Summary Basis of Decision for Praxbind

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 Praxbind is located below.

Recent Activity for Praxbind

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 Praxbind

Updated:

2020-12-02

The following table describes post-authorization activity for Praxbind, a product which contains the medicinal ingredient, idarucizumab. 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.

  • DIN 02454343 - 50 mg/mL idarucizumab, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control numberDate submittedDecision and dateSummary of activities
NC # 2241092019-01-28Issued NOL
2019-04-18
Submission filed as a Level II (90 day) Notifiable Change to improve traceability of biological medicinal products. As a result, additions were made to the Dosage and Administration section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 2174832018-06-26Cleared
2019-01-15
Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-10-16 to 2018-04-15. The information was reviewed and found acceptable.
NC # 2193792018-08-27Issued NOL
2018-11-26
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes related to a release test for the drug substance. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 2164262018-05-29Issued NOC
2018-07-30
Submission filed as a Level I - Supplement to update the inner and outer labels. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS-C # 2074682017-07-26Issued NOC
2018-06-28
Submission filed as a Level I - Supplement to fulfill the commitment in the Letter of Undertaking dated 2016-03-28, issued for NDS # 182503. The SNDS filed final results from Study 1321.3 to verify Praxbind's reversal effect in patients and further demonstrate the clinical benefit. The overall benefit/risk profile of Praxbind is considered favourable in the targeted patient population. An NOC was issued and the conditions associated with NDS # 182503 are considered to have been met.
PBRER-C # 2122492017-12-22Cleared
2018-05-22
Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #4 for the period 2017-04-16 to 2017-10-15. The information was reviewed and found acceptable.
PBRER-C # 2069782017-06-27Cleared
2017-08-03
Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C #3 for the period 2016-10-16 to 2017-04-15. The information was reviewed and found acceptable.
PBRER-C # 2014612016-12-21Cleared
2017-03-03
Submission filed in response to commitments made as per the provisions of the NOC/c Guidance, PBRER-C for the period 2016-04-16 to 2016-10-15. The information was reviewed and found acceptable.
PBRER-C # 1964922016-06-27Cleared
2016-08-26
Submission filed in response to commitments made as per the provisions of the NOC/c Guidance, PBRER-C for the period 2015-10-16 to 2016-04-15. The information was reviewed and found acceptable.
Drug product (DIN 02454343) market notificationNot applicableDate of first sale:
2016-05-24
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 1825032015-03-04Issued NOC under NOC/c Guidance
2016-04-29
NOC issued under the NOC/c Guidance for NDS.
Summary Basis of Decision (SBD) for Praxbind

Date SBD issued: 2016-08-08

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

Idarucizumab, 50 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02454343

Boehringer Ingelheim Canada Ltd.

New Drug Submission Control Number: 182503

On April 29, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to Boehringer Ingelheim (Canada) Ltd for the drug product Praxbind. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

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 Praxbind is favourable as an antidote, specific for dabigatran, and is indicated for adult patients treated with Pradaxa when rapid specific reversal of the anticoagulant effects of dabigatran is required for:

1 What was approved?

Praxbind, a monoclonal antibody fragment, was authorized as an antidote, specific for dabigatran, and is indicated for adult patients treated with Pradaxa when rapid specific reversal of the anticoagulant effects of dabigatran is required for:

  • emergency surgery/urgent procedures
  • life-threatening or uncontrolled bleeding.

Praxbind has been issued marketing authorization with conditions, pending the final clinical trial results to verify its reversal effect in patients and promising evidence of clinical benefit. Patients should be advised of the nature of this authorization.

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

Praxbind (50 mg/mL, idarucizumab) is available as a sterile solution for bolus injection or intravenous infusion. It is supplied in glass vials each containing 2.5 g idarucizumab in 50 mL of an aqueous vehicle. In addition to the medicinal ingredient, the dosage form also contains acetic acid glacial, polysorbate 20, sodium acetate trihydrate, and water for injection.

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

2 Why was Praxbind approved?

Health Canada considers that the benefit/risk profile of Praxbind is favourable as an antidote, specific for dabigatran, and is indicated for adult patients treated with Pradaxa when rapid specific reversal of the anticoagulant effects of dabigatran is required for:

  • emergency surgery/urgent procedures
  • life-threatening or uncontrolled bleeding.

