Summary Basis of Decision for Anoro Ellipta

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Anoro Ellipta is located below.

Recent Activity for Anoro Ellipta

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Anoro Ellipta

Updated: 2024-06-27

The following table describes post-authorization activity for Anoro Ellipta, a product which contains the medicinal ingredients umeclidinium (as umeclidinium bromide) and vilanterol (as vilanterol trifenatate). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs).

 

For additional information about the drug submission process, refer to the  Guidance Document: The Management of Drug Submissions and Applications.

Drug Identification Number (DIN):

  • DIN 02418401 - 62.5 mcg umeclidinium and 25 mcg vilanterol per actuation, powder, oral inhalation

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

SNDS # 268656

2022-10-13

Issued NOC 2023-03-09

Submission filed as Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Contraindications; Adverse Reactions; Drug Interactions; Clinical Pharmacology; and Non-Clinical Toxicology sections of the PM, and corresponding changes were made to Patient Medication Information and to the package insert. An NOC was issued.

NC # 204866

 

 

2017-04-19

Issued NOL

2017-08-02

 

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 204767

2017-04-13

Issued NOL

2017-05-18

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to amend the text on the back panel of the inner label for improved clarity. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 201182

2016-12-16

Issued NOC

2017-02-23

Submission filed as a Level I – Supplement to update the website address on the labels, Product Monograph and Package Insert and to change a graphic on the carton labels due to change in company name. The submission was reviewed and considered acceptable, and an NOC was issued.

NC # 198790

2016-09-29

Issued NOL

2017-02-17

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 187996

2015-09-25

Issued NOL 2016-01-05

Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) based on recently completed safety assessments. As a result of the Notifiable Change, additions were made to the Warnings and Precautions and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.

NC # 177062

2014-08-12

Issued NOL 2014-11-14

Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to make editorial changes to the Product Monograph (PM) to either improve the clarity of the PM or align it with the approved PM for Incruse Ellipta. After review of the submission, changes were made to the Warnings and Precautions, Adverse Reactions and Dosing and Administration sections of the Product Monograph. Changes were also made to the PM Part III: Consumer Information. A No Objection Letter was issued.

Drug product (DIN 02418401) market notification

Not applicable

Date of first sale: 2014-03-14

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS # 161585

2013-01-10

Issued NOC 2013-12-23

Notice of Compliance issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Anoro Ellipta

Date SBD issued: 2014-02-27

The following information relates to the New Drug Submission for Anoro Ellipta.

Umeclidinium bromide and vilanterol trifenatate
62.5 µg of umeclidinium (as umeclidinium bromide) and 25 µg of vilanterol (as vilanterol trifenatate)
Powder, oral inhalation

Drug Identification Number (DIN):

  • 02418401

GlaxoSmithKline Inc.

New Drug Submission Control Number: 161585

 

On December 23, 2013, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product, Anoro Ellipta.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Anoro Ellipta is favourable for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Anoro Ellipta is not indicated for the relief of acute deterioration of COPD and is not indicated for the treatment of asthma.

 

1 What was approved?

 

Anoro Ellipta, is a combination bronchodilator treatment that contains two medicinal ingredients: umeclidinium (as umeclidinium bromide), a long-acting muscarinic antagonist (LAMA); and vilanterol (as vilanterol trifenatate), a long-acting beta2-adrenergic agonist (LABA). Anoro Ellipta was authorized for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Anoro Ellipta is not indicated for the relief of acute deterioration of COPD.

Anoro Ellipta is not indicated for the treatment of asthma.

Anoro Ellipta is not indicated for use in children and therefore should not be used in patients under 18 years of age. The safety and efficacy in pediatric patients have not been established.

No dosage adjustment is required in patients over 65 years of age.

Anoro Ellipta is contraindicated for patients who are hypersensitive to either umeclidinium or vilanterol, or any ingredient in the formulation or component of the container; as well as patients with a severe hypersensitivity to milk proteins. All LABAs are contraindicated in patients with asthma without use of a long-term asthma control medication. Anoro Ellipta was approved for use under the conditions stated in the Anoro Ellipta Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Anoro Ellipta [umeclidinium (as umeclidinium bromide)/vilanterol (as vilanterol trifenatate) 62.5 µg/25 µg] is presented as a dry powder for oral inhalation. In addition to the medicinal ingredients, the powder contains lactose monohydrate (which contains milk proteins) and magnesium stearate.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Anoro Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Anoro Ellipta approved?

