT 160/4.5, two orfour inhalations twice daily for 5 days in healthy subjects, plasmaconcentration of budesonide generally increased in proportion to dose. Theaccumulation index for the group that received 2 inhalations twice daily was1.32 for budesonide.

Asthma Patients

In a single-dose study, higher than recommended doses ofSYMBICORT (12 inhalations of SYMBICORT 160/4.5) were administered to patientswith moderate asthma. Peak budesonide plasma concentration of 4.5 nmol/Loccurred at 20 minutes following dosing. This study demonstrated that the totalsystemic exposure to budesonide from SYMBICORT was approximately 30% lower thanfrom inhaled budesonide via a dry powder inhaler (DPI) at the same delivereddose. Following administration of SYMBICORT, the half-life of the budesonidecomponent was 4.7 hours.

In a repeat dose study, the highest recommended dose ofSYMBICORT (160/4.5, two inhalations twice daily) was administered to patientswith moderate asthma and healthy subjects for 1 week. Peak budesonide plasmaconcentration of 1.2 nmol/L occurred at 21 minutes in asthma patients. Peakbudesonide plasma concentration was 27% lower in asthma patients compared to thatin healthy subjects. However, the total systemic exposure of budesonide wascomparable to that in asthma patients.

Peak steady-state plasma concentrations of budesonideadministered by DPI in adults with asthma averaged 0.6 and 1.6 nmol/L at dosesof 180 mcg and 360 mcg twice daily, respectively. In asthmatic patients,budesonide showed a linear increase in AUC and Cmax with increasing dose afterboth single and repeated dosing of inhaled budesonide.

COPD Patients

In a single-dose study, 12 inhalations of SYMBICORT80/4.5 (total dose 960/54 mcg) were administered to patients with COPD. Meanbudesonide peak plasma concentration of 3.3 nmol/L occurred at 30 minutesfollowing dosing. Budesonide systemic exposure was comparable between SYMBICORTpMDI and coadministration of budesonide via a metered-dose inhaler andformoterol via a dry powder inhaler (budesonide 960 mcg and formoterol 54 mcg).In the same study, an open-label group of moderate asthma patients alsoreceived the same higher dose of SYMBICORT. For budesonide, COPD patientsexhibited 12% greater AUC and 10% lower Cmax compared to asthma patients.

In the 6-month pivotal lung function clinical study,steady-state pharmaco*kinetic data of budesonide was obtained in a subset ofCOPD patients with treatment arms of SYMBICORT pMDI 160/4.5, SYMBICORT pMDI80/4.5, budesonide 160 mcg, budesonide 160 mcg and formoterol 4.5 mcg giventogether, all administered as 2 inhalations twice daily. Budesonide systemicexposure (AUC and Cmax) increased proportionally with doses from 80 mcg to 160mcg and was generally similar between the 3 treatment groups receiving the samedose of budesonide (SYMBICORT pMDI 160/4.5, budesonide 160 mcg, budesonide 160mcg and formoterol 4.5 mcg administered together).

Formoterol

Inhaled formoterol is rapidly absorbed; peak plasmaconcentrations are typically reached at the first plasma sampling time, within5-10 minutes after dosing. As with many drug products for oral inhalation, itis likely that the majority of the inhaled formoterol delivered is swallowedand then absorbed from the gastrointestinal tract.

Healthy Subjects

Following administration of SYMBICORT (160/4.5, two orfour inhalations twice daily) for 5 days in healthy subjects, plasma concentrationof formoterol generally increased in proportion to dose. The accumulation indexfor the group that received 2 inhalations twice daily was 1.77 for formoterol.

Asthma Patients

In a single-dose study, higher than recommended doses ofSYMBICORT (12 inhalations of SYMBICORT 160/4.5) were administered to patientswith moderate asthma. Peak plasma concentration for formoterol of 136 pmoloccurred at 10 minutes following dosing. Approximately 8% of the delivered doseof formoterol was recovered in the urine as unchanged drug.

In a repeat dose study, the highest recommended dose ofSYMBICORT (160/4.5, two inhalations twice daily) was administered to patientswith moderate asthma and healthy subjects for 1 week. Peak formoterol plasmaconcentration of 28 pmol/L occurred at 10 minutes in asthma patients. Peakformoterol plasma concentration was about 42% lower in asthma patients comparedto that in healthy subjects. However, the total systemic exposure of formoterolwas comparable to that in asthma patients.

COPD Patients

Following single-dose administration of 12 inhalations ofSYMBICORT 80/4.5, mean peak formoterol plasma concentration of 167 pmol/L wasrapidly achieved at 15 minutes after dosing. Formoterol exposure was slightlygreater (~16-18%) from SYMBICORT pMDI compared to coadministration ofbudesonide via a metered-dose inhaler and formoterol via a dry powder inhaler(total dose of budesonide 960 mcg and formoterol 54 mcg). In the same study, anopen label group of moderate asthma patients received the same dose ofSYMBICORT. COPD patients exhibited 12-15% greater AUC and Cmax for formoterolcompared to asthma patients.

In the 6-month pivotal lung function clinical study,steady-state pharmaco*kinetic data of formoterol was obtained in a subset of COPDpatients with treatment arms of SYMBICORT pMDI 160/4.5, SYMBICORT pMDI 80/4.5,formoterol 4.5 mcg, budesonide 160 mcg and formoterol 4.5 mcg given together,all administered as 2 inhalations twice daily. The systemic exposure offormoterol as evidenced by AUC, was about 30% and 16% higher from SYMBICORTpMDI compared to formoterol alone treatment arm and coadministration ofindividual components of budesonide and formoterol treatment arm, respectively.

Distribution

Budesonide

The volume of distribution of budesonide wasapproximately 3 L/kg. It was 85%-90% bound to plasma proteins. Protein bindingwas constant over the concentration range (1-100 nmol/L) achieved with, andexceeding, recommended inhaled doses. Budesonide showed little or no binding tocorticosteroid binding globulin. Budesonide rapidly equilibrated with red bloodcells in a concentration independent manner with a blood plasma ratio of about0.8.

