Summary Basis of Decision for Imbruvica

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 Imbruvica is located below.

Recent Activity for Imbruvica

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 Imbruvica

Updated:

2022-11-28

The following table describes post-authorization activity for Imbruvica a product which contains the medicinal ingredient ibrutinib. 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 02434407 - 140 mg, ibrutinib, capsule, oral administration
  • DIN 02486733 - 140 mg, ibrutinib, tablet, oral administration
  • DIN 02486741 - 280 mg, ibrutinib, tablet, oral administration
  • DIN 02486768 - 420 mg, ibrutinib, tablet, oral administration
  • DIN 02486776 - 560 mg, ibrutinib, tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Health Professional Risk Communication Not applicable Posted 2022-08-29 Health Professional Risk Communication posted (Imbruvica [ibrutinib] - Risk of Serious and Fatal Cardiac Arrhythmias or Cardiac Failure), containing new safety information for health professionals.
SNDS # 261088 2022-02-01 Issued NOC 2022-06-29 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Warnings and Precautions, and Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 255285 2021-07-29 Issued NOC 2021-12-16 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 248172 2021-01-08 Issued NOC 2021-06-02 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and to migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 238064 2020-04-03 Issued NOC 2021-03-05 Submission filed as a Level I – Supplement to update the PM with new safety information. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Adverse Reactions, and Drug Interactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 235706 2020-01-31 Issued NOC 2020-12-15 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL) in combination with rituximab. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 233164 2019-11-01 Issued NOC 2020-09-28 Submission filed as a Level I – Supplement to update the PM with pediatric pharmacokinetic data. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Dosage and Administration sections of the PM. An NOC was issued.
Summary Safety Review Not applicable Posted 2020-09-15 Summary Safety Review posted for Imbruvica (Assessing the potential risk of hemophagocytic lymphohistiocytosis).
NC # 235078 2020-01-10 Issued NOL 2020-04-20 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 222804 2018-12-06 Issued NOC 2019-11-06 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with obinutuzumab, the treatment of patients with previously untreated active chronic lymphocytic leukemia (CLL), including those with 17p deletion. The PM was also updated with new safety information. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOC was issued.
PBRER-C # 207718 2017-07-20 Filed
2019-08-19		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-11-13 to 2017-05-12. The information was reviewed and found acceptable.
SNDS # 221044 2018-10-16 Issued NOC
2019-05-06		 Submission filed as a Level I - Supplement to add an alternate manufacturing process for the drug substance and to add manufacturing sites. The information was reviewed and considered acceptable. An NOC was issued.
SNDS # 214952 2018-04-11 Issued NOC
2019-03-20		 Submission filed as a Level I – Supplement to extend the current marketing authorization to new film-coated tablet formulations. New DINs were issued for the new formulations: 02486733 (140 mg), 02486741 (280 mg), 02486768 (420 mg), and 02486776 (560 mg). Regulatory Decision Summary published.
NC # 223074 2018-12-17 Issued NOL
2019-02-27		 Submission filed as a Level II (90 day) Notifiable 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: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
Summary Safety Review posted Not applicable Posted
2018-07-26		 Summary Safety Review posted for Imbruvica (Assessing the potential risk of a serious and life-threatening abnormal heart rhythm [ventricular tachyarrhythmia]).
SNDS # 212632 2018-01-05 Issued NOC
2018-07-24		 Submission filed as a Level I - Supplement for new indication. Upon review, the indication was revised to the treatment of patients with marginal zone lymphoma who require systemic therapy and have received at least one prior anti-CD20-based therapy. Regulatory Decision Summary published.
PBRER-C # 197028 2016-07-22 Filed
2018-01-26		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2015-11-13 to 2016-05-12. The information was reviewed and found acceptable.
NC # 214410 2018-03-09 Issued NOL
2018-06-26		 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, Adverse Reactions, and Drug Interactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information.
The submission was reviewed and considered acceptable, and an NOL was issued.
New safety review started by Health Canada Not applicable Started between
2018-01-01		 Health Canada started a safety review for Imbruvica related to ventricular arrhythmias (abnormal heart rhythm that comes from an area of the lower chamber [ventricle] of the heart) and sudden death.
PBRER-C # 202109 2017-01-19 Filed
2018-01-26		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-05-13 to 2016-11-12. No further action was required.
NC # 210084 2017-10-10 Issued NOL
2018-01-15		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to include hepatitis B reactivation. 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: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 204436 2017-04-04 Issued NOC
2017-10-25		 Submission filed as a Level I - Supplement for a new indication: treatment of patients with steroid dependent or refractory chronic graft  versus host disease.  Regulatory Decision Summary published.
SNDS-C # 198803 2016-09-30 Issued NOC
2017-09-12		 Submission filed as a Level I - Supplement to remove the conditions from the NOC for the use of Imbruvica for the treatment of patients with relapsed or refractory mantle cell carcinoma. The final analysis results of Study 1104, and complete study results of Studies MCL2001 and MCL3001, were submitted. The data were reviewed and considered to demonstrate evidence of clinical effectiveness, confirming the promising evidence of efficacy previously concluded, and continued to support an acceptable safety profile. As a result of the submission, the conditions were removed from the NOC that had been issued 2015-07-28.
NC # 203931 2017-03-20 Issued NOL
2017-07-06		 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 Warnings and Precautions and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 192718 2016-02-29 Issued NOC
2017-02-01		 Submission filed as a Level I - Supplement for a new indication, the use of Imbruvica in combination with bendamustine and rituximab for the treatment of patients with previously treated chronic lymphocytic leukemia. Regulatory Decision Summary published.
NC # 199713 2016-10-27 Issued No Objection Letter
2017-01-05		 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: Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
PBRER-C # 191214 2016-01-12 Filed
2016-12-15		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #1 for the period 2015-04-21 to 2015-11-12. No further action was required.
NC # 194722 2016-05-02 Issued No Objection Letter
2016-09-07		 Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM based on post-market 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: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 190730 2015-12-21 Issued NOC
2016-07-19		 Submission filed as a Level I - Supplement to broaden the existing indication for chronic lymphocytic leukemia to include all previously untreated patients. Regulatory Decision Summary published.
SNDS # 183766 2015-04-16 Original NOC issued under NOC/c Guidance 2016-03-31