 

Health Canada considers that the benefit/risk profile of Anoro Ellipta, a combination drug product of umeclidinium (as umeclidinium bromide)/vilanterol (as vilanterol trifenatate), 62.5 µg/25 µg, is favourable for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Chronic obstructive pulmonary disease (COPD) is a major public health problem. It is one of the leading causes of morbidity and mortality in Canada. Chronic obstructive pulmonary disease is characterized by air flow limitation that is not fully reversible, is usually progressive, and is associated with pathological changes in the lung - a combination, varying between individual patients, of obstructive bronchiolitis and parenchymal destruction (emphysema). Dyspnea, a major reason for seeking medical care, develops over many years and eventually limits daily activities, resulting in significant disability and handicap and reductions in health related quality of life.

Bronchodilators form the mainstay of pharmacological therapy for COPD. Two classes of inhaled bronchodilators [that is (i.e.) beta2-agonists and muscarinic antagonists or anticholinergics] are widely used in the management of COPD. Chronic obstructive pulmonary disease treatment guidelines recommend an incremental approach to pharmacological treatment as the disease state worsens, involving the use of combinations of drug classes with different or complementary mechanisms of action to improve airflow obstruction.

Anoro Ellipta has been shown to be efficacious in treating airflow obstruction in patients with COPD. The market authorization was based on three 24-week clinical Phase III studies. One was a randomized, double-blind, parallel-group, placebo-controlled study (DB2113373), and two were active comparator-controlled studies (DB2113360 and DB2113374). Results of the primary efficacy endpoint [change from baseline in trough forced expiratory volume in 1 second (FEV1) at Day 169] from all three 24-week pivotal studies supported the efficacy of Anoro Ellipta as a bronchodilator.

Based on the four clinical Phase III studies, adverse events (AE) which occurred more frequently in Anoro Ellipta compared to placebo at a rate of ≥1% include pharyngitis, sinusitis, lower respiratory tract infection, diarrhea, constipation, pain in extremity, muscle spasms, neck pain, and chest pain.

A Black Box Warning describing serious warnings and precautions has been included in the Anoro Ellipta Product Monograph. Although Anoro Ellipta is not indicated for asthma, a serious warning for asthma-related death was included because Anoro Ellipta contains a LABA, vilanterol; LABAs are associated with an increased risk of asthma-related death.

A Risk Management Plan (RMP) for Anoro Ellipta was submitted by GlaxoSmithKline Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

Overall, the therapeutic benefits seen in the pivotal studies are positive and the benefits of Anoro Ellipta therapy seem to outweigh the potential risks. Anoro Ellipta has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling. Appropriate warnings and precautions are in place in the Anoro Ellipta Product Monograph.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Anoro Ellipta?

 

Submission Milestones: Anoro Ellipta

Submission Milestone Date
Submission filed: 2013-01-10
Screening  
Screening Acceptance Letter issued: 2013-03-01
Review  
Quality Evaluation complete: 2013-12-12
Clinical Evaluation complete: 2013-12-19
Labelling Review complete: 2013-12-12
Notice of Compliance issued by Director General: 2013-12-23

 

The Canadian regulatory decision on the non-clinical and clinical review of Anoro Ellipta was based on a critical assessment of the Canadian data package. The foreign review assessments by the European Union's centralized procedure European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as an added reference.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Anoro Ellipta?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Anoro Ellipta is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Anoro Ellipta is a combination of a long-acting muscarinic antagonist (umeclidinium bromide, a LAMA) and a long-acting beta2-adrenergic agonist (vilanterol trifenatate, a LABA). Following oral inhalation, both compounds act locally on airways via different modes of action targeting different receptors and pathways to optimize bronchodilation. Umeclidinium exerts its bronchodilatory activity by competitively inhibiting the binding of acetylcholine with muscarinic acetylcholine receptors on airway smooth muscle. Vilanterol exerts, in part, some of its pharmacologic effects through stimulation of intracellular adenylate cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from cells, especially from mast cells. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects.

