Summary Basis of Decision for Tudorza Genuair

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 Tudorza Genuair is located below.

Recent Activity for Tudorza Genuair

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 Tudorza Genuair

Updated: 2023-09-25

The following table describes post-authorization activity for Tudorza Genuair, a product which contains the medicinal ingredient aclidinium bromide. 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 and Applications Guidance.

Drug Identification Number (DIN):

  • DIN 02409720 - 400 mcg aclidinium bromide, powder (metered dose), oral inhalation

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
NDS # 266599 2022-08-02 Issued NOC 2022-09-12 Submission filed to transfer ownership of the drug product from AstraZeneca Canada Inc. to Covis Pharma GmbH. An NOC was issued.
SNDS # 249236 2021-02-05 Issued NOC 2021-09-17 Submission filed as a Level I – Supplement for the introduction of an alternative primary container closure system. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 214984 2018-03-29 Issued NOC
2018-06-07		 Submission filed as a Level I - Supplement to meet the Plain Language Labelling requirements. The package insert was reviewed and considered acceptable, and an NOC was issued.
NC # 202742 2017-02-10 Issued NOL
2017-05-18		 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, 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.
Drug product (DIN 02409720) market notification Not applicable Date of first sale:
2016-04-04		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 189443 2015-11-12 Cancellation Letter Received
2016-01-26		 Submission filed as a Level I – Supplement for a label change. Issues were identified that required the review to be cancelled before review began; the submission will be refiled at a later time.
SNDS # 174465 2014-05-02 Issued NOC
2015-04-22		 Submission filed as a Level I – Supplement to update the Product Monograph (PM) by including two new Phase IIIb clinical studies that evaluated the effect of Tudorza Genuair on exercise tolerance and 24 hour bronchodilatory profile in patients with moderate to severe chronic obstructive pulmonary disease (COPD). As a result of the SNDS, changes were made to the Warnings and Precautions, Clinical Trials, Detailed Pharmacology, and Reference sections of the PM. Corresponding changes were also made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable. The existing positive benefit-risk assessment of Tudorza Genuair remains unchanged with respect to the currently approved indication. A Notice of Compliance was issued.
NDS # 181451 2015-02-17 Issued NOC
2015-03-06		 Submission filed to transfer ownership of the product from Almirall, S. A. to AstraZeneca Canada Inc.
NC # 178867 2014-10-14 Issued No Objection Letter
2015-01-21		 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 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 a No Objection Letter was issued.
Drug product (DIN 02409720) market notification Not applicable Date of first sale:
2013-09-13		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 157598 2012-07-31 Issued NOC
2013-07-29		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Tudorza Genuair

Date SBD issued: 2013-09-24

The following information relates to the New Drug Submission for Tudorza Genuair.

Aclidinium bromide, 400 mcg, powder (metered dose), oral inhalation

Drug Identification Number (DIN):

  • 02409720

Almirall, S.A.

New Drug Submission Control Number: 157598

 

On July 29, 2013, Health Canada issued a Notice of Compliance to Almirall, S. A. for the drug product, Tudorza Genuair.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (clinical pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Tudorza Genuair is favourable as a long-term maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Tudorza Genuair is not indicated for the relief of an acute deterioration of COPD.

 

1 What was approved?

 

Tudorza Genuair (aclidinium bromide, 400 mcg, twice daily), a bronchodilator also classified as a long-acting muscarinic antagonist (LAMA), was authorized as a long-term maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Tudorza Genuair is not indicated for the relief of an acute deterioration of COPD.

Tudorza Genuair can be used at the recommended dose in elderly patients 70 years of age and older. Tudorza Genuair should not be used in patients under 18 years of age. The safety and effectiveness of Tudorza Genuair in patients less than 18 years of age have not been established.

Tudorza Genuair is contraindicated for patients with a hypersensitivity to aclidinium bromide or to any other component of Tudorza Genuair. Tudorza Genuair was approved for use under the conditions stated in the Tudorza Genuair Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Tudorza Genuair (400 mcg aclidinium bromide) is presented as a multi-dose dry powder inhaler. In addition to the medicinal ingredient, aclidinium bromide, the powder contains lactose monohydrate.

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 Tudorza Genuair Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Tudorza Genuair approved?

 

Health Canada considers that the benefit/risk profile of Tudorza Genuair (aclidinium bromide) is favourable as a long-term maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. Tudorza Genuair is not indicated for the relief of an acute deterioration of COPD.

