Summary Basis of Decision for Breo 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 Breo Ellipta is located below.

Recent Activity for Breo Ellipta

SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Breo Ellipta

Updated:

2019-01-18

The following table describes post-authorization activity for Breo Ellipta, a product which contains the medicinal ingredients fluticasone furoate 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 that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02408872 - 100 µg fluticasone furoate, 25 µg vilanterol (as vilanterol trifenatate), powder, oral inhalation
  • DIN 02444186 - 200 µg fluticasone furoate, 25 µg vilanterol (as vilanterol trifenatate), powder, oral inhalation

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 213290 2018-01-31 Issued NOC
2019-01-09		 Submission filed as a Level I - Supplement to update the PM based on two 12-month, open-label effectiveness clinical trials. As a result of the SNDS, modifications were made to the Adverse Reactions, and Drug Interactions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued. The benefit/risk profile for Breo Ellipta remains positive when used for its approved indication.
NC # 218271 2018-07-16 Issued NOL
2018-10-22		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, 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 NOL was issued.
SNDS # 202721 2017-02-09 Issued NOC
2018-01-30		 Submission filed as a Level I - Supplement to remove the long-acting beta2-adrenergic agonist (LABA) class safety information, including the Serious Warnings and Precautions Box, from the PM. Based on the available evidence that LABA in a fixed-dose combination inhaled corticosteroids (ICS) does not increase the risk of serious asthma-related events, including death, compared to ICS alone in patients with asthma, the Serious Warnings and Precautions Box for "Asthma-Related Death" has been removed. To provide adequate safety information, text regarding serious asthma related events with LABA monotherapy and text that includes the results of the meta-analysis has been added to the warnings and precautions in the PM. Overall, the benefit-harm uncertainty profile of Breo Ellipta remains favourable. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 197729 2016-08-17 Issued NOC
2017-07-24		 Submission filed as a Level I - Supplement to provide a safety and efficacy update to the PM based on longer term follow-up of patients. As a result of the submission, the following sections of the PM were updated: Warnings and Precautions and Adverse Reactions. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOC was issued. The benefit/risk profile for Breo Ellipta remains positive when used for its approved indication.
NC # 204760 2017-04-03 Issued NOL
2017-05-19		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to amend the text of the back panel of the inner label for improved clarity. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 198835 2016-09-30 Issued NOL
2017-02-23		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM and labels to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Adverse Reactions, Storage and Stability, and Special Handling Instructions sections of the PM. Corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 200857 2016-12-06 Issued NOC
2017-02-17		 Submission filed as a Level I - Supplement to update the colour gradient of the 200 mcg strength to be consistent with the colour gradient of the 100 mcg strength on the labels and to include a new partner logo. The submission was reviewed and considered acceptable, and an NOC was issued.
Drug product (DIN 02444186) market notification Not applicable Date of first sale:
2015-10-02		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 188217 2015-10-01 Issued No Objection Letter
2016-01-29		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the Product Monograph (PM) to reflect revisions in the company core data sheet. 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 # 184788 2015-05-22 Issued No Objection Letter
2015-08-27		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph (PM) based on post-market safety information. As a result of this submission, changes were made to the Adverse Reactions, and the Part III Consumer Information sections of the PM. The submission was reviewed and considered acceptable. A No Objection Letter was issued.
SNDS # 177501 2014-08-26 Issued NOC
2015-08-05		 Regulatory Decision Summary published. A new DIN (02444186) was issued for the new strength.
NC # 181724 2015-01-29 Issued No Objection Letter
2015-05-08		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions, Adverse Reactions, and Part III Consumer Information sections of the Product Monograph. The submission was reviewed and considered acceptable. A No Objection Letter was issued.
NC # 176573 2014-07-21 Issued No Objection Letter
2014-10-30		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) changes associated with hypersensitivity reactions for fluticasone furoate/vilanterol trifenatate. As a result of the Notifiable Change (NC), additions were made to the Warnings and Precautions and Adverse Reactions sections, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued.
NC # 174799 2014-05-16 Issued No Objection Letter
2014-08-29		 Level II (90 day) Notifiable Change (Safety Change) to revise the Product Monograph and package labels. Revisions include updates to: Warnings and Precautions; Dosage and Administration; Action and Clinical Pharmacology; and the Part III Consumer Information sections of the Product Monograph. Numerous editorial changes were also made to provide clarity.
NC # 173917 2014-04-10 Cancellation Letter Received
2014-04-28		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Product Monograph and package labels. Additional information was to be incorporated so the submission was cancelled administratively by the sponsor at Health Canada's request before screening began and was refiled as a Level II (90 day) Notifiable Change (NC #174799).
Drug product (DIN 02408872) market notification Not applicable Date of first sale:
2013-11-29		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 157301 2012-07-20 Issued NOC
2013-07-03		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Breo Ellipta