NOC corrected
2018-06-13		 Submission filed as a Level I - Supplement for a new indication, the treatment of patients with Waldenström's Macroglobulinemia and to revise the Product Monograph with new pharmacology information. Regulatory Decision Summary published. No new conditions were added as a result of this submission, and the NOC was corrected without reference to the NOC/c Guidance.
SNDS # 187673 2015-09-11 Original NOC issued under NOC/c Guidance 2016-03-18

NOC corrected
2018-06-13		 Submission filed as a Level I - Supplement to add an alternate manufacturing process for the drug product. There were no changes proposed to the drug substance. The data were reviewed and considered acceptable, and an NOC was issued. No new conditions were added as a result of this submission, and the NOC was corrected without reference to the NOC/c Guidance.
NC # 187662 2015-09-11 Issued No Objection Letter
2015-12-24		 Submission filed as a Level II (90 day) Notifiable Change (Safety Change) for Product Monograph (PM) changes related to hepatic events. As a result of the Notifiable Change, additions were made to the Adverse Reactions and Overdosage sections of the PM. and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued.
NC # 188423 2015-10-09 Cancellation Letter Received
2015-10-22		 Submission filed as a Level II (120 day) Notifiable Change (Safety Change) to update the Product Monograph. The proposed revisions exceeded the scope of a Notifiable Change. The submission was therefore cancelled administratively by the sponsor (without prejudice to refiling), so as to be filed as a Supplemental New Drug Submission.
NC # 185130 2015-06-04 Issued No Objection Letter
2015-09-14		 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 Warnings and Precautions, Adverse Reactions, Drug Interactions, and Part III Consumer Information sections of the PM. The submission was reviewed and considered acceptable. A No Objection Letter was issued.
NDS # 179136 2014-10-24 Issued NOC under the NOC/c Guidance
2015-07-28		 New Drug Submission filed for the treatment of patients with previously treated mantle cell lymphoma. Regulatory Decision Summary published.
Drug product (DIN 02434407) market notification Not applicable Date of first sale:
2014-11-19		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS #174029 2014-04-17 Issued NOC
2014-11-17		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Imbruvica

Date SBD issued: 2015-03-18

The following information relates to the new drug submission for Imbruvica.