Three pivotal studies (one of 6 months duration and two of 3 months duration) demonstrated the bronchodilator efficacy of Tudorza Genuair in patients with moderate to severe COPD. The primary endpoint in these studies was the change from baseline in morning pre-dose (trough) FEV1 at 12 weeks compared to placebo. Inhalation of Tudorza Genuair 400 mcg, twice daily (BID) by patients with moderate to severe COPD resulted in a statistically significant increase in FEV1 ranging from 72 to 124 mL compared to placebo across studies. In these studies, Tudorza Genuair was associated with clinically significant bronchodilatory effects in the 12 hours following morning and evening administration. These effects were observed within 30 minutes of the first dose. Peak bronchodilation compared to baseline was achieved within 1 hour to 3 hours following dosing and was maintained for the duration of the study treatment period. Furthermore, Phase II studies showed the overall bronchodilation of Tudorza Genuair 400 mcg BID to be broadly comparable to that of commercially available bronchodilators, tiotropium and formoterol. Supportive evidence for the persistence of bronchodilation when Tudorza Genuair is administered over a one-year treatment period was obtained from the long-term safety studies. In addition, some improvements were also shown in a range of efficacy assessments, including dyspnea, disease-specific health status, COPD exacerbations and exercise tolerance. However, the pivotal studies did not provide robust evidence for the drug's efficacy in symptom relief. Therefore, the Sponsor's proposed indication for long-term maintenance treatment of bronchospasm to relieve symptoms associated with Chronic Obstructive Pulmonary Disease (COPD) was not found acceptable. It is considered that the proposed 400 mcg BID dose of Tudorza Genuair provides effective bronchodilation in the target population and the efficacy claim for Tudorza Genuair as a long-term maintenance bronchodilator in patients with moderate and severe COPD is acceptable.

The safety and tolerability of Tudorza Genuair were evaluated in one 6- month and two 3-month placebo-controlled trials in patients with COPD. In these trials, 636 COPD patients were treated with Tudorza Genuair at the recommended dose of 400 mcg twice daily. Of these, 367 patients were treated with Tudorza Genuair for 3 months and 269 patients were treated with Tudorza Genuair for 6 months. Patients with unstable cardiac disease, QT prolongation, narrow-angle glaucoma, symptomatic prostatic hyperplasia or bladder-neck obstruction were excluded from these studies.

Tudorza Genuair was well-tolerated at the recommended dose, 400 mcg BID in patients with moderate to severe COPD. Across the pivotal studies, 5.1% of patients who received placebo and 4.6% of patients who received Tudorza Genuair 400 mcg BID discontinued prematurely due to adverse events (AEs). Pooled data from these placebo-controlled clinical studies showed that the most frequently reported AEs with Tudorza Genuair were headache (6.6%) and nasopharyngitis (5.5%), none of which were serious, and none of which lead to discontinuation. Other AEs that occurred with a frequency of =1% in patients treated with Tudorza Genuair and where rates exceeded placebo were diarrhea, vomiting, sinusitis, rhinitis, falls, toothache, and cough. The AEs reported in the long-term safety studies were similar to those reported in the placebo-controlled studies of 3 to 6 months.

In all completed studies, 14 deaths occurred, of which six were in the pivotal studies and 8 in the long-term safety studies. For the pivotal studies, slightly more on-treatment deaths were reported for the Tudorza Genuair 400 mcg group (n = 3, 0.5%) than the placebo group (n = 2, 0.3%) or the aclidinium bromide 200 mcg treatment group (n = 1, 0.2%). The most common causes of death were reported as cardiac disorders, followed by lung cancer. Of the 5 cardiovascular deaths, 2 were sudden cardiac deaths reported as cardiac arrest, while the remaining deaths were due to possible myocardial infarction, acute cardiac failure, and subarachnoid haemorrhage.

The incidence of anticholinergic undesirable effects such as dry mouth was low (0.8% in patients treated with Tudorza Genuair 400 mcg BID versus (vs.) 0.6% in placebo-treated patients).

The sponsor examined cardiovascular treatment-emergent AEs by conducting analysis of Major Adverse Cardiovascular Events (MACE), as well as analysis of cardiac events of interest based on Standardized MedDRA queries (SMQs). No apparent differences between treatment groups were observed in MACE Scores or in the incidences of cardiovascular death, non-fatal myocardial infarction or nonfatal stroke. The sponsor will be monitoring cardiovascular AEs and reports of conduction abnormalities, as well as perform further studies on selected cardiovascular endpoints, post-authorisation. Results of these studies will be provided as soon as they become available.