Formoterol

Over the concentration range of 10-500 nmol/L, plasmaprotein binding for the RR and SS enantiomers of formoterol was 46% and 58%,respectively. The concentrations of formoterol used to assess the plasmaprotein binding were higher than those achieved in plasma following inhalationof a single 54 mcg dose.

Metabolism

Budesonide

In vitro studies with human liver hom*ogenates have shownthat budesonide was rapidly and extensively metabolized. Two major metabolitesformed via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) catalyzedbiotransformation have been isolated and identified as16α-hydroxyprednisolone and 6ß-hydroxybudesonide. The corticosteroidactivity of each of these two metabolites was less than 1% of that of theparent compound. No qualitative differences between the in vitro and in vivo metabolicpatterns were detected. Negligible metabolic inactivation was observed in humanlung and serum preparations.

Formoterol

The primary metabolism of formoterol is by directglucuronidation and by O-demethylation followed by conjugation to inactivemetabolites. Secondary metabolic pathways include deformylation and sulfateconjugation. CYP2D6 and CYP2C have been identified as being primarily responsiblefor Odemethylation.

Elimination

Budesonide

Budesonide was excreted in urine and feces in the form ofmetabolites. Approximately 60% of an intravenous radiolabeled dose wasrecovered in the urine.

No unchanged budesonide was detected in the urine. The22R form of budesonide was preferentially cleared by the liver with systemicclearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life,2 to 3 hours, was the same for both epimers and was independent of dose.

Formoterol

The excretion of formoterol was studied in four healthysubjects following simultaneous administration of radiolabeled formoterol viathe oral and IV routes. In that study, 62% of the radiolabeled formoterol wasexcreted in the urine while 24% was eliminated in the feces.

Special Populations

Geriatric

The pharmaco*kinetics of SYMBICORT in geriatric patientshave not been specifically studied.

Pediatric

Plasma concentrations of budesonide were measuredfollowing administration of four inhalations of SYMBICORT 160/4.5 in asingle-dose study in pediatric patients with asthma, 6 to less than 12 years ofa*ge. Peak budesonide concentrations of 1.4 nmol/L occurred at 20 minutespost-dose. This study also demonstrated that the total systemic exposure tobudesonide from SYMBICORT was approximately 30% lower than from inhaledbudesonide via a dry powder inhaler that was also evaluated at the samedelivered dose. The dose-normalized Cmax and AUC0-inf of budesonide followingsingle dose inhalation in children 6 to less than 12 years of age werenumerically lower than that observed in adults.

Following 2 inhalations of SYMBICORT 160/4.5 twice dailytreatment, formoterol Cmax and AUC0-6 at steady state in children 6 to lessthan 12 years of age were comparable to that observed in adults.

Gender/Race

Specific studies to examine the effects of gender andrace on the pharmaco*kinetics of SYMBICORT have not been conducted. PopulationPK analysis of the SYMBICORT data indicates that gender does not affect thepharmaco*kinetics of budesonide and formoterol. No conclusions can be drawn onthe effect of race due to the low number of non-Caucasians evaluated for PK.

Nursing Mothers

The disposition of budesonide when delivered byinhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily forat least 3 months was studied in eight lactating women with asthma from 1 to 6months postpartum. Systemic exposure to budesonide in these women appears to becomparable to that in non-lactating women with asthma from other studies.Breast milk obtained over eight hours post-dose revealed that the maximumconcentration of budesonide for the 400 and 800 mcg total daily doses was 0.39and 0.78 nmol/L, respectively, and occurred within 45 minutes after dosing. Theestimated oral daily dose of budesonide from breast milk to the infant isapproximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in thisstudy, which represents approximately 0.3% to 1% of the dose inhaled by themother. Budesonide levels in plasma samples obtained from five infants at about90 minutes after breastfeeding (and about 140 minutes after drug administrationto the mother) were below quantifiable levels (<0.02 nmol/L in four infantsand <0.04 nmol/L in one infant) [see Use In Specific Populations].

Renal Or Hepatic Insufficiency

There are no data regarding the specific use of SYMBICORTin patients with hepatic or renal impairment. Reduced liver function may affectthe elimination of corticosteroids. Budesonide pharmaco*kinetics was affected bycompromised liver function as evidenced by a doubled systemic availabilityafter oral ingestion. The intravenous budesonide pharmaco*kinetics was, however,similar in cirrhotic patients and in healthy subjects. Specific data withformoterol is not available, but because formoterol is primarily eliminated viahepatic metabolism, an increased exposure can be expected in patients withsevere liver impairment.

Drug-Drug Interactions

A single-dose crossover study was conducted to comparethe pharmaco*kinetics of eight inhalations of the following: budesonide,formoterol, and budesonide plus formoterol administered concurrently. Theresults of the study indicated that there was no evidence of a pharmaco*kineticinteraction between the two components of SYMBICORT.

Inhibitors Of Cytochrome P450 Enzymes

Ketoconazole

Ketoconazole, a strong inhibitor of cytochrome P450 (CYP)isoenzyme 3A4 (CYP3A4), the main metabolic enzyme for corticosteroids,increased plasma levels of orally ingested budesonide.

Cimetidine

At recommended doses, cimetidine, a non-specificinhibitor of CYP enzymes, had a slight but clinically insignificant effect onthe pharmaco*kinetics of oral budesonide.

Specific drug-drug interaction studies with formoterolhave not been performed.

Animal Toxicology And/Or Pharmacology

Preclinical

Studies in laboratory animals (minipigs, rodents, anddogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death(with histologic evidence of myocardial necrosis) when beta-agonists andmethylxanthines are administered concurrently. The clinical significance ofthese findings is unknown.