Date SBD issued: 2013-08-06

The following information relates to the new drug submission for Breo Ellipta.

Fluticasone furoate and vilanterol (as vilanterol trifenatate)
100 µg of fluticasone furoate and 25 µg of vilanterol (as vilanterol trifenatate)
Powder, oral inhalation

Drug Identification Number (DIN):

  • 02408872

GlaxoSmithKline Inc.

New Drug Submission Control Number: 157301

 

On July 3, 2013, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product, Breo 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 Breo Ellipta is favourable for the long-term once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with a history of exacerbations. Breo Ellipta is not indicated for the relief of acute bronchospasm in COPD and is not indicated for the treatment of asthma.

1 What was approved?

 

Breo Ellipta is a controller medication that contains two medicinal ingredients: fluticasone furoate, an inhaled corticosteroid (ICS); and vilanterol (as trifenatate), a long-acting beta2-adrenergic agonist (LABA). Breo Ellipta was authorized for the long-term once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with a history of exacerbations.

Breo Ellipta is not indicated for the relief of acute bronchospasm in COPD.

Breo Ellipta is not indicated for the treatment of asthma.

Breo 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.

Breo Ellipta is contraindicated for patients who are hypersensitive to fluticasone furoate, vilanterol, or any ingredient in the formulation or component of the container; as well as patients with a severe hypersensitivity to milk proteins. Breo Ellipta was approved for use under the conditions stated in the Breo Ellipta Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Breo Ellipta [fluticasone furoate/vilanterol (as trifenatate) 100 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 Breo Ellipta Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Breo Ellipta approved?

 

Health Canada considers that the benefit/risk profile of Breo Ellipta, a combination drug product of fluticasone furoate and vilanterol 100 µg/25 µg, is favourable for the long-term once-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with a history of exacerbations. Fluticasone furoate is an inhaled corticosteroid (ICS) and vilanterol is a long acting beta2-agonist (LABA).

Chronic obstructive pulmonary disease is a common, preventable and treatable disease, characterised by persistent airflow limitation that is usually progressive and associated with an enhanced inflammatory response in the airways and the lung to noxious particles or gases. This disease is a major public health problem in Canada. It represents a major cause of morbidity and mortality, with a high and increasing prevalence. Based on the 2005 Canadian Community Health Survey, 4.4% of the adult population over 35 years of age (over 700,000 adults) had self-reported physician-diagnosed COPD. In men, the reporting rate was 3.9% and in women 4.8%. Use of combination products for treatment of COPD is established in guidelines when treatment with beta2-agonists alone is not sufficient. To improve patient compliance, use of fixed combination products may be preferred over use of two single products separately. Currently, there are two other ICS/LABA combination drugs for the treatment of COPD in Canada. However, there are no drugs approved for the reduction of COPD exacerbations.

Breo Ellipta has been shown to be efficacious in treating airflow obstruction in patients with COPD, as well as reducing exacerbations in COPD patients with a history of exacerbations. The market authorization was based on four clinical Phase III studies. Two pivotal 6-month, randomized, double-blind, placebo-controlled, parallel-group, lung function studies demonstrated sustained 24-hour bronchodilator efficacy of Breo Ellipta in patients with moderate to severe COPD, thus showing the contribution of vilanterol to the combination. Two pivotal 12-month randomized, parallel-group exacerbation studies showed that treatment with Breo Ellipta resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol alone, thus showing the contribution of fluticasone furoate to the combination.