Praxbind was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Similarly to other anticoagulants, Pradaxa (dabigatran) is associated with a potential risk of severe and life-threatening bleeding. Currently, there is no specific antidote for dabigatran in Canada. Management of hemorrhage associated with dabigatran therapy is limited to supportive care, administration of blood or blood products and hemodialysis. Similarly, there are no alternative treatment options for patients who are receiving dabigatran therapy and requiring emergency surgery or procedures.

The active substance in Praxbind, idarucizumab, is a humanized monoclonal antibody fragment (Fab). A monoclonal antibody is a type of protein that has been designed to recognize and attach to a specific structure called an antigen. Praxbind works by attaching with high affinity to dabigatran and forming a complex in the blood. This rapidly stops dabigatran's anticoagulant effect.

The market authorization under conditions was based primarily on three Phase I clinical studies in healthy volunteers (Studies 1321.1, 1321.2 and 1321.5) and the interim analysis of an ongoing single arm case series study in patients (Study 1321.3).

In healthy volunteers treated with dabigatran etexilate, administration of 5 g idarucizumab resulted in an immediate reduction of unbound dabigatran in plasma and a rapid, complete and durable reversal of the anticoagulant effect of dabigatran measured by established coagulation parameters. A limited number of female subjects, elderly and subjects with renal impairment were evaluated.

The interim analysis of an ongoing single arm case series study in dabigatran-treated patients with life-threatening/uncontrolled bleeding or requiring emergency surgery/procedures also showed a complete reversal in more than 89% of the patients treated with 5 g idarucizumab. Re-elevation of unbound dabigatran was observed in 21% of the patients between 2 and 24 hours after administration of 5 g idarucizumab, with corresponding elevation of coagulation parameters. No serious bleeding events resulted from the re-elevation in coagulation parameters. The study is still ongoing, and the final results are pending.

In healthy volunteers (either treated with Pradaxa or not treated), the frequency of adverse events (AEs) between Praxbind-treated subjects (24.6%) versus (vs.) placebo-treated subjects (24.8%) was overall similar. The most common AE reported in both Praxbind-treated and placebo-treated subjects was headache (8.4% vs. 5.7%). No serious adverse events were reported. The immunogenicity of Praxbind appeared to be low in healthy subjects.

Special safety concerns obtained in 123 patients include:

  • the reversal of the anticoagulation effect of dabigatran without re-start of anticoagulation therapy exposes patients to the thrombotic risk of their underlying diseases;
  • re-elevation of coagulation parameters may lead to re-bleeding;
  • there is a potential risk of serious adverse reactions due to sorbitol excipient in the patients with hereditary fructose intolerance; and
  • possible hypersensitivity reactions.

The immunogenicity of idarucizumab in the target patient population appeared to be low. The safety database is currently limited for the target patient populations who are elderly, in emergency situations, with multiple co-morbidities/organ dysfunctions and receiving multiple concomitant medications, and with anticipated high mortality in case of life-threatening or emergency medical conditions.

A Risk Management Plan (RMP) for Praxbind was submitted by Boehringer Ingelheim (Canada) Ltd. 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 Praxbind has been deemed acceptable.

Overall, the therapeutic benefits seen in the three Phase I studies and the ongoing Phase III case series study are promising and the benefits of Praxbind therapy are considered to outweigh the potential risks. Praxbind has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Praxbind Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring of the use of Praxbind will be ongoing. Further evaluation will take place upon the submission of the requested studies after they become available.

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 Praxbind?

Praxbind (idarucizumab) New Drug Submission (NDS) was initially filed under the Notice of Compliance with Conditions (NOC/c). The efficacy and safety assessments (with the target clinical dose) relied largely on the results obtained from three Phase I studies in healthy volunteers. While complete reversal of the dabigatran-induced anticoagulation effects was reported in all healthy volunteers, limited information was provided from these three studies.

In addition, while the patient outcomes provided supportive evidence for the benefit of Praxbind, as observed by the reversal of the dabigatran-induced anticoagulation effects, it was determined by Health Canada that the number of patients available was too small to allow for an adequate assessment. Furthermore, the safety profile is different for healthy volunteers (a relatively young population with minimal disease at baseline) as compared to the target patient populations who are elderly, with multiple co-morbidities and either bleeding or in need of emergency intervention. As such, the risk of Praxbind in the target patient populations cannot be predicted from the safety profiles in healthy volunteers. Consequently, the data submitted in the NDS was considered insufficient to conduct an adequate benefit/risk assessment for the proposed indication for Praxbind.