Clinical Studies

Asthma

Patients With Asthma 12 Years Of Age And Older

In two clinical studies comparing SYMBICORT with theindividual components, improvements in most efficacy end points were greaterwith SYMBICORT than with the use of either budesonide or formoterol alone. Inaddition, one clinical study showed similar results between SYMBICORT and theconcurrent use of budesonide and formoterol at corresponding doses fromseparate inhalers.

The safety and efficacy of SYMBICORT were demonstrated intwo randomized, double-blind, placebo-controlled US clinical studies involving1076 patients 12 years of age and older. Fixed SYMBICORT dosages of 160/9 mcg,and 320/9 mcg twice daily (each dose administered as 2 inhalations of the80/4.5 and 160/4.5 mcg strengths, respectively) were compared with themonocomponents (budesonide and formoterol) and placebo to provide informationabout appropriate dosing to cover a range of asthma severity.

Study 1: Clinical Study With SYMBICORT 160/4.5

This 12-week study evaluated 596 patients 12 years of ageand older by comparing SYMBICORT 160/4.5, the free combination of budesonide160 mcg plus formoterol 4.5 mcg in separate inhalers, budesonide 160 mcg,formoterol 4.5 mcg, and placebo; each administered as 2 inhalations twicedaily. The study included a 2-week run-in period with budesonide 80 mcg, 2inhalations twice daily. Most patients had moderate to severe asthma and wereusing moderate to high doses of inhaled corticosteroids prior to study entry.Randomization was stratified by previous inhaled corticosteroid treatment(71.6% on moderate-and 28.4% on high-dose inhaled corticosteroid). Mean percentpredicted FEV₁ at baseline was 68.1% and was similar across treatment groups.The co-primary efficacy end points were 12-hour-average post-dose FEV₁ at week2, and pre-dose FEV₁ averaged over the course of the study. The study alsorequired that patients who satisfied a predefined asthma-worsening criterion bewithdrawn. The predefined asthma-worsening criteria were a clinically importantdecrease in FEV₁ or PEF, increase in rescue albuterol use, nighttime awakeningdue to asthma, emergency intervention or hospitalization due to asthma, orrequirement for asthma medication not allowed by the protocol. For thecriterion of nighttime awakening due to asthma, patients were allowed to remainin the study at the discretion of the investigator if none of the otherasthma-worsening criteria were met. The percentage of patients withdrawing dueto or meeting predefined criteria for worsening asthma is shown in Table 4.

Table 4 : The number and percentage of patientswithdrawing due to or meeting predefined criteria for worsening asthma (Study1)

Mean percent change from baseline in FEV₁ measuredimmediately prior to dosing (pre-dose) over 12 weeks is displayed in Figure 1.Because this study used predefined withdrawal criteria for worsening asthma,which caused a differential withdrawal rate in the treatment groups, pre-doseFEV₁ results at the last available study visit (end of treatment, EOT) are alsoprovided. Patients receiving SYMBICORT 160/4.5 had significantly greater meanimprovements from baseline in pre-dose FEV₁ at the end of treatment (0.19 L,9.4%), compared with budesonide 160 mcg (0.10 L, 4.9%), formoterol 4.5 mcg(-0.12 L, -4.8%), and placebo (-0.17 L, -6.9%).

Figure 1 : Mean Percent Change From Baseline inPre-dose FEV₁ Over 12 Weeks (Study 1)

The effect of SYMBICORT 160/4.5two inhalations twice daily on selected secondary efficacy variables, includingmorning and evening PEF, albuterol rescue use, and asthma symptoms over 24hours on a 0-3 scale is shown in Table 5.

Table 5 : Mean values forselected secondary efficacy variables (Study 1)

The subjective impact of asthmaon patients' health-related quality of life was evaluated through the use ofthe standardized Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a7-point scale where 1 = maximum impairment and 7 = no impairment). Patientsreceiving SYMBICORT 160/4.5 had clinically meaningful improvement in overallasthma-specific quality of life, as defined by a mean difference betweentreatment groups of >0.5 points in change from baseline in overall AQLQscore (difference in AQLQ score of 0.70 [95% CI 0.47, 0.93], compared toplacebo).

Study 2: Clinical Study With SYMBICORT 80/4.5

This 12-week study was similarin design to Study 1, and included 480 patients 12 years of age and older. Thisstudy compared SYMBICORT 80/4.5, budesonide 80 mcg, formoterol 4.5 mcg, andplacebo; each administered as 2 inhalations twice daily. The study included a2-week placebo run-in period. Most patients had mild to moderate asthma andwere using low to moderate doses of inhaled corticosteroids prior to study entry.Mean percent predicted FEV₁ at baseline was 71.3% and was similar acrosstreatment groups. Efficacy variables and end points were identical to those inStudy 1.

The percentage of patientswithdrawing due to or meeting predefined criteria for worsening asthma is shownin Table 6. The method of assessment and criteria used were identical to thatin Study 1.

Table 6 : The number andpercentage of patients withdrawing due to or meetingpredefined criteria forworsening asthma (Study 2)

Mean percent change from baseline in pre-dose FEV₁ over 12 weeks is displayed in Figure 2.

Figure 2 : Mean Percent Change From Baseline in Pre-dose FEV₁ Over 12 Weeks (Study 2)

Efficacy results for other secondary end points,including quality of life, were similar to those observed in Study 1.

Onset And Duration Of Action And Progression Of Improvement In Asthma Control

The onset of action and progression of improvement inasthma control were evaluated in the two pivotal clinical studies. The mediantime to onset of clinically significant bronchodilation (>15% improvement inFEV₁) was seen within 15 minutes. Maximum improvement in FEV₁ occurred within 3hours, and clinically significant improvement was maintained over 12 hours.Figures 3 and 4 show the percent change from baseline in post-dose FEV₁ over 12hours on the day of randomization and on the last day of treatment for Study 1.

Reduction in asthma symptoms and in albuterol rescue use,as well as improvement in morning and evening PEF, occurred within 1 day of thefirst dose of SYMBICORT; improvement in these variables was maintained over the12 weeks of therapy.