The common adverse event (AE) profile for Breo Ellipta in COPD patients was similar to other ICS/LABA products in patients with COPD. The combination of fluticasone furoate and vilanterol was well-tolerated at the recommended dose in patients with moderate to severe COPD. In terms of serious adverse events (SAEs), an increased risk for pneumonia was identified as being fluticasone furoate dose-related. In the two 12-month studies, there was a higher incidence of pneumonia reported in patients receiving fluticasone furoate doses of 50 µg, 100 µg and 200 µg in fixed combination with vilanterol 25 µg (6-7%) than in those receiving vilanterol 25 µg alone. However, pneumonia is a known risk in other ICS/LABA products and current product labelling contains warnings regarding this risk. The safety issues identified during the review have been adequately addressed by the sponsor. The Breo Ellipta Product Monograph approved by Health Canada contains the relevant information.

Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. An increase in the incidence of bone fracture was observed in patients with COPD receiving Breo Ellipta. In two replicate 12-month studies in a total of 3,255 patients with COPD, bone fractures were reported by 2% of patients receiving fluticasone furoate doses of 50, 100, or 200 µg in fixed combination with vilanterol 25 µg and in <1% of patients receiving vilanterol 25 µg. Risk minimization measures are discussed in the Breo Ellipta Product Monograph.

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

A Risk Management Plan (RMP) for Breo 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 Breo Ellipta therapy seem to outweigh the potential risks. Breo 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 Breo 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 Breo Ellipta?

 

Submission Milestones: Breo Ellipta

Submission Milestone Date
Pre-submission meeting: 2012-05-30
Submission filed: 2012-07-20
Screening  
Screening Acceptance Letter issued: 2012-09-07
Review  
Quality Evaluation complete: 2013-06-17
Clinical Evaluation complete: 2013-06-27
Labelling Review complete: 2013-06-27
Notice of Compliance issued by Director General: 2013-07-03

 

The Canadian regulatory decision on the non-clinical and clinical review of Breo 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 Breo 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 Breo 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

Breo Ellipta contains both fluticasone furoate (a synthetic corticosteroid) and vilanterol (a selective long-acting beta2-receptor agonist). Fluticasone furoate has been shown to have potent anti-inflammatory activity. The precise mechanism through which fluticasone furoate affects chronic obstructive pulmonary disease (COPD) symptoms is not known. Vilanterol stimulates intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cyclic AMP). Increased levels of cyclic AMP cause relaxation of bronchial smooth muscle and inhibit the release of mediators of immediate hypersensitivity from cells, especially mast cells.

The comprehensive clinical pharmacology program included studies in COPD and asthma patients and healthy, hepatically impaired and renally impaired subjects.

Higher systemic exposure to fluticasone furoate was observed in East Asian populations compared to Caucasians after inhalation. In subjects with mild, moderate, and severe hepatic impairment, systemic exposure to vilanterol was not affected however, fluticasone furoate systemic exposure was higher (up to 3-fold) compared to healthy subjects. These results correlated with a 34% decrease in weighted mean serum cortisol in patients with moderate hepatic impairment. Therefore, use with caution is recommended in patients with hepatic impairment. In subjects with severe renal impairment (creatinine clearance <30 mL/min), systemic exposure to fluticasone furoate was lower and systemic exposure to vilanterol was higher compared to healthy subjects. However, the increased vilanterol systemic exposure did not result in associated pharmacodynamic effects.

The effects of fluticasone furoate/vilanterol on electrocardiogram parameters were also investigated and fluticasone furoate/vilanterol was associated with a dose-dependent increase in heart rate and QTc prolongation.

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

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

Clinical Efficacy

The efficacy of Breo Ellipta was evaluated in four Phase III clinical studies in patients with a clinical diagnosis of COPD. Two were lung function studies and the other two were exacerbation studies. The four studies were considered pivotal studies for the COPD indication.