The clinical pharmacology program included studies in healthy individuals, patients with chronic obstructive pulmonary disease (COPD), as well as hepatically impaired and renally impaired patients, and otherwise healthy individuals with reduced cytochrome P450 (CYP) 2D6 metabolism. Studies were performed with umeclidinium and vilanterol alone and in combination. The clinical pharmacology profile of vilanterol alone was characterized previously for Breo Ellipta (New Drug Submission Control number 157301, authorized July 3, 2013). For more information, see the Breo Ellipta Summary Basis of Decision.

Administration of vilanterol alone with ketoconazole (400 mg), a strong CYP3A4 inhibitor, resulted in a 1.9-fold increase in vilanterol area under the concentration-time curve (AUC), with no change in Cmax. Caution is warranted for co-administration of Anoro Ellipta with this class of drug. Umeclidinium is a substrate of CYP2D6, however, umeclidinium pharmacokinetics were not significantly affected in a population of CYP2D6 poor metabolizers. Co-administration of umeclidinium/vilanterol with verapamil, a P-glycoprotein inhibitor, resulted in a 1.4-fold increase in umeclidinium based on AUC with no effect observed for vilanterol systemic exposure.

The effect of umeclidinium/vilanterol [125/25 µg (2X/1X therapeutic dose) and 500/100 µg (8X/4X therapeutic dose)] on electrocardiogram parameters were investigated in a thorough QT study. Umeclidinium/vilanterol was associated with an apparently dose-dependent QTc prolongation (using Fridericia's correction formula) evident with maximal placebo-adjusted mean changes in the QTcF interval at 10 minutes following umeclidinium/vilanterol 125/25 µg (4.3 ms) and at 30 minutes following umeclidinium/vilanterol 500/100 µg. There was also an apparently dose-dependent increase in heart rate across the two doses of umeclidinium/vilanterol. Umeclidinium alone at 500 µg was not associated with QTc prolongation but was associated with a small increase in heart rate.

Overall, the clinical pharmacological data support the use of Anoro Ellipta for the specified indication. Appropriate warnings and precautions are in place in the approved Anoro Ellipta Product Monograph to address the identified potential safety considerations.

For further details, please refer to the Anoro Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Pivotal Studies

The efficacy of Anoro Ellipta (umeclidinium/vilanterol 62.5/25 µg once daily) and its individual components (umeclidinium 62.5 µg once daily and vilanterol 25 µg once daily) was evaluated in one 24-week randomized, double-blind, parallel-group, placebo-controlled study (DB2113373), and two 24-week active comparator-controlled studies (DB2113360 and DB2113374). All three pivotal studies had similar inclusion/exclusion criteria and concomitant medications. Key withdrawal criteria in all studies included chronic obstructive pulmonary disease (COPD) exacerbation and adverse events.

The primary efficacy endpoint in all three studies was trough forced expiratory volume in 1 second (FEV1) at Day 169 (Week 24); and the secondary efficacy endpoint was weighted mean FEV1 over 0-6 hours at Day 168 (Week 24). Transitional Dyspnea Index (TDI) focal score at Day 168, St. George's Respiratory Questionnaire (SGRQ) and daily rescue medication use were assessed as other efficacy endpoints in all pivotal studies.

A total of 3,244 patients were randomized and received at least one drug treatment in the three pivotal studies. The patients enrolled had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had moderate to very severe airflow obstruction (a post-salbutamol FEV1 ≤70% of predicted normal values and a ratio of FEV1/FVC <0.7), and dyspnea [a Modified Medical Research Council (mMRC) score ≥2]. Concurrent use of systemic corticosteroids, long-acting bronchodilators, including theophyllines, was not allowed and previous use of umeclidinium and/or vilanterol was not allowed. Concurrent use of inhaled corticosteroids (ICS) at a stable dose and study-provided rescue salbutamol were allowed. Patients with a current diagnosis of asthma, alpha 1-antitrypsin deficiency, any clinically significant uncontrolled disease, a clinically significant electrocardiogram (ECG) or clinically significant laboratory finding, or a lower respiratory tract infection or recent COPD exacerbation were excluded from study enrollment.