Ibrutinib, 140 mg, capsules, oral

Drug Identification Number (DIN):

  • 02434407

Janssen Inc.

New Drug Submission Control Number: 174029

 

On November 17, 2014, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product Imbruvica.

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 Imbruvica is favourable for the treatment of patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least one prior therapy, or for the frontline treatment of patients with CLL with 17p deletion. Clinical effectiveness of Imbruvica in the frontline setting is based on the benefit observed in CLL patients with 17p deletion who have received at least one prior therapy. Clinical trial data in the frontline setting are very limited.

1 What was approved?

Imbruvica, a Bruton's Tyrosine Kinase (BTK) Inhibitor, was authorized for the treatment of patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least one prior therapy, or for the frontline treatment of patients with CLL with 17p deletion.

Clinical effectiveness of Imbruvica in the frontline setting is based on the benefit observed in CLL patients with 17p deletion who have received at least one prior therapy. Clinical trial data in the frontline setting are very limited.

The safety and efficacy of Imbruvica in children and adolescents have not been evaluated.

Imbruvica is contraindicated in patients who have known hypersensitivity to ibrutinib or to any ingredient in the formulation or component of the container. Imbruvica was approved for use under the conditions stated in the Imbruvica Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Imbruvica (140 mg ibrutinib) is presented as hard gelatin capsules. In addition to the medicinal ingredient, the hard gelatin capsule contains croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The white capsule shell contains gelatin and titanium dioxide (E171). Capsules are printed with ink containing iron oxide black (E172) and shellac.

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

2 Why was Imbruvica approved?

Health Canada considers that the benefit/risk profile of Imbruvica is favourable for the treatment of patients with chronic lymphocytic leukemia (CLL), including those with 17p deletion, who have received at least one prior therapy, or for the frontline treatment of patients with CLL with 17p deletion.

Clinical effectiveness of Imbruvica in the frontline setting is based on the benefit observed in CLL patients with 17p deletion who have received at least one prior therapy. Clinical trial data in the frontline setting are very limited.

Chronic lymphocytic leukemia (CLL) is a hematologic cancer characterized by an accumulation of monoclonal mature B-cells (CD5+ CD23+) in the blood, bone marrow, and secondary lymph organs. The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines state that it is the most common form of adult leukemia in the Western world, with an incidence of 4 per 100,000 persons per year. The age-adjusted incidence rate of CLL in Canada as reported by the Alberta Health Services Clinical Practice Guideline for CLL (effective October 2014) is 7.5 per 100,000 persons per year.

The CLL cells in some patients have a deletion of part of the short arm of chromosome 17 (del17p). The del17p abnormality is associated with poor outcomes, with lower rates of progression-free survival (PFS) and overall survival (OS) in response to almost all treatments.

The benefit of Imbruvica in patients with CLL who received at least one prior therapy was demonstrated by efficacy results in the pivotal Phase III study, PCYC-1112-CA, and supported by data in the Phase II study, PCYC-1102-CA. The results of the pivotal study demonstrated that treatment with Imbruvica at a dose of 420 mg/day resulted in significant improvements in PFS, OS, and overall response rate (ORR) compared to ofatumumab. Robust results were obtained for the subgroup of patients with del17p, which were consistent with those observed in the overall patient population. Imbruvica can also be a beneficial treatment option in the frontline setting for patients with CLL with del17p. Cross-study comparison of efficacy outcomes in previously treated patients with del17p receiving Imbruvica from studies PCYC-1112-CA and PCYC-1102-CA are favourable when compared with outcomes reported in treatment-naïve or previously treated patients receiving the combination of fludarabine, cyclophosphamide, and rituximab (FCR).

In clinical studies, overall, Imbruvica had an acceptable safety profile in CLL patients.

In the pivotal study, diarrhea, fatigue, nausea, pyrexia, anemia, and neutropenia were the most common adverse events (AEs). Serious AEs included hemorrhagic events, infections, and cardiac events (atrial fibrillation).