Lung Function Studies

Two 6-month multicentre, randomized, placebo-controlled, double-blind, parallel group studies (HZC112206, HZC112207) were designed to evaluate the efficacy of Breo Ellipta in improving lung function in patients with moderate to severe COPD. Of the 2,254 randomized patients who received at least one treatment dose, the majority were male (70%) and Caucasian (84%), and ranged in age from 40 to 85 years (mean age: 62 years). At screening, the mean post-bronchodilator percent predicted Forced Expiratory Volume in 1 second (FEV1) was 48.1% and the mean percent reversibility was 13.8%. The mean smoking history was 44.1 pack years, and 54% of the patients were current smokers.

Study HZC112206 evaluated the efficacy of fluticasone furoate/vilanterol 50/25 µg [number of patients (n) = 206)], and Breo Ellipta 100/25 µg (n = 206) compared with fluticasone furoate 100 µg (n = 206), vilanterol 25 µg (n = 205) and placebo (n = 207), all administered once daily.

Study HZC112207 evaluated the efficacy of Breo Ellipta 100/25 µg (n = 204) and fluticasone furoate/vilanterol 200/25 µg (n = 205) compared with fluticasone furoate 100 µg (n = 204) and 200 µg (n = 203) and vilanterol 25 µg (n = 203) and placebo (n = 205), all administered once daily.

The co-primary endpoints in both studies were the weighted mean FEV1 from 0 to 4 hours post-dose at Day 168 and change from baseline in pre-dose trough FEV1 at the end of the study.

In Study HZC112206, for the first co-primary endpoint, Breo Ellipta 100/25 µg increased the weighted mean FEV1 (0 4 hours) relative to placebo by 173 mL by the end of the 24-week treatment period. Similarly, an increase of 209 mL was observed in Study HZC112207. In addition, patients receiving Breo Ellipta 100/25 µg had a greater increase in weighted mean FEV1 (0-4 hours) compared with those receiving fluticasone furoate 100 µg.

The second co-primary endpoint, change from baseline in trough FEV1 following the final treatment day, was increased by 115 mL in Study HZC112206 and increased by 144 mL in Study HZC112207 compared with placebo. Improvement in trough FEV1 with Breo Ellipta 100/25 µg compared with vilanterol (45 to 48 mL) did not achieve statistical significance in either study.

Exacerbation Studies

Two 12-month studies (HZC102970, HZC102871) were designed to evaluate the efficacy of Breo Ellipta in reducing COPD exacerbations in COPD patients with a history of exacerbations.

Studies HZC102970 and HZC102871 were 12-month, multicentre, randomized, double-blind, parallel-group studies comparing the effect of fluticasone furoate/vilanterol 200/25 µg, Breo Ellipta 100/25 µg, fluticasone furoate/vilanterol 50/25 µg and vilanterol 25 µg, all administered once daily (OD), on the annual rate of moderate/severe exacerbations in patients with COPD. The intent-to-treat population included 3,255 patients with an established history of COPD and a history of exacerbations (but no other significant respiratory disorders) and a smoking history of a mean of 46.2 pack years. The majority of the patients were male (57%) and Caucasian (85%), and ranged in age from 40 to 90 (mean age: 64 years) and had moderate to very severe airflow obstruction.

The primary endpoint was the annual rate of moderate and severe exacerbations. Moderate/severe exacerbations were defined as worsening symptoms that required treatment with oral corticosteroids and/or antibiotics or in-patient hospitalization. Both studies had a 4-week run-in period during which all patients received open-label fluticasone propionate/salmeterol 250/50 µg twice daily to standardize COPD pharmacotherapy and stabilize disease prior to randomization to blinded study medication for 52 weeks. Prior to run-in, patients discontinued use of previous COPD medications except short-acting bronchodilators. The use of concurrent inhaled long-acting bronchodilators (beta2-agonist and anticholinergic), ipratropium/salbutamol combination products, oral beta2-agonists, and theophylline preparations were not allowed during the treatment period. Oral corticosteroids and antibiotics were allowed for the acute treatment of COPD exacerbations with specific guidelines for use. Patients used salbutamol on an as-needed basis throughout the studies.