The majority of the 3,244 patients recruited in the 24-week pivotal studies were male (70%), white (83%), with a mean age of 63.5 years. At baseline, the mean post-bronchodilator FEV1 was 1.38 mL [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II 46%, Stage III 42%, and Stage IV 12%]. No GOLD Stage I patients were enrolled. The distribution by GOLD stage was similar across treatment groups. Mean beta2-agonist responsiveness was 14.2% of baseline (146 mL).

The primary objective of the placebo-controlled study (DB2113373) was to evaluate the efficacy and safety of Anoro Ellipta compared to either umeclidinium alone, or vilanterol alone, or to a placebo treatment. Eligible patients were therefore randomized to receive either Anoro Ellipta (umeclidinium /vilanterol 62.5/25 µg), umeclidinium 62.5 µg, vilanterol 25 µg, or placebo treatment over a 24 week period. All treatments were administered once-daily in the morning by inhalation.

Patients who met the eligibility criteria at Screening (Visit 1) completed a 7- to 14-day Run-in Period followed by a 24-week Treatment Period. Clinic visits (1 through 9) were at Screening, Randomization (Day 1), Day 2, after 4, 8, 12, 16, and 24 weeks of treatment, and 1 day after the Week 24 Visit (also referred to as Treatment Day 169). A Follow-Up clinic visit (Visit 10) for lung function and adverse event (AE) assessments was conducted approximately 7 days after Visit 9 or the Early Withdrawal Visit. The total duration of patient participation, including Follow-Up, was approximately 27 weeks. All patients were provided with salbutamol for use on an as-needed basis throughout the Run-in and Treatment Periods. A total of 1,532 patients constituted the intent-to-treat (ITT) population.

Results of the DB2113373 study showed that at week 24, Anoro Elliptastatistically significantly increased the change from Baseline in trough FEV1 by 167 mL [95% confidence interval (CI) = 128 mL to 207 mL, p<0.001] compared with placebo. Anoro Elliptaalso provided a statistically significant improvement compared with placebo in change from baseline in weighted mean FEV1 over 0-6 hours post-dose at week 24 (242 mL, p<0.001). In addition, patients receiving Anoro Ellipta had a statistically significant greater increase from Baseline in trough FEV1 and weighted mean FEV1 over 0-6 hours at Week 24 compared with those receiving umeclidinium 62.5 µg (trough FEV1 52 mL, p = 0.004 and weighted mean FEV1 over 0-6 hours 92 mL, p<0.001) and vilanterol 25 µg (trough FEV1 95 mL, p<0.001 and weighted mean FEV1 over 0-6 hours 120 mL, p<0.001), indicating a contribution of vilanterol 25 µg and umeclidinium 62.5 µg to the improvement of lung function.

Greater bronchodilation with Anoro Ellipta compared with placebo was evident after the first day of treatment and improvement in lung function was maintained over the 24-week treatment period. Serial spirometric evaluations throughout the 24-hour dosing interval were performed in a subset of patients [Number (n) =197] at days 1, 84 and 168 in Study DB2113373. The median time to onset on Day 1, defined as a 100 mL increase from Baseline in FEV1, was 27 minutes in patients receiving Anoro Ellipta. Improvement in lung function from Baseline was maintained for 24-hours after dosing and was consistent over days 1, 84 and 168.

The two active comparator-controlled studies (DB2113360 and DB2113374), were also reviewed to evaluate the efficacy of Anoro Ellipta. The study design of active comparator-controlled studies was similar to that of the DB2113373 study. Study DB2113360 compared the efficacy of Anoro Ellipta (62.5/25 µg) and umeclidinium/vilanterol 125/25 µg with vilanterol 25 µg, and with triotropium 18 µg; all administered once daily. Study DB2113374 compared the efficacy of Anoro Ellipta (62.5/25 µg) and umeclidinium/vilanterol 125/25 µg with umeclidinium 125 µg, and with triotropium 18 µg; all administered once daily.

In Study DB2113360, treatment with Anoro Ellipta showed a statistically significant greater improvement from baseline in trough FEV1 (90 mL, p<0.001) compared with vilanterol (25 µg) at Week 24. Anoro Ellipta also showed a statistically significant greater improvement from baseline in weighted mean FEV1 over 0-6 hours (77 mL, p = 0.004) at Week 24 compared with vilanterol (25 µg).