The identified safety profile of Imbruvica in the supporting study was consistent with that identified in the Phase III study, despite the longer duration of treatment. Overall, rates for AEs as the primary reason for study drug discontinuation or dose reduction were low for Imbruvica, and most patients remained on treatment with Imbruvica at the time of the data cut-off for analysis. These observations support the conclusion that Imbruvica has a tolerable safety profile.

Identified safety concerns include major bleeding events, use in patients with moderate or severe hepatic impairment, and concomitant use of strong cytochrome P450 (CYP) 3A inhibitors. All of these are listed in a Serious Warnings and Precautions box in the Imbruvica Product Monograph.

The Imbruvica Product Monograph describes relevant information for each of the reported adverse events, and provides recommendations to the prescriber regarding dose modifications/interruptions that may be required to manage adverse events. Risk factors, when present, are described, and recommendations for monitoring are also provided. The Imbruvica Product Monograph is considered an appropriate measure for risk management of Imbruvica.

A Risk Management Plan (RMP) for Imbruvica was submitted by Janssen 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.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Imbruvica has been deemed appropriate and acceptable.

Overall, the benefit-risk assessment is positive for the specified indication. Imbruvica has been shown to be efficacious in patients with CLL, including those with 17p deletion, who have received at least one prior therapy, and based on the results in patients with 17p deletion is considered efficacious in the frontline treatment of patients with CLL with 17p deletion, for whom there is an unmet medical need.

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 Imbruvica?

The drug submission for Imbruvica was reviewed under the Priority Review Policy. Sufficient evidence was provided demonstrating Imbruvica provided an effective treatment of a disease for which no drug is presently marketed in Canada.

Submission Milestones: Imbruvica

Submission Milestone Date
Pre-submission meeting: 2014-03-13
Request for priority status  
Filed: 2014-03-13
Approval issued by Director: 2014-04-14
Submission filed: 2014-04-17
Screening  
Screening Acceptance Letter issued: 2014-05-21
Review  
Biopharmaceutics Evaluation complete: 2014-08-22
Quality Evaluation complete: 2014-10-16
Clinical Evaluation complete: 2014-11-17
Biostatistics Evaluation complete: 2014-09-04
Labelling Review complete: 2014-11-10
Notice of Compliance issued by Director General: 2014-11-17

The Canadian regulatory decision on the non-clinical and clinical review of Imbruvica was based on a critical assessment of the Canadian data package. As an added reference, Health Canada consulted the review reports from the United States Food and Drug Administration (FDA).

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 Imbruvica?

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 Imbruvica 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

Chronic lymphocytic leukemia (CLL) is a hematologic cancer characterized by an accumulation of monoclonal mature B-cells (CD5+ CD23+) in the blood, bone marrow, and secondary lymph organs. Non-clinical studies have shown that ibrutinib, the medicinal ingredient in Imbruvica, inhibits malignant B-cell proliferation and survival as well as cell migration and substrate adhesion.

Clinical Pharmacology

The clinical pharmacology program of ibrutinib included studies in healthy volunteers (mass balance, drug-drug interactions) and in patients with B-cell malignancies (repeated dose). A synoptic report of a pharmacokinetic study in subjects with hepatic impairment was also provided.

Results from these studies showed that ibrutinib is rapidly absorbed following an oral dose. Absolute bioavailability is low due to extensive first-pass metabolism. Ibrutinib is highly bound to plasma protein (98%). The mean terminal half-life of ibrutinib ranged from 4 to 10 hours. Exposure to ibrutinib is higher in patients with hepatic impairment and in patients who take a drug that inhibits CYP3A. Exposure to ibrutinib is also higher in patients ≥65 years of age when compared with those <65 years of age, and in patients who take food at the same time as Imbruvica.

Ibrutinib is extensively metabolised in the liver. Based on the preliminary results in a dedicated pharmacokinetic study, systemic exposures of total and unbound ibrutinib in subjects with various degrees of hepatic impairment were significantly increased. As hepatic impairment can lead to coagulopathy, the risk of bleeding associated with Imbruvica may be further increased. In order to mitigate the risks in this patient population, the Serious Warnings and Precautions box of the Imbruvica Product Monograph indicates that Imbruvica should not be used in patients with moderate or severe hepatic impairment. If the benefit outweighs the risk in a patient with mild hepatic impairment, a reduced dose to 140 mg of Imbruvica is recommended with close monitoring for toxicity.