Following the initial dose of SYMBICORT, FEV₁ improvedmarkedly during the first 2 weeks of treatment, continued to show improvementat the Week 6 assessment, and was maintained through Week 12 for both studies.

No diminution in the 12-hour bronchodilator effect wasobserved with either SYMBICORT 80/4.5 or SYMBICORT 160/4.5, as assessed by FEV₁,following 12 weeks of therapy or at the last available visit.

FEV₁ data from Study 1 evaluating SYMBICORT 160/4.5 is displayedin Figures 3 and 4.

Figure 3 : Mean Percent Change From Baseline in FEV₁ onDay of Randomization (Study 1)

Figure 4 : Mean PercentChange From Baseline in FEV₁ at End of Treatment (Study 1)

Patients With Asthma 6 To Less Than 12 Years Of Age

The clinical program to supportthe efficacy of SYMBICORT 80/4.5 in children 6 to less than 12 years of ageincluded the following: 1) a budesonide dose confirmatory study, 2) aformoterol dose finding study, and 3) an efficacy and safety study of theSYMBICORT combination product.

The selection of budesonide 80mcg is supported by a 6-week, randomized, double-blind, placebo-controlledstudy in 304 pediatric patients (152 budesonide, 152 placebo) 6 to less than 12years of age with asthma. Results showed that budesonide 80 mcg (2 inhalationstwice daily) provided statistically significantly greater improvement comparedto placebo for the primary endpoint of change from baseline to the treatmentperiod average in pre-dose morning PEF and the key secondary endpoint of changein pre-dose morning FEV₁. The selection of the formoterol dose is supported bya randomized, single dose, placebo-controlled, active-controlled (ForadilAerolizer 12 mcg), 5-way cross-over study in which doses of 2.25, 4.5 and 9 mcgformoterol were administered in combination with budesonide in 54 pediatricpatients 6 to less than 12 years of age with asthma. Results showed a doseresponse of formoterol compared to placebo for the primary endpoint of FEV₁ averagedover 12 hours post-dose and the 9 mcg group showed numerically similar resultscompared to the active control.

The confirmatory efficacy studywas a 12-week, randomized, double-blind, multicenter study in which SYMBICORT80/4.5 was compared with budesonide pMDI 80 mcg, each administered as 2inhalations twice daily, in 184 pediatric patients 6 to less than 12 years ofa*ge with a documented clinical diagnosis of asthma. At trial entry, thechildren had a requirement for daily medium-dose range inhaled corticosteroidtherapy or fixed combination of inhaled corticosteroid and LABA therapy, andexhibited symptoms despite treatment with a low-dose inhaled corticosteroidduring a 2 to 4 week run-in period. The primary efficacy variable was changefrom baseline to Week 12 in clinic-measured 1-hour post-dose FEV₁. In patientsreceiving SYMBICORT 80/4.5, there was a statistically significant changecompared to budesonide in 1-hour post-dose FEV₁ which improved by 0.28 L frombaseline to Week 12, as compared with 0.17 L for those receiving budesonide 80mcg (mean difference 0.12 L; 95% CI: 0.03, 0.20) (see Figure 5).

Figure 5 : Change From Baseline in Clinic-Measured1-hour Post-dose FEV₁ over 12 Weeks (Efficacy and Safety Study in Patients 6 toless than 12 years of age).

Similarly, improvement wasnoted in change from baseline to Week 12 for 1-hour post-dose clinic PEF (meandifference 25.5 L/min; 95% CI: 10.9, 40.0). Bronchodilatory effects wereevident from the first assessment at 15 minutes on day 1 and were maintained atWeek 12. The estimated mean difference between SYMBICORT 80/4.5 and budesonidewith respect to change from baseline to Week 12 in 15 minutes post-dose clinicFEV₁ was 0.10 L (95% CI: 0.02, 0.18). No differences between SYMBICORT andbudesonide were noted in nighttime awakenings, rescue albuterol use, orPediatric Asthma Quality of Life Questionnaire (PAQLQ) scores. The proportionof patients with at least 0.5 points improvement from baseline to Week 12 inPAQLQ was 42% on SYMBICORT 80/4.5 and 46% on budesonide 80 mcg.

Postmarketing Safety And Efficacy Study

A randomized, double-blind, parallel-group, safety studycompared SYMBICORT with budesonide, each administered as 2 inhalations twicedaily over 26 weeks (NCT01444430). The primary safety objective was to evaluatewhether the addition of formoterol to budesonide therapy (SYMBICORT) wasnon-inferior to budesonide in terms of the risk of serious asthma-relatedevents (asthma-related hospitalization, endotracheal intubation, and death).The study was designed to rule out a pre-defined risk margin of seriousasthma-related events of 2.0. A blinded adjudication committee determinedwhether events were asthma-related.

This study enrolled patients who were 12 years of age andolder, had a clinical diagnosis of asthma for at least 1 year, and had at least1 asthma exacerbation requiring treatment with systemic corticosteroids or anasthma-related hospitalization in the previous year. Patients were stratifiedto one of the two dose levels of SYMBICORT or budesonide based on assessment ofasthma control and ongoing asthma therapy. Patients with a history oflife-threatening asthma were excluded. The study included 11,693 patients [5846receiving SYMBICORT (80/4.5 or 160/4.5) and 5847 receiving budesonide (80 or160 mcg)], whose mean age was 44 years, and of whom 66% were female and 69%were Caucasian.

SYMBICORT was non-inferior to budesonide in terms of timeto first serious asthma-related events based on the pre-specified risk margin,with an estimated hazard ratio of 1.07 [95% CI: 0.70, 1.65] (Table 7).