In Study DB2113374, Anoro Ellipta showed an improvement of 70 mL (p = 0.003) in change from baseline in weighted mean FEV1 over 0-6 hours at Week 24 compared with umeclidinium 125 µg. However, the treatment difference between Anoro Ellipta and umeclidinium 125 µg in change from baseline in trough FEV1 (22 mL) at Week 24 was not statistically significant.

In terms of secondary efficacy endpoints, in the placebo-controlled DB2113373 study, Anoro Ellipta demonstrated an improvement when compared with placebo in reducing shortness of breath, as measured by the TDI focal score at week 24 (1.2 units; 95% CI = 0.7 to 1.7). However, when compared with individual components (vilanterol 25 µg and umeclidinium 62.5 µg), Anoro Ellipta did not show statistically significant improvement in TDI focal scores. The percentage of patients that responded with a minimum clinically important difference (MCID) of ≥1 unit TDI focal score at week 24 for Anoro Ellipta was 58% (226/389), compared with 41% (106/260) for placebo.

Health-related quality of life was measured using St. George's Respiratory Questionnaire (SGRQ) in all pivotal studies. In the DB2113373 study, following 24 weeks of treatment, the mean difference in change from baseline in SGRQ total score between Anoro Ellipta and placebo was -5.51 units (95% CI = -7.88 units to -3.13 units). Improvements were seen in all 3 SGRQ domains (symptoms, activities, and impact; mean change from baseline -11.44, -6.81 and -6.60 units, respectively). However, treatment differences in the change from baseline in SGRQ total score between Anoro Ellipta and individual components (umeclidinium 62.5 µg and vilanterol 25 µg, respectively) were not observed in this study following 24 weeks of treatment. More patients treated with Anoro Ellipta had an improvement in SGRQ total score greater than the minimum clinically important difference (MCID) (4 units) at Week 24 compared to placebo (49% versus 34%).

In the DB2113373 study, patients treated with Anoro Ellipta required less rescue salbutamol than those treated with placebo, with an average reduction of 0.8 puffs (95% CI = -1.3 puffs to -0.3 puffs) per day.

Supportive Studies
Exercise Studies

The effect of Anoro Ellipta on exercise endurance and lung function in COPD patients was evaluated in two 12-week randomized, double-blind, placebo-controlled, cross-over studies (DB2114417 and DB2114418). The two exercise endurance studies treated 655 patients with a functional residual capacity (FRC) >120%. The co-primary efficacy endpoints were exercise endurance time (EET) measured using the endurance shuttle walk test (ESWT) and trough FEV1 at Day 85.

In the DB2114418 study, treatment with Anoro Ellipta showed statistically significant improvements over placebo of 69.4 seconds (p = 0.003) in exercise endurance time (EET) obtained 3 hours after dosing at Week 12. However, in the DB2114417 study, treatment with Anoro Ellipta did not show statistically significant improvements in EET (21.9 seconds, p = 0.234). Anoro Ellipta demonstrated statistically significant improvements compared to placebo in change from baseline in trough FEV1 at Week 12 (243 mL; p<0.001) in Study DB2114418. Anoro Ellipta also reduced lung hyperinflation (reduced functional residual capacity and residual volume) resulting in increased inspiratory capacity at rest and during exercise compared to placebo.

For more information, refer to the Anoro Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety of Anoro Ellipta was evaluated in four 24-week Phase III studies with a total of 1,674 patients (518 females and 1,156 males) with COPD who received at least one dose of Anoro Ellipta or umeclidinium/vilanterol 125/25 µg. Three of these four studies were previously described in the Clinical Efficacy section of this Summary Basis of Decision. The fourth Phase III study (DB21133361) was a 24-week, randomized, double-blind, placebo-controlled study which evaluated the efficacy and safety of umeclidinium/vilanterol (125/25 µg) and the individual components (umeclidinium 125 µg and vilanterol 25 µg) administered once-daily via inhalation in patients with COPD. The clinical study design for this study was exactly similar to that of the DB2113373 study.