A Risk Management Plan (RMP) for Tudorza Genuair was submitted by the sponsor 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.

The safety issues identified during the review have been adequately addressed by the sponsor. The limitations of the safety database have been discussed in the 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 therapeutic benefits seen in the pivotal studies are positive and the benefits of Tudorza Genuair therapy are considered to outweigh the potential risks for the specified indication. Tudorza Genuair 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 Tudorza Genuair Product Monograph to address the identified safety concerns.

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 Tudorza Genuair?

 

Submission Milestones: Tudorza Genuair

Submission Milestone Date
Pre-submission meeting: 2012-05-09
Submission filed: 2012-07-31
Screening  
Screening Acceptance Letter issued: 2012-10-02
Review  
Quality Evaluation complete: 2013-07-23
Clinical Evaluation complete: 2013-07-24
Labelling Review complete: 2013-07-17
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2013-07-29

 

The Canadian regulatory decision on the quality, non-clinical, and clinical review of Tudorza Genuair was based on a critical assessment of the Canadian data package. The foreign reviews completed 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 Tudorza Genuair?

 

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 Tudorza Genuair 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

Aclidinium bromide, the medicinal ingredient of Tudorza Genuair, is a long-acting muscarinic receptor antagonist administered via a multi-dose dry powder inhaler for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). In the airways, the major action of muscarinic antagonists is bronchodilation and reduced mucus secretion via blockade of acetylcholine-induced effects in the parasympathetic nervous system.

Inhaled aclidinium bromide is rapidly absorbed with a maximum plasma concentration reached by 15 minutes in COPD patients. The lung deposition is approximately 30% with most of the dose deposited in the gastrointestinal tract (55%). After absorption, most of the drug is rapidly metabolized into two inactive metabolites. Only approximately 1% of a single intravenous dose is excreted in the urine as unchanged drug. The remaining is hydrolyzed and excreted as metabolites (65% in urine and 33% in feces).

The effect of age was studied in a single-dose and steady-state study in patients with moderate to severe COPD and age was found to have no impact on the pharmacokinetic (PK) parameters.

Aclidinium was studied in subjects with mild, moderate, and severe renal insufficiency. No clinically significant differences were found and no dose adjustments are required in patients with renal impairment.

Hepatic metabolism plays a minor part in the clearance of aclidinium and hepatic dysfunction is not likely to alter its PK. A study to assess the influence of hepatic dysfunction was considered unnecessary and has not been performed.

Aclidinium had minimal effect on hepatic enzymes, including P-glycoprotein. Doses much higher than the therapeutic levels were necessary to have a mild effect on hepatic enzymes. For that reason, formal drug-drug interaction studies were not conducted.

In summary, the clinical pharmacological data support the use of Tudorza Genuair for the specified indication.

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

Clinical Efficacy

The clinical efficacy program for Tudorza Genuair (aclidinium bromide) 400 mcg twice daily (BID) was comprised of three pivotal studies, and five supportive studies (two Phase II studies and three Phase III long-term safety studies).

The three pivotal studies (Studies M/34273/34, LAS-MD-33, and LAS-MD-38A, also referred to as Studies A, B, and C, respectively) were randomized, double-blind, placebo-controlled clinical studies. The treatment duration was 6 months in Study A and 3 months in Studies B and C. The three studies enrolled 1,933 patients aged =40 years who had a clinical diagnosis of stable moderate to severe COPD and a history of smoking of at least 10 pack-years. The COPD patients were randomized to receive 400 mcg of aclidinium bromide twice daily (BID), 200 mcg of aclidinium bromide BID, or placebo BID.

The two Phase II studies were placebo- and active comparator-controlled, randomised, cross-over studies. Both studies were designed to investigate the 24-hour bronchodilatory profile of aclidinium bromide BID.

Two of the three long-term safety studies were randomised, double-blind, parallel-group studies which were designed primarily to evaluate the safety of aclidinium bromide 400 mcg and 200  mcg BID, administered for up to 12-months. The third long-term study was an open-label, 40-week continuation study of one of the 12-weeks studies that evaluated the safety of aclidinium bromide 400 mcg. They did not include a placebo arm due to ethical concerns.

The inclusion, exclusion criteria, the discontinuation criteria, as well as the allowed/disallowed concomitant medications were similar across all studies and appropriate to assess efficacy.