Table 7 : Serious Asthma-Related Events (PostmarketingSafety and Efficacy study)

The primary efficacy endpointwas asthma exacerbations, defined as a deterioration of asthma that led to useof systemic corticosteroids for at least 3 days, or a hospitalization, or anemergency room visit that required systemic corticosteroids. The estimatedhazard ratio for time to first asthma exacerbation rate for SYMBICORT relativeto budesonide was 0.84 [95% CI: 0.75, 0.94]. This outcome was primarily drivenby a reduction in systemic corticosteroid use.

Chronic Obstructive Pulmonary Disease

Lung Function

The efficacy of SYMBICORT 80/4.5 and SYMBICORT 160/4.5 inthe maintenance treatment of airflow obstruction in COPD patients was evaluatedin two randomized, double-blind, placebo-controlled multinational studies,conducted over 6 months (Study 1) and 12 months (Study 2), in a total of 3668patients (2416 males and 1252 females). The majority of patients (93%) wereCaucasian. All patients were required to be at least 40 years of age, with aFEV₁ of less than or equal to 50% predicted, a clinical diagnosis of COPD withsymptoms for at least 2 years, and a smoking history of at least 10 pack years,prior to entering the trial. The mean prebronchodilator FEV₁ at baseline of thepatients enrolled in the study was 34% predicted. Forty-eight percent of thepatients enrolled were on inhaled corticosteroids and 52.7% of patients were onshort-acting anticholinergic bronchodilators during run-in. On randomization,inhaled corticosteroids were discontinued, and ipratropium bromide was allowedat a stable dose for those patients previously treated with short-actinganticholinergic bronchodilators. The co-primary efficacy variables in bothstudies were the change from baseline in average pre-dose and 1-hour post-doseFEV₁ over the treatment period. The results of both studies 1 and 2 aredescribed below.

Study 1

This was a 6-month, placebo-controlled study of 1704 COPDpatients (mean % predicted FEV₁ at baseline ranging from 33.5% -34.7%)conducted to demonstrate the efficacy and safety of SYMBICORT in the treatmentof airflow obstruction in COPD. The patients were randomized to one of thefollowing treatment groups: SYMBICORT 160/4.5 (n=277), SYMBICORT 80/4.5(n=281), budesonide 160 mcg + formoterol 4.5 mcg (n=287), budesonide 160 mcg(n=275), formoterol 4.5 mcg (n=284), or placebo (n=300). Patients receivingSYMBICORT 160/4.5, two inhalations twice daily, had significantly greater meanimprovements from baseline in pre-dose FEV₁ averaged over the treatment period[0.08 L, 10.7%] compared with formoterol 4.5 mcg [0.04 L, 6.9%] and placebo[0.01 L, 2.2%] (see Figure 6). Patients receiving SYMBICORT 80/4.5, twoinhalations twice daily, did not have significantly greater improvement frombaseline in the pre-dose FEV₁ averaged over the treatment period compared withformoterol 4.5 mcg.

Figure 6 : Mean PercentChange From Baseline in Pre-dose FEV₁ over 6 Months (Study 1)

Patients receiving SYMBICORT160/4.5, two inhalations twice daily, had significantly greater meanimprovements from baseline in 1-hour post-dose FEV₁ averaged over the treatmentperiod [0.20 L, 22.6%], compared with budesonide 160 mcg [0.03 L, 4.9%] andplacebo [0.03 L, 4.1%] (see Figure 7).

Figure 7 : Mean PercentChange From Baseline in 1-hour Post-dose FEV₁ Over 6 months (Study 1)

Study 2

This was a 12-month,placebo-controlled study of 1964 COPD patients (mean % predicted FEV₁ atbaseline ranging from 33.7% -35.5%) conducted to demonstrate the efficacy andsafety of SYMBICORT in the treatment of airflow obstruction in COPD. Thepatients were randomized to one of the following treatment groups: SYMBICORT160/4.5 (n=494), SYMBICORT 80/4.5 (n=494), formoterol 4.5 mcg (n=495), orplacebo (n=481). Patients receiving SYMBICORT 160/4.5, two inhalations twicedaily, had significantly greater improvements from baseline in mean pre-doseFEV₁ averaged over the treatment period [0.10 L, 10.8%] compared withformoterol 4.5 mcg [0.06 L, 7.2%] and placebo [0.01 L, 2.8%]. Patientsreceiving SYMBICORT 80/4.5, two inhalations twice daily, did not havesignificantly greater improvements from baseline in the mean pre-dose FEV₁ averagedover the treatment period compared to formoterol. Patients receiving SYMBICORT160/4.5, two inhalations twice daily, also had significantly greater meanimprovements from baseline in 1-hour post-dose FEV₁ averaged over the treatmentperiod [0.21 L, 24.0%] compared with placebo [0.02 L, 5.2%].

Serial FEV₁ measures over 12hours were obtained in a subset of patients in Study 1 (n=99) and Study 2(n=121). The median time to onset of bronchodilation, defined as an FEV₁ increaseof 15% or greater from baseline, occurred at 5 minutes post-dose. Maximumimprovement (calculated as the average change from baseline at each timepoint)in FEV₁ occurred at approximately 2 hours post-dose.

In both Studies 1 and 2,improvements in secondary endpoints of morning and evening peak expiratory flowand reduction in rescue medication use were supportive of the efficacy ofSYMBICORT 160/4.5.

Exacerbations

Studies 3 and 4 were primarily designed to evaluate theeffect of SYMBICORT 160/4.5 on COPD exacerbations.