During the review cycle, additional efficacy and safety data became available. A Notice of Deficiency (NOD) was issued on August 14, 2015 to bring these data into the review process for a proper risk/benefit assessment. The response to the NOD was received on August 28, 2015 and accepted into review on September 8, 2015. On April 29, 2016, the sponsor was issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance, in recognition of the promising but unconfirmed evidence of clinical effectiveness in the submission. In keeping with the provisions of the NOC/c Guidance, the sponsor has agreed to provide the final report upon completion of Study 1321.3 to confirm the overall clinical benefit (see What follow-up measures will the company take? section).

Submission Milestones: Praxbind

Submission MilestoneDate
Pre-submission meeting:2015-01-14
Request for priority status
Filed:2015-02-19
Acceptance of Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance:2015-02-26
Submission filed:2015-03-04
Screening 1
Screening Deficiency Notice issued:2015-03-30
Response filed:2015-04-22
Screening Acceptance Letter issued:2015-05-19
Review 1
Quality Evaluation complete:2015-05-19
Clinical Evaluation complete:2015-05-19
Notice of Deficiency (NOD) issued by Director General, Biologics and Genetic Therapies Directorate (efficacy and safety issues):2015-08-14
Response filed:2015-08-28
Screening 2
Screening Acceptance Letter issued:2015-09-08
Review 2
On-Site Evaluations:
Quality Evaluation complete:2016-03-23
Clinical Evaluation complete:2016-04-27
Labelling Review complete:2016-01-18
Notice of Compliance with Conditions (NOC/c) Qualifying Notice issued:2016-03-24
Response filed (Letter of Undertaking):2016-03-28
Notice of Compliance (NOC) issued by Director General, Biologics and Genetic Therapies Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance:2016-04-29

The Canadian regulatory decision on the non-clinical and clinical review of Praxbind was based on a critical assessment of the Canadian data package. For parts of the quality (chemistry and manufacturing), non-clinical, and clinical review, foreign reviews from both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) were used as 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?

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, in order to confirm the clinical benefit of Praxbind, the sponsor has agreed to provide final results from the ongoing clinical study 1321.3 entitled "A Phase III, case series clinical study of the reversal of the anticoagulant effects of dabigatran by intravenous administration of 5 g idarucizumab (BI 655075) in patients treated with dabigatran etexilate who have uncontrolled bleeding or require emergency surgery or procedures (RE-VERSE AD [A study of the RE-VERSal Effects of Idarucizumab on Active Dabigatran] trial)" as confirmatory data.

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

Idarucizumab (medicinal ingredient in Praxbind) is a humanized monoclonal antibody fragment (Fab) with high affinity for the oral direct thrombin inhibitor dabigatran. Idarucizumab has been developed as a reversal agent for the anticoagulant effect of dabigatran to which there is no antidote currently available on the market. Idarucizumab binds to dabigatran with very high affinity, that is approximately 300-fold more potent than the binding affinity of dabigatran for thrombin.

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Praxbind for the recommended indication.

When idarucizumab is administered intravenously, it encounters dabigatran at a level that is effectively at steady-state between the central and the extravascular space.

As an antibody fragment, idarucizumab is a larger entity than dabigatran and has an estimated volume of distribution of 5-8 L, which suggests that unlike dabigatran, it does not distribute extensively to the peripheral tissues. Its concentration over time indicates a rapid distribution and elimination phase (half-life of 45 minutes) with a decline to less than 20% of its peak concentration 2 hours after administration (terminal half-life of about 10 hours). The elimination of unchanged idarucizumab in the urine is estimated to be about 36.1% for a dose of 5 g.

The interaction of idarucizumab and dabigatran upsets the existing steady-state levels for the unbound form of both drugs due to the effective elimination of the unbound form of dabigatran by idarucizumab in the central compartment. In the process of re-establishing a new steady state, unbound dabigatran from the peripheral tissues enters the plasma. The shift of unbound dabigatran from peripheral tissues to plasma may contribute to the observed re-elevation of dabigatran in plasma of some patients and corresponding re-elevation of the coagulation parameters within 24 hours following administration of idarucizumab in the patient study.