Ibrutinib is metabolised primarily by the cytochrome P450 isozyme CYP3A. A dedicated drug-drug interaction study showed 29- and 26-fold increases in ibrutinib Cmax and AUC∞ (measurements of drug exposure), respectively, when concomitantly administered with ketoconazole, a strong inhibitor of CYP3A. A simulated physiologically-based pharmacokinetic model revealed up to 4-fold higher exposure of ibrutinib (at a reduced dose of 140 mg) when taken with ketoconazole when compared with that in patients administered 420 mg daily dose. In order to mitigate the safety risks associated with increased exposure, a statement is included in the Serious Warnings and Precautions box, and the Drug Interactions section of the Imbruvica Product Monograph was revised to include recommendations that Imbruvica should not be used concomitantly with a strong CYP3A inhibitor. If a strong inhibitor must be used, practitioners should consider withholding Imbruvica treatment for the duration of the inhibitor treatment.

The population PK analysis showed higher steady-state exposures of ibrutinib in patients of ≥65 years of age than those <65 years. The higher exposures are consistent with the clinical safety findings, that is (i.e.) severe, serious, and fatal adverse events occurred more frequently among elderly patients.

Administration with food increases the exposure of ibrutinib and the dihydrodiol metabolite exposures by approximately 2-fold. As the clinical efficacy and safety studies were conducted under modified fasting conditions, i.e., half an hour before or two hours after a meal, the differences in mean systemic exposures between the modified fasting and fasting, or fed conditions do not warrant a specific recommendation. Imbruvica can be administered with or without food.

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

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

Clinical Efficacy

The safety and efficacy of Imbruvica in patients with CLL who have received at least one prior therapy were demonstrated in one randomized, controlled study (PCYC-1112-CA), and one uncontrolled study (PCYC-1102-CA). The clinical data support the use of Imbruvica for the treatment of patients with CLL who have received at least one prior therapy and for the frontline treatment of patients with CLL with 17p deletion.

The pivotal study, PCYC-1112-CA, was a randomized, multicentre, open-label Phase III study of Imbruvica versus ofatumumab in 391 patients with previously treated CLL. Patients were eligible for the study if they failed to respond to prior therapy, relapsed following a response to prior therapy, or otherwise met the 2008 International Workshop on CLL (IWCLL) criteria for active disease requiring treatment following at least one prior therapy, and were not appropriate for treatment or retreatment with a purine analog. Patients were randomized 1:1 to receive either 420 mg Imbruvica daily or ofatumumab The primary efficacy endpoint of study PCYC-1112-CA was progression-free survival (PFS), as assessed by the study Independent Review Committee (IRC) using the 2008 IWCLL criteria. Overall survival (OS) and overall response rate (ORR, including both complete response and partial response) were evaluated as secondary endpoints. The evaluation of response in this study required CT scans for initial documentation of response as well as for confirmation of response. The treatment phase of the study was planned to extend from randomization until study drug discontinuation. Patients randomized to ofatumumab were to receive treatment for up to 6 months as per the package insert, and patients randomized to ibrutinib were to receive study drug daily until disease progression or until no longer tolerated by the patient. The study protocol specified that an interim analysis be conducted at approximately 117 PFS events and the final analysis was planned for 176 PFS events. The significance level for the interim analysis was to be determined based on the actual number of PFS events using O'Brien-Fleming boundary.

The patient population of PCYC-1112-CA had a median age of 67 years (range, 30 to 88 years), 68% were male, and 90% were Caucasian. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The median time since diagnosis was 91 months and the median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, 58% (225/391) of patients had at least one tumour ≥5 cm. Thirty-two percent (127/391) of patients had a deletion of the short arm of chromosome 17 (del17p) and 31% (122/391) had a deletion of the long arm of chromosome 11 (del11q).