Study 3

This was a 6-month, active-control study conducted toevaluate the effect of SYMBICORT 160/4.5 compared to formoterol 4.5 mcg, eachadministered as 2 inhalations twice daily, on the rate of moderate and severeCOPD exacerbations. COPD exacerbations were defined as worsening of 2 or moremajor symptoms (dyspnea, sputum volume, sputum color/purulence) or worsening ofany 1 major symptom together with at least 1 of the minor symptoms: sorethroat, colds (nasal discharge and/or nasal congestion), fever without othercause, increased cough or increased wheeze for at least 2 consecutive days.COPD exacerbations were considered of moderate severity if treatment ofsymptoms with systemic corticosteroids (≥3 days) and/or antibiotics wererequired, and were considered severe if hospitalization was required. The studyrandomized 1219 subjects to SYMBICORT 160/4.5 (606) and formoterol 4.5 mcg(613) of which 57% were male and 92% were Caucasian. They had a mean age of 64years and a median smoking history of 39 pack years, with 46% identified ascurrent smokers. At run-in, the mean post-bronchodilator % predicted normal FEV₁was 48.7% (range: 16.0% to 78.1%), and patients had a history of at least 1COPD exacerbation in the previous year treated with systemic corticosteroidsand/or hospitalization. All subjects were treated with SYMBICORT 160/4.5, twoinhalations twice daily during a 4-week run-in period prior to being assignedtrial treatment.

Study 4

This was a 12-month, active-control study which included811 subjects treated with SYMBICORT 160/4.5 or formoterol 4.5 mcg, eachadministered as 2 inhalations twice daily. The study was conducted to evaluatefor COPD exacerbation reduction in patients with COPD. COPD exacerbations weredefined as worsening of COPD that required a course of oral steroids fortreatment and/or hospitalization. This study randomized 407 subjects toSYMBICORT 160/4.5 and 404 to formoterol 4.5 mcg of which 61% were male and 83%were Caucasian. They had a mean age of 63 years and a median smoking history of45 pack years, with 36% identified as current smokers. At run-in, the meanpost-bronchodilator % predicted normal FEV₁ was 37.8% (range: 11.75% to76.50%), and a history of at least 1 COPD exacerbation in the previous yeartreated with systemic corticosteroids and/or antibiotics.

In Study 3, subjects treated with SYMBICORT 160/4.5, twoinhalations twice daily had a significantly lower annual rate ofmoderate/severe COPD exacerbations compared with formoterol 4.5 mcg with areduction of 26% (95% CI: 9%, 39%). In Study 4, a significantly lower annualrate of exacerbations was also observed in subjects treated with SYMBICORT160/4.5 compared with formoterol 4.5 mcg with a reduction of 35% (95% CI: 20%,47%) (Table 8).

Table 8 : Chronic Obstructive Pulmonary DiseaseExacerbations

Health-related quality of lifewas measured using the St. George's Respiratory Questionnaire (SGRQ) in bothCOPD exacerbation clinical studies.

In Study 3, the SGRQ responderrates at 6-months (defined as an improvement in score of 4 or more as athreshold) were 40% and 33% for SYMBICORT 160/4.5 and formoterol 4.5 mcg,respectively, with an odds ratio of 1.5 (95% CI: 1.0, 2.0) for SYMBICORT160/4.5 vs. formoterol 4.5 mcg. In Study 4, the responder rates at 12-monthswere 50% and 49% for SYMBICORT 160/4.5 and formoterol 4.5 mcg, respectively,with an odds ratio of 1.0 (95% CI: 0.8, 1,4) for SYMBICORT 160/4.5 vs.formoterol 4.5 mcg.

Patient Information for Symbicort

SYMBICORT
(SIM-bi-kort) (budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol

SYMBICORT
(SIM-bi-kort) (budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol

What is SYMBICORT?

SYMBICORT combines an inhaled corticosteroid medicine(ICS), budesonide and a long-acting beta2-adrenergic agonist (LABA) medicine,formoterol.

• Inhaled corticosteroids help to decrease inflammation in the lungs. Inflammation in the lungs can lead to breathing problems.
• LABA medicines are used in people with chronic obstructive pulmonary disease (COPD) and asthma. LABA medicines help the muscles around the airways in your lungs stay relaxed to prevent symptoms such as wheezing, cough, chest tightness, and shortness of breath. These symptoms can happen when the muscles around the airways tighten. This makes it hard to breathe. In severe cases, wheezing can stop your breathing and may lead to death if not treated right away.

SYMBICORT is not used to relieve sudden breathingproblems and will not replace a rescue inhaler. SYMBICORT is used for asthmaand COPD as follows:

• Asthma: SYMBICORT is used to control symptoms of asthma, and prevent symptoms such as wheezing in adults and children ages 6 and older. SYMBICORT contains formoterol. LABA medicines such as formoterol when used alone increase the risk of death and hospitalizations from asthma problems. SYMBICORT contains an ICS and a LABA. When an ICS and LABA are used together, there is not a significant increased risk in hospitalizations and death from asthma problems. SYMBICORT is not for adults and children with asthma who are well controlled with an asthma-control medicine, such as a low to medium dose of an ICS. SYMBICORT is for adults and children with asthma who need both an ICS and LABA medicine.
  It is not known if SYMBICORT is safe and effective in children less than 6 years of age with asthma.
• COPD: COPD is a long-term (chronic) lung disease that includes chronic bronchitis, emphysema, or both. SYMBICORT 160/4.5 mcg is used long-term, as 2 inhalations 2 times each day, to improve symptoms of COPD for better breathing and to reduce the number of flare-ups (the worsening of your COPD symptoms for several days).

Do not use SYMBICORT:

• to treat sudden severe symptoms of asthma or COPD.
• if you are allergic to any of the ingredients in SYMBICORT. See the end of this leaflet for a list of ingredients in SYMBICORT.

Before you use SYMBICORT, tell your healthcare providerabout all of your medical conditions, including if you:

• have heart problems.
• have high blood pressure.
• have seizures.
• have thyroid problems.
• have diabetes.
• have liver problems.
• have osteoporosis.
• have an immune system problem.
• have eye problems such as increased pressure in the eye, glaucoma, or cataracts.
• are allergic to any medicines.
• have any type of viral, bacterial, fungal, or parasitic infection.
• are exposed to chicken pox or measles.
• are pregnant or plan to become pregnant. It is not known if SYMBICORT may harm your unborn baby.
• are breastfeeding. Budesonide, one of the active ingredients in SYMBICORT, passes into breast milk. You and your healthcare provider should decide if you will take SYMBICORT while breast-feeding.