In addition, a total of 335 COPD patients were also treated for up to 12 months with umeclidinium/vilanterol 125/25 µg or a placebo in a long-term safety study (DB2113359). This was a 52-week, randomized, double-blind, parallel-group, placebo-controlled study which evaluated the safety and tolerability of umeclidinium 125 µg alone and in combination with vilanterol 25 µg, both administered once daily via inhalation. Eligible patients were randomized to receive either umeclidinium/vilanterol 125/25 µg, umeclidinium 125 µg, or a placebo. Patients who met the eligibility criteria at Screening (Visit 1) completed a Run-in Period of approximately 7 to 10 days followed by a 52-week Treatment Period. There was a total of 7 study visits. Clinic visits were at Screening (Visit 1), Randomization (Visit 2), and at 1 month, 3 months, 6 months, 9 months, and 12 months after starting blinded study drug (Visits 3 through Visit 7). A follow-up phone call was conducted approximately 1 week after Visit 7 or the Early Withdrawal Visit, if applicable. The total duration of patient participation was approximately 54 weeks. Spirometry assessments were conducted at Visit 1/1A (pre- and post-salbutamol) and pre-dose (trough) at Visits 2 to 7 to obtain forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC). Vital signs and electrocardiograms (ECGs) were collected prior to salbutamol dosing for spirometry at Visit 1/1A and pre-dose and 10 minutes and 45 minutes post-dose at Visits 2 to 7. An ECG was also performed at any Early Withdrawal Visit.

In the integration of all four 24-week studies, adverse events (AEs) that occurred more frequently with Anoro Ellipta 62.5/25 µg compared to a placebo at a rate of ≥1% included: pharyngitis, sinusitis, lower respiratory tract infection, diarrhea, constipation, pain in extremity, muscle spasms, neck pain, and chest pain. Adverse events that occurred more frequently with Anoro Ellipta compared to placebo at a rate of <1% included: atrial fibrillation, atrial flutter, ECG PR prolongation, increased heart rate, palpitation, tachycardia, supraventricular extrasystoles, supraventricular tachycardia (SVT), ectopic supraventricular rhythm, cardiac ischemia, dry mouth, and cough. The incidence of any on-treatment SAE was similar across all treatment groups (5% to 6%). The only SAE reported by 1% or more of subjects in any treatment group was COPD. The incidence of AEs leading to withdrawal or permanent discontinuation of study drug was low (5% to 7% across all treatment groups). The only AEs leading to permanent discontinuation or withdrawal of 1% or more of patients in any treatment group were COPD and pneumonia. 

In the 52-week safety study, AEs that occurred with a frequency of ≥1% in the group receiving umeclidinium/vilanterol 125/25 µg and exceeded placebo included: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, respiratory tract infection viral, toothache, and diabetes mellitus. The incidence of on-treatment SAE was similar across all treatment groups (6% to 7%). The only SAEs reported for at least 1% of subjects in any treatment group were COPD and pneumonia. The incidence of AEs leading to withdrawal or permanent discontinuation of study drug was low (8% to 11% across all treatment groups).

A total of 22 on-treatment or post-treatment deaths were reported in all 24-week Phase III studies combined. The incidence of deaths reported was <1% for all categories across all treatment groups. No dose- or treatment-related patterns were identified within these reports. In the 52-week safety study, a total of 5 on-treatment or post-treatment deaths also occurred. None of these deaths in the umeclidinium/vilanterol 125/25 µg group or were reported by the investigator as related to study treatment. Overall, there were no apparent imbalances regarding number of deaths between Anoro Ellipta (62.5/25 µg) and placebo.

Analysis of common AEs, laboratory parameters, and vital signs did not show any specific findings of concern.

Due to the potential for muscarinic antagonism and beta-adrenergic stimulation to affect cardiovascular function, and the prevalence of cardiovascular disease in the COPD population, cardiovascular safety was closely monitored in the clinical development program through an assessment of cardiovascular adverse events of special interest (AESI).

Cardiovascular effects such as cardiac arrhythmias [for example (e.g.) atrial fibrillation and tachycardia] may be seen after the administration of sympathomimetic agents and muscarinic receptor antagonists, including Anoro Ellipta. In case such effects occur, treatment may need to be discontinued. Cardiovascular effects such as tachycardia, arrhythmia, palpitations, myocardial ischemia, angina pectoris, hypertension or hypotension have been associated with use of beta-adrenergic agonists. In addition, beta-adrenergic agonists have been reported to produce electrocardiogram (ECG) changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. Therefore, Anoro Ellipta, like all products containing beta-adrenergic agonists, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, acute myocardial infarction, cardiac arrhythmias, and hypertension.

