PRODUCT MONOGRAPH SYMBICORT …

1 COPYRIGHT 2002-2021 ASTRAZENECACANADA 1 of 58 PRODUCT MONOGRAPHPrSYMBICORT TURBUHALER budesonide/formoterol fumarate dihydrate dry powder for oral inhalationPrSYMBICORT 100 TURBUHALER 100 mcg budesonide and 6 mcgformoterol fumarate dihydratePrSYMBICORT 200 TURBUHALER 200 mcg budesonide and 6 mcg formoterol fumarate dihydratePrSYMBICORT FORTETURBUHALER 400 mcg budesonide and 12 mcg formoterolfumarate dihydrateCorticosteroid and bronchodilator for oral inhalationAstraZeneca Canada Middlegate RoadMississauga, OntarioL4Y of Revision: February 8, 2021 Submission Control No: 244507 SYMBICORT , SYMBICORT SMART , TURBUHALER , PULMICORT , OXEZE , and the AstraZeneca logo are registered trademarks of AstraZeneca AB, used under license by AstraZeneca Canada Inc. COPYRIGHT 2002-2021 ASTRAZENECACANADA 2 of 58 TABLE OF CONTENTSPART I: HEALTH PROFESSIONAL PRODUCT 3 INDICATIONS AND CLINICAL AND AND 23 ACTION AND CLINICAL AND HANDLING FORMS, COMPOSITION AND 26 PART II: SCIENTIFIC 28 CLINICAL 29 DETAILED III: CONSUMER 2002-2021 ASTRAZENECACANADA 3 of 58 PrSYMBICORT TURBUHALER budesonide/formoterol fumarate dihydratePART I.

2 HEALTH PROFESSIONAL INFORMATIONSUMMARY PRODUCT INFORMATIONR oute of AdministrationDosage Form / StrengthNon-medicinalIngredientsOral inhalationDry powder for oral inhalation, Turbuhaler / 100 mcg budesonide / 6 mcg formoterol fumarate dihydrate200 mcg budesonide / 6 mcg formoterol fumarate dihydrate400 mcg budesonide / 12 mcg formoterolfumarate dihydrateLactose monohydrate (which may contain milk protein residue)INDICATIONS AND CLINICAL USEA sthmaSYMBICORT TURBUHALER (budesonide and formoterol fumarate dihydrate) is indicated for the treatment of asthma in patients 12 years and older with reversible obstructive airways can be used according to three different treatment TURBUHALER Anti-inflammatory Reliever Therapy: in patients with mild persistent asthma, SYMBICORT 200 TURBUHALER is taken as needed for relief of asthma symptoms when they TURBUHALER has not been evaluated in patients whose asthma can be managed by occasional use of a rapid onset, short duration, inhaled TURBUHALER Anti-inflammatory Reliever plus Maintenance Therapy: in patients with moderate or severe asthma, SYMBICORT 100 TURBUHALER or SYMBICORT 200 TURBUHALER aretaken both as dailymaintenance therapyand as needed for relief of asthma symptoms when they TURBUHALER Maintenance Therapy.

3 In patients with moderate or severe asthma, SYMBICORT TURBUHALER is taken as a fixed-dose daily COPYRIGHT 2002-2021 ASTRAZENECACANADA 4 of 58treatment with a separate short-acting bronchodilator for relief of symptomswhen they asthma control is achieved and maintained, the patient should be assessed at regular Obstructive Pulmonary Disease (COPD) SYMBICORT 200 TURBUHALER and SYMBICORT FORTETURBUHALER areindicated for the maintenance treatment of moderate to severe COPD including chronic bronchitis and emphysema, in patients with persistent symptoms and a history of exacerbations, where the use of a combination PRODUCT is considered is NOTindicated for the relief of acute bronchospasm in COPD DOSAGE AND ADMINISTRATION and WARNINGS AND :No dosage adjustment is required in patients 65 years of age and :In the treatment of asthma, safety and efficacy in pediatric patients younger than 12 years have not been the treatment of COPD,safety and efficacy in patients younger than 18 years have not been TURBUHALER is contraindicated in patients with a known hypersensitivity to budesonide, formoterol or inhaled AND PRECAUTIONSG eneralSerious Asthma-Related Events Hospitalizations, Intubations, DeathUse of long-acting beta2-agonists (LABA) as monotherapy (without inhaled corticosteroids [ICS]) for asthma is associated with an increased risk of asthma-related death (see Salmeterol Multicenter Asthma Research Trial).

4 Available data from controlled clinical trials also suggest that the use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA LABA are used in fixed-dose combination with ICS, data from large clinical trials donot show a significant increase in the risk of serious asthma-related events (hospitalizations, COPYRIGHT 2002-2021 ASTRAZENECACANADA 5 of 58intubations, death) compared with ICS alone (see Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonist Combination Products).Serious Asthma-Related Events with Inhaled Corticosteroid/Long-acting Beta2-adrenergic Agonist Combination ProductsFour (4) large, 26-week, randomized, double-blind, active-controlled clinical safety trials were conducted to evaluate the riskof serious asthma-related events when LABA were used in fixed-dose combination with ICS compared with ICS alone in subjects with asthma.