The results of both studies showed that treatment with Breo Ellipta 100/25 µg OD resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol. Both of the 12-month exacerbation studies (HZC102970 and HZC102871) demonstrated that all three strengths of fluticasone furoate/vilanterol OD were more efficacious than vilanterol 25 µg OD alone in reducing the annual rate of moderate and severe COPD exacerbations Treatment with all three strengths of fluticasone furoate/vilanterol decreased the annual rate of moderate and severe exacerbations by between 13% and 34% compared with treatment with VI 25 OD alone across the two studies. In particular, compared with vilanterol 25 µg OD alone, treatment with Breo Ellipta 100/25 µg consistently reduced the annual rate of moderate and severe COPD exacerbations, with reductions of 34% and 21%. In Study HZC102970, Breo Ellipta 100/25 µg significantly lowered the risk for time to first moderate or severe exacerbation at any time point compared to treatment with vilanterol 25 µg alone [hazard ratio 0.8, 95% confidence interval (CI): 0.66, 0.99]. In Study HZC102871, the risk for time to first moderate or severe exacerbation at any time point was numerically lower for Breo Ellipta 100/25 µg compared to vilanterol 25 µg alone (hazard ratio of 0.72; 95% CI: 0.59, 0.89). In Study HZC102970, Breo Ellipta 100/25 µg significantly reduced the annual rate of COPD exacerbations requiring systemic/oral corticosteroids compared to treatment with vilanterol 25 µg alone (hazard ratio of 0.77; 95% CI 0.60, 0.99). In Study HZC102871, the annual rate of COPD exacerbations requiring systemic/oral corticosteroids was numerically lower for Breo Ellipta 100/25 µg compared to vilanterol 25 µg alone (ratio of 0.62; 95% CI 0.49, 0.78).

Efficacy Conclusion

Three doses of the fluticasone furoate/vilanterol combination were taken to Phase III: fluticasone furoate/vilanterol 50/25 µg; fluticasone furoate/vilanterol 100/25 µg, and fluticasone furoate/vilanterol 200/25 µg. The totality of the data supports the dose of fluticasone furoate/vilanterol 100/25 µg OD, in the morning or in the evening, as the most appropriate dose for the specified indication. While the dose of fluticasone furoate/vilanterol 50/25 µg was sub-optimal, the dose of fluticasone furoate/vilanterol 200/25 µg did not provide any added benefits, while at the same time increased the risks.

Overall, the contribution of the vilanterol component to the combination product, Breo Ellipta (fluticasone furoate/vilanterol 100/25 µg), has been shown based on the totality of the data, including an analysis of both co-primary endpoints from the lung function studies, as well as the 24-hour spirometric time curve from the preliminary dose-ranging study. The results were both statistically significant and clinically meaningful, demonstrating the contribution of the vilanterol component to the combination.

The benefit that fluticasone furoate provides to the combination product was demonstrated in the exacerbation studies with support drawn from the trough FEV1 results obtained in the four pivotal Phase III studies. Since the contribution of an inhaled corticosteroid (ICS) in a combination product on lung function (trough FEV1) is relatively small, the major contribution of fluticasone furoate to the combination was evaluated in the 1-year, exacerbation studies by measuring the effect of the combination on the annual rate of moderate and severe COPD exacerbations. Treatment with Breo Ellipta 100/25 µg once daily resulted in a lower annual rate of moderate/severe COPD exacerbations compared with vilanterol thus showing the contribution of fluticasone furoate to the combination.

In conclusion, the efficacy results from the pivotal Phase III studies are considered positive. The totality of the data provided by the sponsor supports the specified indication of Breo Ellipta for the long-term once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema, and to reduce exacerbations of COPD in patients with a history of exacerbations.

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

Clinical Safety

The primary COPD safety database for Breo Ellipta included data from the four pivotal Phase III COPD studies described in the Clinical Efficacy section. A total of 2,257 patients were included in the 6-month lung function studies, and 3,255 patients in the 12-month exacerbation studies. Additional safety results were obtained from 2,342 patients in various other COPD studies. Overall, the safety database was considered large and adequate.