The primary efficacy endpoint in the three pivotal studies was the change from baseline in morning pre-dose (trough) of forced expiratory volume in 1 second (FEV1) at 12 weeks compared to placebo. Other efficacy variables included: change from baseline in peak FEV1 at the end of study, health-related quality of life measurements using the St. George's Respiratory Questionnaire (SGRQ), transition dyspnea index (TDI), rescue medication usage, COPD symptoms (recorded using an electronic patient diary), and FEV1 assessed at various time points over the treatment period.

In the three pivotal studies, the inhalation of aclidinium bromide 400 mcg BID resulted in statistically significantly greater bronchodilation compared to placebo as assessed by the change from baseline in trough FEV1 at 12 weeks. While the effect size observed in Study C was smaller (72 mL), the effect sizes demonstrated for Studies A and B were of reasonable magnitude (105 mL and 124 mL, respectively), and represent an outcome that is clinically meaningful. The robustness of these results was confirmed by analyses conducted for various subgroups. In addition, results for secondary and other spirometry endpoints, which included standardized area under the curve (AUC) levels, peak FEV1, and serial spirometry were generally numerically supportive of the primary efficacy results regarding the bronchodilatory effects of aclidinium bromide 400 mcg BID in airflow obstructions in patients with moderate to severe COPD. Although exploratory, the two Phase II studies provided some additional support by showing that the effect of the 400 mcg BID dose of aclidinium was similar to the approved doses of tiotropium and formoterol. With regards to persistence of bronchodilatory efficacy, the overall results for lung function parameters from Study A at 6 months were generally consistent with the results at 3 months. These findings are supportive of the findings for the primary endpoint and provide evidence of continued efficacy at 6 months' time. In addition, the three long-term safety studies demonstrated that the treatment effects of aclidinium bromide 400 mcg BID seen in the pivotal studies were maintained for up to 52 weeks with little deterioration. Overall, these results provide replicate evidence of efficacy for Tudorza Genuair and support an indication of bronchodilation.

Symptom related outcomes, such as TDI focal score, SGRQ, COPD exacerbations, and rescue medication use, were also studied. TDI focal score and SGRQ total score were key secondary endpoints in one pivotal study, Study A, which demonstrated statistically significant improvements for aclidinium bromide 400 mcg BID over placebo for both the TDI focal score and the SGRQ total score after 6 months of treatment. It should be noted, however, that for the other two pivotal studies, the symptom-related outcomes were considered exploratory. Furthermore, they showed a numerical improvement, but were not clinically meaningful.

Based on the review of the current drug submission, it was concluded that the data provided substantial evidence for the efficacy of Tudorza Genuair (aclidinium bromide 400 mcg BID) as a bronchodilator; however, the studies did not provide robust evidence for the drug's efficacy in symptom relief. Consequently, the indication was revised from "Tudorza Genuair(aclidinium bromide) is indicated for long-term maintenance treatment of bronchospasm to relieve symptoms associated with Chronic Obstructive Pulmonary Disease (COPD), including chronic bronchitis and emphysema." to "Tudorza Genuair (aclidinium bromide) is indicated as a long-term maintenance bronchodilator treatment in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema" to reflect the efficacy conclusions from these studies.

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

Clinical Safety

The clinical safety of Tudorza Genuair was evaluated in three pivotal studies (described in the Clinical Efficacy section), two long-term safety studies, one dedicated one-year safety study, and short-term Phase II studies.

In the three pivotal studies, 636 COPD patients were treated with Tudorza Genuair at the recommended dose of 400 mcg BID. Of these, 367 patients were treated for 3 months and 269 patients were treated for 6 months. Also, a thorough QT study (aclidinium bromide 800 mcg once a day) was conducted. The size of the safety database was adequate, the demographics of the population represented the targeted population for this indication, and the submitted data supported the safety of the 400 mcg BID dosing of Tudorza Genuair in patients with moderate to severe COPD. However, patients with unstable cardiac disease, long QT syndrome or QT prolongation, narrow-angle glaucoma, symptomatic prostatic hyperplasia, or bladder-neck obstruction were excluded from the studies. This information is reflected in the Tudorza Genuair Product Monograph.

No dose-related trends were observed in the percentage of patients with adverse events (AEs) in the pivotal study population or the long-term study population.