Tell your healthcare provider about all the medicines youtake including prescription and over-the-counter medicines, vitamins, andherbal supplements. SYMBICORT and certain other medicines may interact witheach other. This may cause serious side effects. Especially tell yourhealthcare provider if you take antifungal or anti-HIV medicines.

Know all the medicines you take. Keep a list and show itto your healthcare provider and pharmacist each time you get a new medicine.

How should I use SYMBICORT?

See the step-by-step instructions for using SYMBICORTat the end of this Patient Information leaflet. Do not use SYMBICORT unlessyour healthcare provider has taught you and you understand everything. Ask yourhealthcare provider or pharmacist if you have any questions.

• Use SYMBICORT exactly as prescribed. Do not use SYMBICORT more often than prescribed. SYMBICORT comes in 2 strengths. Your healthcare provider has prescribed the strength that is best for you. Note the differences between SYMBICORT and your other inhaled medications, including the differences in prescribed use and physical appearance.
• Children should use SYMBICORT with an adult's help, as instructed by the child's healthcare provider.
• SYMBICORT should be taken every day as 2 puffs in the morning and 2 puffs in the evening about 12 hours apart.
• If you miss a dose of SYMBICORT, you should take your next dose at the same time you normally do.
• Rinse your mouth with water and spit the water out after each dose (2 puffs) of SYMBICORT. Do not swallow the water. This will help to lessen the chance of getting a fungus infection (thrush) in the mouth and throat.
• If you take too much SYMBICORT, call your healthcare provider or go to the nearest hospital emergency room right away if you have any unusual symptoms, such as worsening shortness of breath, chest pain, increased heart rate, or shakiness.
• Do not spray SYMBICORT in your eyes. If you accidentally get SYMBICORT in your eyes, rinse your eyes with water, and if redness or irritation persists, consult your healthcare provider.
• Do not change or stop any medicines used to control or treat your breathing problems. Your healthcare provider will change your medicines as needed.
• While you are using SYMBICORT 2 times each day, do not use other medicines that contain a LABA for any reason. Ask your healthcare provider or pharmacist if any of your other medicines are LABA medicines.
• SYMBICORT does not relieve sudden symptoms. Always have a rescue inhaler medicine with you to treat sudden symptoms. If you do not have a rescue inhaler, call your healthcare provider to have one prescribed for you.
• Call your healthcare provider or get medical care right away if:
  • your breathing problems worsen with SYMBICORT.
  • you need to use your rescue inhaler medicine more often than usual.
  • your rescue inhaler medicine does not work as well for you at relieving symptoms.
  • your peak flow meter results decrease. Your healthcare provider will tell you the numbers that are right for you.
  • your symptoms do not improve after using SYMBICORT regularly for 1 week.

What are the possible side effects of SYMBICORT?

SYMBICORT may cause serious side effects, including:

• Using too much of a LABA medicine may cause:
  • chest pain
  • increased blood pressure
  • a fast and irregular heartbeat
  • headache
  • tremor
  • nervousness
• Fungal infection in your mouth or throat (thrush). Rinse your mouth with water without swallowing after using SYMBICORT to help reduce your chance of getting thrush.
• Pneumonia and other lower respiratory tract infections. People with COPD have a higher chance of getting pneumonia and other lung infections. Inhaled corticosteroids may increase the chance of getting pneumonia. Call your healthcare provider if you notice any of these symptoms:
  • increase in mucus (sputum) production
  • change in mucus color
  • fever
  • chills
  • increased cough
  • increased breathing problems
• Immune system effects and a higher chance for infections. Tell your healthcare provider about any signs of infection such as:
  • fever
  • pain
  • body aches
  • chills
  • feeling tired
  • nausea
  • vomiting
• Adrenal insufficiency. Adrenal insufficiency is a condition in which the adrenal glands do not make enough steroid hormones. This can happen when you stop taking oral corticosteroid medicines and start inhaled corticosteroid medicine.
• Increased wheezing right after taking SYMBICORT. Always have a rescue inhaler with you to treat sudden wheezing.
• Serious allergic reactions including rash, hives, swelling of the face, mouth, and tongue, and breathing problems. Call your healthcare provider or get emergency medical care if you get any symptoms of a serious allergic reaction.
• Lower bone mineral density. This can happen in people who have a high chance for low bone mineral density (osteoporosis). Your healthcare provider should check you for this during treatment with SYMBICORT.
• Slowed growth in children. A child's growth should be checked regularly while using SYMBICORT.
• Eye problems including glaucoma and cataracts. You should have regular eye exams while using SYMBICORT.
• Swelling of your blood vessels. This can happen in people with asthma. Tell your healthcare provider right away if you have:
  • a feeling of pins and needles or
  • flu like symptoms numbness of your arms or legs
  • pain and swelling of the sinuses
  • rash
• Decreases in blood potassium levels (hypokalemia).
• Increases in blood sugar levels (hyperglycemia).

The most common side effects of SYMBICORT include:

People with asthma:

• throat irritation
• headache
• upper respiratory tract infection
• throat pain
• inflammation of mucous membranes of the sinuses
• flu (sinusitis)
• nasal congestion
• back pain
• vomiting
• stomach discomfort
• thrush in the mouth and throat. Rinse your mouth with water without swallowing after use to help prevent thrush

People with COPD:

• throat irritation.
• thrush in the mouth and throat. Rinse your mouth with water without swallowing after use to help prevent thrush.
• infection and inflammation of the mucous membranes of the bronchial tubes (bronchitis).
• inflammation of mucous membranes in the sinuses (sinusitis).
• upper respiratory tract infection.

Tell your healthcare provider about any side effect thatbothers you or that does not go away.

These are not all the possible side effects of SYMBICORT.

Call your doctor for medical advice about side effects.You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to AstraZeneca at1-800-236-9933.