At the time of the interim analysis, there were 146 PFS events; the monitoring boundary (O'Brien-Fleming) that corresponds to 146 PFS events was a p-value (two-sided) of <0.028 for superiority. The interim PFS result crossed the superiority boundary with a two-sided p-value <0.0001, and therefore it is considered as the final analysis for the study, based on the independent Data Monitoring Committee's recommendation. After a median duration of follow-up of 9.6 months in the Imbruvica group and 9.2 months in the comparator group, the study demonstrated statistically significant improvements in PFS, OS and ORR for Imbruvica compared with ofatumumab. For the primary endpoint of PFS, there was a 78% reduction in risk of progression or death (p <0.0001) in favour of Imbruvica; the hazard ratio (HR) and 95% confidence interval (95% CI) for PFS were HR = 0.22 (95% CI: 0.15; 0.32). Analysis of OS demonstrated a statistically significant 57% reduction in the risk of death [p = 0.005, HR = 0.43 (95% CI: 0.24; 0.79)] in favour of Imbruvica. The ORR was significantly higher (p<0.0001) for patients in the Imbruvica group (43%) compared with subjects in the ofatumumab group (4.1%). The amended study protocol allowed patients in the comparator group who experienced disease progression to cross over to Imbruvica and 57 patients randomized to ofatumumab received Imbruvica following disease progression.

The CLL cells in some patients have a deletion of part of the short arm of chromosome 17 (del17p). The del17p mutation is associated with poor outcomes, including lower rates of PFS and OS in response to almost all treatments, and is considered to be an important prognostic factor for this disease. Results for PFS and OS were robust and consistent across all subgroups analyzed, including patients with the del17p mutation. The HR for PFS was 0.25 for the subgroup of patients with del17p (p <0.0001), which was similar to the subgroup of patients without del17p (HR = 0.19, p <0.0001). The HR for OS was 0.46 for subjects with del17p (p = 0.064), which was similar to the subgroup of patients without del17p (HR = 0.42, p = 0.037).

The supportive study PCYC-1102-CA was an open-label, multicentre Phase II study that included multiple cohorts, including a cohort of 51 patients with a confirmed diagnosis of relapsed or refractory CLL who have failed at least 1 prior therapy. Patients received Imbruvica 420 mg once daily until disease progression or unacceptable toxicity. In this cohort, the median age was 68 (range, 37 to 82 years), median time since diagnosis was 80 months, and median number of prior treatments was 4 (range, 1 to 12 treatments). At baseline, 39% of patients had Rai Stage IV, 45% had bulky disease (at least one tumour ≥5 cm), 35% had del17p, and 31% had del11q.

The ORR was investigator-assessed according to the 2008 IWCLL criteria. At a median duration of follow up of 16.4 months, ORR was 78% (95% CI: 65%; 89%), median duration of response was not reached, and median (range) time to initial response was 1.8 months (1.4 to 12.2 months).

The supportive study PCYC-1102-CA also included a cohort that enrolled 31 patients with treatment-naïve disease, only 2 of whom were positive for the del17p mutation. Data from this cohort were the only clinical trial data available at the time of review, in which previously-untreated CLL patients (regardless of del17p status) were administered Imbruvica. However, as shown above, Imbruvica has shown significant efficacy in previously-treated patients with high-risk CLL (del17p) that frequently have poor outcomes with standard therapies, including the combination of fludarabine, cyclophosphamide, and rituximab (FCR).

During the original filing of this New Drug Submission, the sponsor originally sought approval for use in patients with small lymphocytic lymphoma (SLL) or CLL. While CLL and SLL are considered to be clinical manifestations of the same underlying disorder, their clinical presentations are different, and thus responses to treatment may not necessarily be the same. In the pivotal study, there were only 10 patients (5.1%) in the Imbruvica group and 8 (4.1%) in the comparator treatment group with a diagnosis of SLL. As a result the authorized indication does not include SLL.

In order to specify treatment of patients with the del17p mutation, it was important to verify that these patients could be accurately identified in Canada. Most of the recent prognostic studies have used fluorescent in situ hybridization (FISH) testing, and the Imbruvica clinical studies used FISH testing to determine the del17p status of patients. As FISH testing is available to most physicians treating patients with blood cancers in Canada, it is possible to identify patients with this mutation.