In the three pivotal, placebo-controlled studies, the most common AEs with Tudorza Genuair were headache [6.6% versus (vs.) 5.0% with placebo] and nasopharyngitis (5.5% vs. 3.9% with placebo). Serious adverse events (SAEs) were reported by 4.8% of patients treated with placebo, 4.8% of patients treated with aclidinium bromide 200 mcg and 4.4% of patients treated with aclidinium bromide 400 mcg. The most frequently reported SAE was COPD (exacerbation) which was reported at a lower incidence in the aclidinium bromide treatment groups compared to the placebo group (placebo 2.7%, aclidinium bromide 200 mcg 1.4%, aclidinium bromide 400 mcg 1.6%).

In the long-term study population, the most frequently reported SAE was COPD (exacerbation) and the incidence was numerically higher in the aclidinium bromide 400 mcg group compared with the aclidinium bromide 200 mcg group (3.6% vs. 2.5%, respectively). Other than COPD (exacerbation), pneumonia was the only additional SAE reported in at least 1% of the patients, but the incidence was not higher with aclidinium bromide 400 mcg compared to aclidinium bromide 200 mcg (0.6% vs. 1.1%, respectively).

Haematological data obtained during the 3 pivotal placebo-controlled studies did not disclose any clinically relevant changes from baseline to end-of-study for any parameter and the results were not dose dependent. Mean change from baseline values for the chemistry determinations also showed no relevant changes or dose dependence in any treatment arm at the end of the study except for an apparent dose-associated increase in uric acid levels.

There were some minor increases in the liver enzymes alanine transaminase (ALT) and aspartate aminotransferase (AST) but there was no consistent dose response.

In all of the completed studies, 14 deaths occurred, of which six were in the pivotal studies and 8 in the long-term safety studies. For the pivotal efficacy and safety studies, slightly more on-treatment deaths were reported for the aclidinium bromide 400 mcg treatment group [number of patients (n) = 3, 0.5%) than the placebo group (n = 2, 0.3%) or the aclidinium bromide 200 mcg treatment group (n = 1, 0.2%). The most common causes of death were classed as cardiac disorders, followed by lung cancer. Of the 5 cardiovascular deaths, 2 were sudden cardiac deaths reported as cardiac arrest, while the remaining deaths were due to possible myocardial infarction, acute cardiac failure, and subarachnoid haemorrhage.

The sponsor examined cardiovascular treatment-emergent AEs by conducting analysis of Major Adverse Cardiovascular Events (MACE), as well as analysis of cardiac events of interest based on Standardized MedDRA queries (SMQs). No apparent differences between treatment groups were observed in the MACE Scores or in the incidences of cardiovascular death, non-fatal myocardial infarction, or nonfatal stroke.

The sponsor will be monitoring cardiovascular AEs and reports of conduction abnormalities, as well as conduct further studies regarding cardiovascular endpoints. The sponsor will provide Health Canada the results from these studies as soon as they become available. A Risk Management Plan was also submitted and reviewed by Health Canada. All safety issues identified during the review have been adequately addressed by the sponsor.

Appropriate warnings and precautions are in place in the approved Tudorza Genuair Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

Aclidinium bromide, the medicinal ingredient of Tudorza Genuair, is a long-acting muscarinic receptor antagonist with a similar potency at all five human muscarinic receptors M1 to M5, but kinetically, shows a preference for the M3 receptor. Aclidinium bromide was shown to have a long residence at M3 receptors and provided dose-dependent and long-lasting (longer than 24 hours) protection against bronchoconstriction.

In the repeat-dose toxicity studies in mice, rats, and dogs, most of the toxicity effects were related to the pharmacological action of an anticholinergic drug, including increased heart rate, mydriasis, decreased tear production, and tremors. The no-observed-adverse-effect levels in the chronic toxicity studies in rats and dogs were approximately 17 and 19 times the recommended human daily dose based on the systemic exposure of aclidinium bromide.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Tudorza Genuair Product Monograph. Appropriate warnings and precautionary measures are in place to address the identified safety concerns.

In view of the intended use of Tudorza Genuair there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Tudorza Genuair 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 Tudorza Genuair 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 of three years is considered acceptable.

Proposed limits of drug-related impurities are considered adequately qualified (that is within International Conference on Harmonisation limits and/or qualified from toxicological studies).

All sites involved in production are compliant with Good Manufacturing Practices.

Lactose monohydrate is the only non-medicinal ingredients found in the drug product, and it is acceptable for use in drugs according to the Food and Drug Regulations. The excipient, lactose monohydrate, is provided from a certified supplier and the milk used in the manufacture of the lactose monohydrate is obtained from healthy cattle under the same conditions as milk intended for human consumption.

 

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