Immediately after the administration of idarucizumab, the plasma concentration of unbound dabigatran was reduced by more than 99%. This reduction in unbound dabigatran resulted in an immediate, complete and sustained reversal of the anticoagulant effect induced by dabigatran.

In a subset of patients (number of patients [n] = 19 of 90; 21%), recurrence of plasma levels of unbound dabigatran and concomitant elevation of clotting tests was observed, possibly due to re-distribution of dabigatran. This occurred 2-24 hours after administration of idarucizumab mainly at time-points ≥12 hours. These re-elevations were not associated with any bleeding, except for one patient with a mild urethral bleed.

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

Clinical Efficacy

The clinical efficacy of Praxbind was evaluated primarily based on three Phase I trials (Studies 1321.1, 1321.2, and 1321.5) conducted in 283 healthy volunteers and one ongoing Phase III case series study (Study 1321.3) which included interim efficacy data for 123 patients.

Studies in Healthy Volunteers

Three randomised, double-blind, placebo-controlled Phase I studies in 283 subjects (224 treated with idarucizumab) were conducted to assess the safety, efficacy, tolerability, pharmacokinetics and pharmacodynamics of idarucizumab, given alone or after administration of dabigatran etexilate. The investigated population included 6.7% (19/283) females, 10.6% (30/283) subjects 65 years or older and 6.4% (18/283) subjects with renal deficiencies (CrCL<80 mL/min). The doses of idarucizumab received ranged from 20 mg to 8 g. Thirty-five (35) subjects received the target clinical dose of 5 g idarucizumab.

The efficacy of Praxbind was evaluated in a central laboratory by diluted Thrombin Time (dTT) and Ecarin Clotting Time (ECT). Thrombin Time (TT), and activated Partial Thrombin Time (aPTT) were also measured in the central laboratory. All subjects that were pre-treated with dabigatran and had post-Praxbind/placebo measurements of coagulation parameters were included in the evaluation of the efficacy points.

Results obtained demonstrated that administration of 5 g idarucizumab resulted in an immediate reduction of unbound dabigatran in plasma and a rapid and complete reversal of anticoagulant effect of dabigatran measured by dTT, ECT and aPTT. The effects lasted the entire observation period of over 24 hours. The rate of clearance of idarucizumab was reduced in subjects with renal impairment. However, age, gender, race, body weight and mild or moderate renal deficiencies did not appear to affect the reversal effect.

Ongoing Single Arm Case Series Study in Patients

A prospective, open-label, non-randomized, uncontrolled study (RE-VERSE AD, 1321.3) is currently ongoing to investigate the treatment of adult patients who presented with dabigatran-related life-threatening or uncontrolled bleeding (Group A) or who required emergency surgery or urgent procedures (Group B). The primary endpoint is the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, based on central laboratory determination of dTT or ECT. A key secondary endpoint is the restoration of hemostasis.

An interim analysis included data for 123 patients: 66 patients (37 male/29 female) with serious bleeding (Group A) and 57 patients (28 male/29 female) who required an urgent procedure (Group B). The median age was 77 years (range 48-93 years) and the median creatinine clearance was 55 mL/min (11-193 mL/min). Approximately 67% of patients in Group A and 63% of patients in Group B had been treated with dabigatran 110 mg twice daily. Results of central laboratory evaluations of efficacy were available for a subset of 90 patients (51 in Group A, 39 in Group B).

Most patients (>89%), in both Groups A and B, achieved complete reversal of the anticoagulant effect of dabigatran as measured by dTT or ECT in the first 4 hours after administration of 5 g idarucizumab. Reversal effects were evident immediately after administration.

These results were further supported by secondary assessments, aPTT and TT, which were also measured at the central laboratory. In addition, aPTT was measured at local laboratories. The duration of complete reversal lasted up to 12 to 24 hours in approximately 80% of the patients. Re-elevation of unbound dabigatran was observed in 21% of the patients within 2 and 24 hours following administration of 5 g Praxbind with corresponding elevations of coagulation parameters.

There were 22 out of 90 patients who had dTT values in the normal range already at baseline, of whom 9 patients also had ECT values in the normal range at baseline. Consequently, a reversal of anticoagulant effect could not be evaluated for these patients.