Based on the positive effect of Imbruvica on PFS in the setting of del17p, as well as the unmet medical need in previously untreated CLL patients with del17p, it was considered appropriate to extend the indication to the frontline setting specifically for patients with the del17p mutation. However, it is also important to emphasize the lack of robust clinical trial data for this patient subgroup; therefore, the indication was modified to specify that there are very limited clinical trial data in this setting.

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

Clinical Safety

The clinical safety of Imbruvica has been assessed in an integrated safety population of 504 Imbruvica-treated patients. The median duration of Imbruvica exposure in the pivotal study (PCYC-1112-CA) was 8.6 months (compared to 5.3 months for the ofatumumab group). The median duration of exposure to 420 mg Imbruvica among the 51 subjects with previously treated CLL in the supportive study (PCYC-1102-CA) was 15.6 months. In addition to the pivotal and supporting studies discussed in the Clinical Efficacy section above, supportive safety data included a Phase II study of patients with mantle cell lymphoma (MCL) receiving 560 mg Imbruvica daily, a cohort of patients in the supportive study PCYC-1102-CA using 840 mg Imbruvica daily, and a Phase I study of patients with B-cell lymphomas who received Imbruvica at various doses. Overall, the safety profile of Imbruvica identified from clinical studies was consistent regardless of the dose administered or the indication studied for each study. The data from the supportive study (PCYC-1102-CA) demonstrated a safety profile for Imbruvica that was consistent with that observed in the pivotal study despite the longer duration of treatment.

In the pivotal study PCYC-1112-CA, 195 patients received Imbruvica and 191 patients received the comparator ofatumumab. Diarrhea was the most frequently reported adverse event (48% of Imbruvica-treated patients), followed by fatigue (28%), nausea (26%), pyrexia (24%), anemia (23%), and neutropenia (22%). Grade 3 or 4 treatment emergent adverse events (TEAEs) were reported for 55% of patients in the Imbruvica group and 46% of patients in the ofatumumab group. The most common Grade 3/4 TEAEs (≥5%) were neutropenia (16% of Imbruvica-treated patients), pneumonia (10%), thrombocytopenia (6%) and anemia (5%). These TEAEs occurred at similar incidences in both treatment groups. The most common Serious Adverse Event was pneumonia in both groups. Approximately 4% of patients receiving Imbruvica in the study discontinued treatment due to adverse events, which included infections, diarrhea, atrial fibrillation, and subdural hematoma. Adverse events leading to dose reduction occurred in approximately 4% of patients taking Imbruvica.

Of the AEs reported, minor hemorrhagic events, including contusion, epistaxis, and petechiae, were reported in approximately half of the Imbruvica-treated patients. Major hemorrhagic events (Grade 3 or higher), including subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage, occurred in 3% of Imbruvica-treated patients. The mechanism for the bleeding events is not well understood. Due to the potentially serious nature of these events, hemorrhage is included in the Serious Warnings and Precautions box as well as the Warnings and Precautions section of the Imbruvica Product Monograph. As Imbruvica-treated patients using concomitant antiplatelet or anticoagulant agents had more minor bleeding events compared to those without these concomitant drugs, and because patients were excluded from participation in Imbruvica studies if they required warfarin or other vitamin K antagonists, warnings are also included that warfarin or other vitamin K antagonists should not be administered concomitantly with Imbruvica, and that Imbruvica should be used with caution in patients requiring other anticoagulants or medications that inhibit platelet function.

Atrial fibrillation was also identified as a concern, warranting inclusion in the Warnings and Precautions section of the Imbruvica Product Monograph. Patients treated with Imbruvica reported events of atrial fibrillation (including ≥Grade 3 events) and atrial flutter. Most patients reporting these AEs had cardiac risk factors, acute infections, and/or a previous history of atrial fibrillation; however,atrial fibrillation was more frequently reported in Imbruvica-treated patients (5%; Grade 3+4, 3%) compared to patients in the comparator arm (1%; Grade 3+4, 0%). Atrial flutter was reported in 1% of Imbruvica-treated patients (Grade 3+4, 0%) compared to 0% of patients in the comparator arm. Of the subjects who experienced atrial flutter, one also experienced atrial fibrillation. Additionally, many patients with CLL (the Imbruvica target patient population) may also have these cardiac risk factors, putting them at a higher risk of atrial fibrillation. The Imbruvica Product Monograph recommends monitoring of all patients for symptoms of atrial fibrillation.