How should I store SYMBICORT?

• Store SYMBICORT at room temperature between 68°F to 77°F (20°C to 25°C).
• Store SYMBICORT with the mouthpiece down.
• The contents of your SYMBICORT canister are under pressure. Do not puncture or throw the canister into a fire or incinerator. Do not use or store it near heat or open flame. Storage above 120°F may cause the canister to burst.
• Throw away SYMBICORT when the counter reaches zero (“0”) or 3 months after you take SYMBICORT out of its foil pouch, whichever comes first.
• Keep SYMBICORT and all medicines out of the reach of children.

General Information about the safe and effective useof SYMBICORT.

Medicines are sometimes prescribed for purposes otherthan those listed in a Patient Information leaflet. Do not use SYMBICORT for acondition for which it was not prescribed. Do not give SYMBICORT to otherpeople, even if they have the same symptoms that you have. It may harm them.

You can ask your healthcare provider or pharmacist for informationabout SYMBICORT that is written for health professionals.

What are the ingredients in SYMBICORT?

Active ingredients: micronized budesonide and micronizedformoterol fumarate dihydrate

Inactive ingredients: hydrofluroalkane (HFA 227),povidone K25 USP, and polyethylene glycol 1000 NF

Instructions for Use

SYMBICORT
(SIM-bi-kort)(budesonide 80 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol

SYMBICORT
(SIM-bi-kort) (budesonide 160 mcg and formoterol fumarate dihydrate 4.5 mcg)Inhalation Aerosol

Figure 1

How to Use SYMBICORT

Follow the instructions belowfor using SYMBICORT. You will breathe-in (inhale) the medicine. If you have anyquestions, ask your doctor or pharmacist.

Preparing your SYMBICORTinhaler for use

1. Take your SYMBICORT out of the moisture-protective foil pouch before you use it for the first time and throw the foil away. Write the date that you open the foil pouch on the box.
2. A counter is attached to the top of the metal canister. The counter will count down each time you release a puff of SYMBICORT. The arrow points to the number of inhalations (puffs) left in the canister. The counter will stop counting at zero (“0”).
3. Use the SYMBICORT canister only with the red SYMBICORT inhaler supplied with the product. Parts of the SYMBICORT inhaler should not be used with parts from any other inhalation product.
4. Shake your SYMBICORT inhaler well for 5 seconds right before each use. Remove the mouthpiece cover by squeezing gently at both sides, then pulling out (see Figure 2). Check the mouthpiece for foreign objects before use.

Figure 2

5. Priming your SYMBICORTinhaler

Before you use SYMBICORT forthe first time, you will need to prime it. To prime SYMBICORT, hold it in theupright position. See Figure 1. Shake the SYMBICORT inhaler well for 5 seconds.Hold your SYMBICORT inhaler facing away from you and press down firmly and fullyon the top of the counter on the SYMBICORT inhaler to release a test spray.Then shake it again for 5 seconds and release a second test spray. YourSYMBICORT inhaler is now primed and ready for use. After you have primed theSYMBICORT inhaler for the first time, the counter will read either 120 or 60,depending on which size was provided to you.

If you do not use yourSYMBICORT inhaler for more than 7 days or if you drop it, you will need toprime again.

Ways to hold the SYMBICORTinhaler for use

Figure 3

OR

Figure 4

Using your SYMBICORT inhaler

6. Shake your SYMBICORT inhalerwell for 5 seconds. Remove the mouthpiece cover. Check the mouthpiece forforeign objects.

7. Breathe out fully (exhale).Hold the SYMBICORT inhaler up to your mouth. Place the white mouthpiece fullyinto your mouth and close your lips around it. Make sure that the SYMBICORTinhaler is upright and that the opening of the mouthpiece is pointing towardsthe back of your throat (see Figure 5).

Figure 5

8. Breathe in (inhale) deeplyand slowly through your mouth. Press down firmly and fully on the top of thecounter on the SYMBICORT inhaler to release the medicine (see Figures 3 and 4).

9. Continue to breathe in(inhale) and hold your breath for about 10 seconds, or for as long as iscomfortable. Before you breathe out (exhale), release your finger from the topof the counter. Keep the SYMBICORT inhaler upright and remove from your mouth.

10. Shake the SYMBICORT inhaleragain for 5 seconds and repeat steps 7 to 9.

After using your SYMBICORTinhaler

11. After use, close themouthpiece cover by pushing until it clicks in place.

12. After you finish takingSYMBICORT (2 puffs), rinse your mouth with water. Spit out the water. Do notswallow it.

Reading the counter

• The arrow on the counter on the top of the SYMBICORT inhaler points to the number of inhalations (puffs) left in your inhaler.

COUNTER

• The counter will count down each time you release a puff of medicine (either when priming your SYMBICORT inhaler or when taking the medicine).
• When the arrow on the counter approaches 20, you will notice the beginning of a yellow area letting you know that it is time to call your healthcare provider for a refill.

COUNTER

• It is important that you pay attention to the number of inhalations (puffs) left in your SYMBICORT inhaler by reading the counter. Throw away SYMBICORT when the counter shows zero (“0”) or 3 months after you take your SYMBICORT inhaler out of its foil pouch, whichever comes first. Your SYMBICORT inhaler may not feel empty and it may continue to operate, but you will not get the right amount of medicine if you keep using it. Use a new SYMBICORT inhaler and follow the instructions for priming (see instruction 5 above).

How to clean your SYMBICORTinhaler

Clean the white mouthpiece ofyour SYMBICORT inhaler every 7 days. To clean the mouthpiece:

• Remove the grey mouthpiece cover
• Wipe the inside and outside of the white mouthpiece opening with a clean, dry cloth
• Replace the mouthpiece cover
• Do not put the SYMBICORT inhaler into water
• Do not try to take apart your SYMBICORT inhaler

This Patient Information and Instructions for Use hasbeen approved by the U.S. Food and Drug Administration.