Indication

The sponsor filed this New Drug Submission (NDS) for Praxbind with the following indication:

Praxbind (idarucizumab) is an antidote specific for dabigatran and is indicated in patients treated with Pradaxa (dabigatran etexilate) when rapid specific reversal of the anticoagulant effects of dabigatran is required:

  • for emergency surgery/urgent procedures
  • in life-threatening or uncontrolled bleeding

The approved indication by Health Canada is as follows:

Praxbind (idarucizumab), is an antidote specific for dabigatran and is indicated for adult patients treated with Pradaxa (dabigatran etexilate) when rapid specific reversal of the anticoagulant effect of dabigatran is required for:

  • emergency surgery/urgent procedures
  • life-threatening or uncontrolled bleeding

Praxbind has been issued a marketing authorization with conditions, pending the final clinical trial results to verify its reversal effect in patients and promising evidence of clinical benefit. Patients should be advised of the conditional nature of the authorization.

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

Clinical Safety

The clinical safety of Praxbind was evaluated in 224 healthy subjects from the three Phase I studies as well as 123 patients from the ongoing case series study (these studies are described in the Clinical Efficacy section).

Safety in Healthy Volunteers

The intensity of adverse events (AEs) in healthy volunteers from all three Phase I studies (Studies 1321.1, 1321.2, and 1321.5) was assessed as mild, with similar frequencies between subjects treated with Praxbind (55/224; 25%) and placebo-treated subjects (16/105; 25%). Very few subjects had AEs of moderate intensity and none of the AEs during the treatment period was classified as severe.

The most common AE reported in both Praxbind and placebo-treated subjects was headache (8.4% vs. 5.7%). No serious adverse events were reported. The immunogenicity of Praxbind appeared to be low in healthy subjects. Re-dosing with 2.5 g Praxbind in six healthy subjects aged 44 to 64 years two months after the first administration did not reveal considerable difference in safety, including allergic reactions.

Safety in Patients

In the interim analysis of the ongoing single arm case series study (Study 1321.3), a total of 123 dabigatran-treated patients were administered Praxbind, either because they required an emergency surgery or urgent procedure, or because they presented with a life-threatening or uncontrolled bleeding event.

Of the total 123 patients, AEs reported in ≥5% of patients were hypokalemia (7%), delirium (7%), constipation (7%), pyrexia (6%), and pneumonia (6%). Of the total, 26 (20%) patients died during the study, 11 (9%) within the first day after Praxbind dosing; each of these deaths could be attributed either to a complication of the index event or to co-morbidities. For the reported AE, no causal relationship to Praxbind treatment could be established.

Thrombotic events were reported in 5 (4%) patients, none of which were on antithrombotic therapy at the time of the event, and in each of these cases, the thrombotic event could be attributed to the underlying medical condition of the patient.

Mild symptoms of potential hypersensitivity (pyrexia, bronchospasm, hyperventilation, rash or pruritus) were reported. A causal relationship to Praxbind could not be established.

Special safety concerns obtained in 123 patients include:

  • reversal of anticoagulation effect of dabigatran without re-start of anticoagulation therapy exposes patients to the thrombotic risk of their underlying diseases;
  • re-elevation of coagulation parameters may lead to re-bleeding;
  • there is a potential risk of serious adverse reactions due to sorbitol excipient in the patients with hereditary fructose intolerance; and
  • possible hypersensitivity reactions.

The safety database is currently limited for the target patient populations who are elderly, in emergency situations, with multiple co-morbidities/organ dysfunctions, receiving multiple concomitant medications, and with anticipated high mortality in case of life-threatening or emergency medical conditions.

Immunogenicity

Serum samples from 283 healthy volunteers (224 treated with Praxbind) were tested for antibodies to Praxbind before and after treatment.

Pre-existing antibodies with cross-reactivity to Praxbind were detected in low titers in 13% (36/283, 224 treated with Praxbind) of the subjects. Treatment-emergent anti-Praxbind antibodies in low titres were detected in 4% (9/224) of the subjects. In a subgroup of six subjects, Praxbind was administered a second time, two months after the first administration. No anti-Praxbind antibodies were detected in these subjects prior to the second administration. In one subject, treatment-emergent anti-Praxbind antibodies were detected after the second administration. No impact on the pharmacokinetics or the reversal effect of Praxbind and no hypersensitivity reactions were observed in these subjects.