5 Three (3) trials included adult and adolescent subjects aged 12 years and older: 1 trial compared budesonide/formoterol with budesonide, 1 trial compared fluticasone propionate/salmeterol with fluticasone propionate, and 1 trial compared mometasone furoate/formoterol with mometasone furoate. The fourth trial included pediatric subjects aged 4 to 11 years and compared fluticasone propionate/salmeterol with fluticasone propionate. The primary safety endpoint for all 4 trials was serious asthma-related events (hospitalizations, intubations, death). A single, blinded, independent, joint adjudication committee determined whether events were asthma 3 adult and adolescent trials were designed to rule out a increase in relative risk for ICS/LABA compared with ICS, and the pediatric trial was designed to rule out a increase in this relative risk. Each individual trial met its pre-specified objective and demonstrated non-inferiority of ICS/LABA to ICS alone.

6 A meta-analysis of the 3 adult and adolescent trials did not show a significant increase in risk of a serious asthma-related event with ICS/LABA fixed-dose combination compared with ICS alone (Table 1). These trials were not designed to rule out all risk for serious asthma-related events with ICS/LABA compared with 2002-2021 ASTRAZENECACANADA 6 of 58 Table 1 Meta-analysis of seriousasthma-related events in subjects with asthma aged 12 years and olderICS/LABA(n=17,537)aICS(n=17,552)aIC S/LABA vs. ICSH azard Ratio(95% CI)bSerious asthma-related eventcAsthma-related death Asthma-related intubation (endotracheal) Asthma-related hospitalization ( 24-hour stay) 116 2 1 115105 0 2 105 ( , )ICS = Inhaled corticosteroid; LABA = Long-acting beta2-adrenergic agonist. aRandomized subjects who had taken at least 1 dose of study drug. Planned treatment used for analysis. bEstimated using a Cox proportional hazards model for time to first event with baseline hazards stratified by each of the 3 trials.

7 CNumber of subjects with an event that occurred within 6 months after the first use of study drug or 7 days after the last date of study drug, whichever date was later. Subjects may have had one or more events, but only the first event was counted for analysis. A single, blinded, independent, joint adjudication committee determined whether events were asthma pediatric safety trial included 6208 pediatric subjects aged 4 to 11 years who received ICS/LABA (fluticasone propionate/salmeterol inhalation powder) or ICS (fluticasone propionate inhalation powder). In this trial, 27/3107 ( ) subjects randomized to ICS/LABA and 21/3101 ( ) subjects randomized to ICS experienced a serious asthma-related event. There were no asthma-related deaths or intubations. ICS/LABA did not show a significant increase in risk of serious asthma-related events compared with ICS based on the pre-specified risk margin ( ), with an estimated hazard ratio of time to first event of (95% CI: , ).

8 SYMBICORT TURBUHALER is not indicated in children younger than 12 years of Multicenter Asthma Research TrialA 28-week, placebo-controlled, trial that compared the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol versus 3/13,179 in subjects treated with placebo; relative risk: [95% CI: , ]). Use of background ICS was not required in the Salmeterol Multicenter Asthma Research Trial. The increased risk of asthma-related death is considered a class effect of LABA Use and Use with Other LABA ProductsWhen beginning treatment with SYMBICORT TURBUHALER, patients who have been taking inhaled beta2-agonist on a regular basis should be instructed to discontinue the regular COPYRIGHT 2002-2021 ASTRAZENECACANADA 7 of 58use of these significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic should be informed not to exceed the prescribed doseof SYMBICORT Reliever MedicationIt is crucial to inform patients with asthma to have their reliever medication available at all times.

9 Asthma patients should be clearly instructed to use medication for relief of symptoms( , SYMBICORTTURBUHALER, terbutaline, or salbutamol) if they develop asthma symptoms while taking reliever inhalations of SYMBICORT TURBUHALER should be taken in response to symptoms but are not intended for regular prophylactic use before in adolescents and asthmaseverity reassessmentIn adolescents the severity of asthma may vary with age and periodic reassessment should be considered to determine if continued therapy with SYMBICORT TURBUHALER is still Effects of CorticosteroidsSystemic effects may occur with any inhaled corticosteroid, particularly at high dosesprescribed for long periods; these effects are much less likely to occur than with oralcorticosteroids. Possible systemic effects include Cushing s syndrome, Cushingoid features,and adrenal suppression, growth retardation in children and adolescents, decrease in bonemineral density (BMD), cataract and glaucoma.

10 It is important therefore, that the dose ofinhaled corticosteroid is titrated to the lowest dose at which effective control is maintained(see Monitoring and Laboratory Tests).A reduction of growth velocity in children or teenagers may occur as a result of inadequatecontrol of chronic diseases such as asthma or from use of corticosteroids for should closely follow the growth of adolescents taking long-term corticosteroidsby any routeand weigh the benefits of the corticosteroid therapy and asthma control againstthe possible risk of growth suppression if any adolescent s growth appears Maintenance treatment with inhaled corticosteroids should not be stopped abruptly,but tapered gradually under the supervision of a withdrawal of inhaled corticosteroids should not be considered unless it is temporarily required to confirm the diagnosis of 2002-2021 ASTRAZENECACANADA 8 of 58 CardiovascularCardiovascular Effects: Although clinically not significant, a small increase in QTc interval has been reported with therapeutic doses of formoterol.