Caution is recommended, if Anoro Ellipta is administered to patients with a known history of QTc prolongation, risk factors for torsade de pointes (for example, hypokalemia), or patients who are taking medications known to prolong the QTc interval. Anoro Ellipta was associated with a dose-dependent increase in heart rate in healthy individuals receiving steady-state treatment.

Anoro Ellipta, like other medications containing sympathomimetic amines, should also be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist salbutamol, when administered intravenously, have been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

Overall, the submitted data support the safety of Anoro Ellipta for the long-term once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. Appropriate warnings and precautions are in place in the approved Anoro Ellipta Product Monograph to address the identified safety concerns. A Black Box Warning is used to warn prescribers and users that Anoro Ellipta is not indicated for the treatment of asthma. Long-acting beta2-adrenergic agonists, including vilanterol (an active ingredient in Anoro Ellipta), are associated with an increased risk of asthma-related death.

For more information, refer to the Anoro Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical program for Anoro Ellipta [umeclidinium (as umeclidinium bromide)/vilanterol (as vilanterol trifenatae)] included studies with the individual monocomponents and in combination via inhalation. Findings for the combination were consistent with those seen in studies with umeclidinium or vilanterol alone and no major interactions or synergistic effects between the two components were observed.

The non-clinical profile (pharmacology and toxicology) of vilanterol alone has already been characterized previously in the Breo Ellipta drug submission (New Drug Submission Control number 157301, authorized July 3, 2013). For more information, see the Breo Ellipta Summary Basis of Decision.

The comprehensive toxicology program of umeclidinium included toxicity studies administered via inhalation for up to 13 weeks in mice, 26 weeks in rats and 39 weeks in dogs. The toxicological findings were generally observed at systemic levels sufficiently in excess of the maximum human exposure. The major findings were those typically associated with systemic exposure to muscarinic antagonists. Umeclidinium was an irritant of the upper respiratory tract and the target organs were identified as the lung, trachea, larynx, heart and nasal cavity.

In a pre- and post-natal study, umeclidinium did decrease maternal body weight gain and food consumption leading to slightly decreased pre-weaning pup body weights.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Anoro Ellipta Product Monograph. In view of the intended use of Anoro Ellipta, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Anoro Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Anoro Ellipta has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf-life is considered acceptable.

The drug substance umeclidinium bromide is a new active substance. The material attributes, manufacturing process critical process parameters and proven acceptable ranges were defined based on a quality-by-design (QbD) approach with supporting experimental results as warranted. Despite the use of the QbD approach to development, control of the drug substance quality is via conventional testing to specifications. The specification limits proposed by the sponsor for several specified impurities exceeded International Conference of Harmonisation (ICH) limits, but the supporting data submitted was determined to be acceptable for qualification of these limits.

The drug substance vilanterol trifenatate is the same as that included in Breo Ellipta (New Drug Submission Control number 157301, authorized July 3, 2013). For more information, see the Breo Ellipta Summary Basis of Decision. The information filed for Anoro Ellipta is aligned to that approved by Health Canada for Breo Ellipta (vilanterol trifenatate/fluticasone furoate) manufactured by the same sponsor. Batch analysis data for vilanterol trifenatate is specific to batches used in manufacture of Anoro Ellipta clinical supplies.

The two drug substances noted above, are filled into two separate blisters strips; one containing the umeclidinium blend [active pharmaceutical ingredient (API) with magnesium stearate and lactose] and the other the vilanterol blend (API with magnesium stearate and lactose). These two blister strips are then inserted into the inhaler device during manufacturing which constitutes the final drug product.

All sites involved in production are compliant with Good Manufacturing Practices. There were minor differences in the manufacturing process for the proposed commercial drug product relative to that drug product used in the pivotal clinical studies. The sponsor provided supporting data demonstrating the differences to have no significant effect on drug product quality or performance.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The excipient lactose is of animal origin. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area has been provided for this product indicating that it is considered to be safe for human use.

 

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