As the Praxbind submission was evaluated under the Notice of Compliance with Conditions (NOC/c) Guidance, additional safety data will be assessed when the final report upon completion of Study 1321.3 is submitted.

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

7.2 Non-Clinical Basis for Decision

The anticoagulant activity of dabigatran was successfully reversed by idarucizumab (the medicinal ingredient in Praxbind) in vitro and in vivo in rats, mice, monkeys, and pig models. Idarucizumab reduced dabigatran-induced anticoagulation and blood loss in murine intracranial hemorrhage, rat tail cut bleeding and pig blunt liver trauma models. Idarucizumab did not interact with other anticoagulants, antiplatelet agents and coagulation factors, or volume expanders (for example [e.g.], crystalloids, colloids and re-transfusion of washed red blood cells) in swine. Fifty-percent (50%) hemodilution with routinely used volume replacement strategies did not influence its neutralization of dabigatran anticoagulant activity.

No significant idarucizumab-related respiratory events were observed up to doses of 500 mg/kg idarucizumab in rats and monkeys or in monkeys when combined with 12 mg/kg dabigatran. There were no notable findings in cardiovascular assessments in two-week repeat dose toxicity studies in monkeys.

No idarucizumab-related adverse effects were observed up to doses of 500 mg/kg idarucizumab administered intravenously in Rhesus monkeys and rats for up to two and four weeks, respectively. Significant findings were limited to the expected pharmacological activity when dabigatran etexilate was co-administered.

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

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

7.3 Quality Basis for Decision

Praxbind contains idarucizumab, which is a special type of protein called a monoclonal antibody fragment. Idarucizumab is a specific antidote to dabigatran (Pradaxa). Praxbind acts by binding to dabigatran and its metabolites and reverses their anticoagulant effects. Idarucizumab is biosynthesized in cell substrate engineered by recombinant deoxyribonucleic acid (DNA) techniques from a Chinese hamster ovary (CHO) cell line.

Characterization of the Drug Substance

Detailed characterization studies were performed to provide assurance that idarucizumab (medicinal ingredient in Praxbind) consistently exhibits the desired characteristic structure and biological activity. Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Idarucizumab (the drug substance) is biosynthesized in cell substrate engineered by recombinant DNA techniques from a CHO cell line. Idarucizumab is purified by a series of chromatographic, filtration, and chemical treatment steps that are designed and validated to remove specific impurities, including viruses. The drug substance is filtered, dispensed into containers, and stored frozen until further processing. All processing steps involved in the manufacturing of the drug substance have been evaluated and the appropriate ranges for process parameters have been established. The manufacturing process is considered to be adequately controlled within justified limits.

The process for the manufacture of the drug product (Praxbind) includes thawing of bottles containing the formulated bulk, pooling and mixing, sterile filtration and aseptic filling. The aseptic filling of vials is followed by their capping, visual inspection, packaging and storage. The manufacturing process performance was validated at the commercial scale to establish the overall consistency and effectiveness of aseptic operations. The performance of the manufacturing process is routinely monitored by in-process testing against justified acceptance criteria.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of idarucizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The quality of the drug substance (idarucizumab) is assessed against respective release specifications, which incorporates tests to assess identity, purity, potency, and relevant characteristics of the drug substance. The associated analytical methods were validated or qualified and the acceptance criteria were appropriately justified. The provided batch analysis data confirm that the proposed manufacturing process consistently yields drug substance of acceptable quality.

The quality of Praxbind drug product lots is routinely assessed against a release specification, which incorporates tests to assess relevant characteristics of the dosage form, the identity, purity, and potency of the reconstituted active ingredient, excipient composition and conformance with compendial requirements. The associated analytical methods were validated or qualified, and the acceptance criteria were appropriately justified. The provided batch analysis data confirm that the proposed manufacturing process consistently yields drug product of acceptable quality.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed shelf-life of 30 months at 2°C-8°C for Praxbind is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.

An On-Site Evaluation (OSE) of the facilities involved in the manufacture and testing of Praxbind was waived as a successful OSE had been recently performed.

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

Adventitious Agents Safety Evaluation

Materials of animal origin were used early in the development of the cell substrate and were subjected to appropriate risk assessment. No materials of human or animal origin are used in the manufacture of Praxbind.