The safety analyses included evaluation of adverse events (AEs), serious adverse events (SAEs), and deaths. Adverse events of special interest, usually associated with ICS use, such as pneumonia, bone disorders and fractures, adrenal function; or associated with long acting beta2-agonist (LABA) use, such as cardiovascular effects (electrocardiograms, Holter monitoring, thorough QT study), tremors, hypokalemia, and hyperglycemia were also assessed.

The most common AEs were nasopharyngitis, headaches, upper respiratory tract infection (URTI), and oral and oropharyngeal candidiasis. In the two 6-month studies, these AEs had the following incidence rate for Breo Ellipta versus (vs.) placebo: nasopharyngitis 9% vs. 8%; headache 7% vs. 5%; URTI 7% vs. 3%; and oral and oropharyngeal candidiasis 5% vs. 2%; respectively.

A total of 43 on-treatment deaths were reported in the 12-month exacerbation studies and 8 on-treatment deaths were reported in the 6-month lung function studies. Common causes of deaths included COPD exacerbation, respiratory failure, and myocardial infarction, which are well known causes of death in older COPD patients. The number of deaths, AEs, and SAEs did not raise any safety concerns.

Two safety findings of interest were pneumonia and bone fractures. Pneumonia was observed in the fluticasone furoate treatment arms, more prominently in the 12-month exacerbation studies that were conducted in COPD patients whose condition was worse. However, pneumonia is a known risk of high-dose inhaled steroids in patients with COPD and has been seen with other ICS/LABA combination products. An increased risk of fractures was also seen with Breo Ellipta compared to vilanterol. Similar to pneumonia, a decrease in bone mineral density and increased fractures are also known risk factors for inhaled corticosteroids and have been seen in previous ICS/LABA combination product development programs for COPD.

Other safety assessments, such as assessments of cardiovascular function and adrenal axis did not show any safety signals. Analysis of common AEs, laboratory parameters, and vital signs also did not show any specific findings of concern.

The limitations of the safety database have been discussed in the Risk Management Plan (RMP) and risk minimization activities, including routine pharmacovigilance practices, as well as action beyond routine pharmacovigilance (post-market cardiovascular safety assessments) plans have been included in the RMP.

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

For more information, refer to the Breo 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 Breo Ellipta (fluticasone furoate/vilanterol) included studies with the individual monocomponents and in combination via inhalation. Findings for the combination were consistent with those seen in studies with fluticasone furoate or vilanterol alone and no major interactions or synergistic effects between the two components were observed.

The non-clinical profile (pharmacology and toxicology) of fluticasone furoate alone has been characterized previously in the Avamys drug submission (New Drug Submission Control number 107372, authorized August 14, 2007). For more information, see the Avamys Summary Basis of Decision.

The comprehensive toxicology program of vilanterol included toxicity studies administered via inhalation for up to 13 weeks in mice, 26 weeks in rats and 52 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 beta2 agonists. The target organs were identified as the upper airways, lung, heart, liver, and the female reproductive tract.

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

For more information, refer to the Breo 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 Breo 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 fluticasone furoate was cross-referenced with the Avamys drug submission (New Drug Submission Control number 107372, authorized August 14, 2007). For more information, see the Avamys Summary Basis of Decision. The particle size specifications for fluticasone furoate have been modified from those accepted for Avamys with acceptance criteria for fluticasone furoate in Breo Ellipta justified based on results for drug substance and drug product batches used in the pivotal clinical trials. The fluticasone furoate information for Breo Ellipta is considered complete and acceptable.

The vilanterol trifenatate specification limits for several specified impurities exceeded International Conference of Harmonisation (ICH) limits and a consult on the acceptability of the impurity limits was requested. The proposed limits of drug-related impurities in the vilanterol trifenatate drug substance is considered acceptable noting that maximum exposure to each specified impurity remained below the general threshold of toxicological concern, based on the maximum daily dose of vilanterol trifenatate for Breo Ellipta.

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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