Infections occurred in 64% of patients treated with Imbruvica, with Grade 3 or greater infections in 21% of patients, and fatal infections in 2% of patients. Most patients reporting infections, including those with fatal infections, also had neutropenia. Adverse events such as cytopenias and infections are common presentations of the underlying disease among patients with CLL, irrespective of treatment, and it is thus not always possible to determine whether such events are related to the study treatment. To manage this risk, the Imbruvica Product Monograph recommends that patients be monitored for fever, neutropenia, and infections, and appropriate anti-infective therapy instituted as indicated.

The following warnings are included in a Serious Warnings and Precautions box in the Product Monograph for Imbruvica:

  • Imbruvica should only be prescribed by a qualified physician who is experienced in the use of anti-cancer agents.
  • Major bleeding events have been reported.
  • Imbruvica should not be used in patients with moderate or severe hepatic impairment.
  • Imbruvica should not be used concomitantly with a strong CYP3A inhibitor.

Overall, Imbruvica presented an acceptable safety profile given the disease setting. Appropriate warnings and precautions are in place in the Imbruvica Product Monograph to address the identified safety concerns.

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

7.2 Non-Clinical Basis for Decision

Ibrutinib, the medicinal ingredient of Imbruvica, is a small molecule covalent inhibitor of Bruton's tyrosine kinase (BTK). The BTK enzyme is a signaling molecule of the B-cell antigen receptor (BCR) pathway, which is implicated in the pathogenesis of several B-cell malignancies, including CLL. In addition to its roles in antigen mediated BCR signaling, BTK is involved in signaling of chemokine receptors that play roles in B-cell trafficking and tissue homing. In vitro studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival as well as cell migration and substrate adhesion. Ibrutinib treatment of mice bearing B-cell lymphoma xenografts inhibited the tumour growth volume in a dose-dependent manner.

Non-clinical studies investigating the pharmacology, pharmacokinetics, and toxicity of ibrutinib were reviewed and determined to be acceptable. The effects of ibrutinib have been evaluated in a comprehensive toxicology program of studies covering all endpoints appropriate for the specified indication and patient population.

Ibrutinib is predominantly metabolized by CYP3A4 to oxidative metabolites in vitro and in vivo. Co-administration of ibrutinib with CYP3A4 inhibitors or inducers is expected to increase or decrease plasma concentrations of ibrutinib, respectively.

Ibrutinib inhibited P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transport in vitro. Ibrutinib may alter the gastrointestinal absorption of drugs which are P-gp and BCRP substrates. Ibrutinib may also inhibit BCRP in the liver and increase the plasma levels of drugs that undergo BCRP-mediated hepatic efflux.

In oral repeated-dose toxicity studies lymphoid organs (spleen, lymph nodes, thymus), non-glandular stomach, intestines, pancreas and bone were identified as target organs/tissues of toxicity. Changes in these target organs/tissues were either completely or partially reversible at dose levels where plasma exposure to ibrutinib was significantly higher than that observed clinically in CLL patients taking 420 mg Imbruvica daily.

In embryo-fetal development studies in animals, ibrutinib treatment was associated with increased post-implantation loss, increased visceral malformations of the heart and major blood vessels, and decreased fetal weights. Ibrutinib is considered to be teratogenic.

The non-clinical program supports the proposed indication of the treatment of patients with CLL, with or without the del17p mutation, who have received at least one prior therapy. The results of the non-clinical studies as well as the potential risks to humans have been included in the Imbruvica Product Monograph. In view of the intended use of Imbruvica, there are no toxicological issues based on the non-clinical program within this submission which preclude authorization of the product. Appropriate warnings and precautionary measures are in place in the Imbruvica Product Monograph to address the identified safety concerns.

For more information, refer to the Imbruvica 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 Imbruvica 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 24 months at 15-30°C is acceptable.

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

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

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

One excipient, in the capsule shell, gelatin, 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.

Report a problem or mistake on this page
Please select all that apply:
Date modified: