Summary Basis of Decision for Defitelio

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 Defitelio is located below.

Recent Activity for Defitelio

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

Post-Authorization Activity Table (PAAT) for Defitelio

Updated: 2025-07-30

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

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

Drug Identification Numbers (DIN):

  • DIN 02465981 - 80 mg/mL defibrotide, solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 283785 2024-02-20 Issued NOC 2024-10-25 Submission filed as a Level I – Supplement for a change to a drug product manufacturing facility and for a change in fill volume. The information was reviewed and considered acceptable and an NOC was issued.
SNDS #  223259 2018-12-21 Issued NOC 2019-12-04 Submission filed as a Level I – Supplement to update the PM with new safety and efficacy data from IND study 2006-05. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Serious Warnings and Precautions Box, Indications and Clinical Use, Warnings and Precautions, Adverse Reactions, Dosage and Administration, Action and Clinical Pharmacology, and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package insert. An NOC was issued.
Drug product (DIN 02465981) market notification Not applicable Date of first sale:
2017-09-06		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 200808 2016-12-09 Issued NOC
2017-07-10		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Defitelio

Date SBD issued: 2017-09-08

The following information relates to the New Drug Submission for Defitelio.

Defibrotide (defibrotide sodium)
80 mg/mL, solution, intravenous

Drug Identification Number (DIN):

  • 02465981

Jazz Pharmaceuticals Ireland Ltd.

New Drug Submission Control Number: 200808

 

On July 10, 2017, Health Canada issued a Notice of Compliance to Jazz Pharmaceuticals Ireland Limited for the drug product Defitelio.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Defitelio is favourable for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) therapy.

 

1 What was approved?

 

Defitelio, an antithrombotic agent, was authorized for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) therapy.

Clinical studies of Defitelio did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

The safety and effectiveness of Defitelio in pediatric patients (≥1 month to <16 years of age) were established in clinical trials in pediatric patients with severe hepatic VOD following HSCT.

Defitelio is contraindicated for:

  • Concomitant administration with systemic anticoagulant or fibrinolytic therapy.
  • Patients who are hypersensitive to the medicinal ingredient or to any ingredient in the formulation or component of the container.

Defitelio was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Defitelio (80 mg/mL defibrotide, also called defibrotide sodium) is presented as a solution. In addition to the medicinal ingredient, the solution contains sodium citrate dihydrate, hydrochloric acid and/or sodium hydroxide 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 Defitelio Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Defitelio approved?

 

Health Canada considers that the benefit-risk profile of Defitelio is favourable for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) therapy.

Hepatic veno-occlusive disease (VOD) occurs most often after HSCT as a serious and potentially fatal complication of the myeloablative conditioning regimens that are used for HSCT. The condition is the result of damage to sinusoidal endothelial cells which leads to the obstruction of hepatic sinusoids and typically is seen within 30 days after HSCT. The clinical presentation of severe forms of hepatic VOD is usually accompanied by multi-organ dysfunction. If left untreated, hepatic VOD with multi-organ dysfunction is associated with a mortality rate greater than 80%. There are no currently approved therapies to treat hepatic VOD in Canada. Defitelio has been available in Canada for prevention and treatment of hepatic VOD through the Health Canada's Special Access Program since 2010.

Defibrotide, the medicinal ingredient in Defitelio, is a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue. The mechanism of action of defibrotide has not been fully elucidated; however, non-clinical data suggest that defibrotide stabilizes endothelial cells by reducing endothelial cell activation and by protecting endothelial cells from further damage, resulting in the restoration of thrombo-fibrinolytic balance.

The market authorization of Defitelio was based on clinical efficacy and safety data derived from one pivotal study (Study 2005-01) and three supportive studies (Study 99-118, Study 2006-05, and a Center for International Blood and Marrow Transplant Research [CIBMTR] Registry Study).

The observed survival rate at Day +100 after HSCT in Study 2005-01 was 38% in the Defitelio group and 25% in the historical control group. Study 99-118 demonstrated a Day +100 post-HSCT survival rate of 44%. In Study 2006-05, the Day +100 post-HSCT survival rate was 45%. The CIBMTR Registry Study demonstrated a survival rate of 39% in the Defitelio group and 31% in the supportive care group at Day +100 after HSCT. The observed survival rates at Day +100 following HSCT across all four studies in patients treated with Defitelio ranged from 38% to 45% and were higher than the survival rates in the historical control group, the CIBMTR Registry Study supportive care group, and those reported in the literature (<20%).

The observed clinical benefits of Defitelio were weighed against inconclusive statistical findings based on limitations in the pivotal study design and the methodologies for data analysis. The clinical benefits were also considered in light of the severity and rareness of hepatic VOD with multi-organ failure, its high mortality rate, and the lack of approved therapies.

A high rate of adverse reactions has been observed in patients being treated for hepatic VOD with multi-organ dysfunction using the proposed dose schedule of Defitelio. Hemorrhage, hypersensitivity, and pharmacologic interaction with anticoagulants and fibrinolytic therapies are the main safety concerns. These safety concerns have been appropriately addressed in a Serious Warnings and Precautions box and the Warnings and Precautions section of the Defitelio Product Monograph. In addition, concomitant administration of Defitelio with systemic anticoagulant or fibrinolytic therapy is contraindicated.

In order to ensure that the benefits continue to outweigh the potential risks, as part of the marketing authorization for Defitelio, Health Canada requested that the sponsor agree to several commitments to be addressed post-market (see What follow-up measures will the company take?).

A Risk Management Plan (RMP) for Defitelio was submitted by Jazz Pharmaceuticals Ireland Limited 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 Defitelio was accepted.

Overall, based on the available safety and effectiveness data, the lack of alternative treatment and the high mortality of severe hepatic VOD following HSCT, the therapeutic benefits of Defitelio are considered to outweigh the potential risks in the target patient population. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Defitelio 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 Defitelio?

 

The drug submission for Defitelio was reviewed under the Priority Review Policy. The sponsor has provided sufficient evidence to demonstrate that Defitelio is intended for the treatment of a serious, life-threatening, or severely debilitating disease for which no other drug is currently marketed in Canada, and to demonstrate a significant increase in efficacy over off-label products for hepatic veno-occlusive disease/sinusoidal obstructive syndrome with multi-organ failure.

 

Submission Milestones: Defitelio

Submission Milestone Date
Pre-submission meeting: 2015-11-03
Request for priority status  
Filed: 2016-10-07
Approval issued by Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, Biologics and Genetic Therapies Directorate: 2016-11-07
Submission filed: 2016-12-09
Screening  
Screening Acceptance Letter issued: 2017-01-11
Review  
Quality Evaluation complete: 2017-06-28
Clinical Evaluation complete: 2017-07-10
Review of Risk Management Plan complete: 2017-05-25
Labelling Review complete, including Look-alike Sound-alike brand name assessment: 2017-06-28
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: 2017-07-10

 

The Canadian regulatory decision on the non-clinical and clinical review of Defitelio was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was 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?

 

As part of the marketing authorization for Defitelio, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) the following:

  • The sponsor will provide Health Canada with Periodic Benefit-Risk Evaluation Reports (PBRER) as per schedule and format accepted by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) (e.g., six-monthly report for the first three years following approval, and an annual report thereafter).
  • Should the EMA consider that the outcomes of the post-authorization safety study (PASS) have not been attained, the sponsor will include Canadian patients who will receive Defitelio therapy in the European veno-occlusive disease (VOD) Registry.
  • Should the EMA consider that the outcomes of the PASS have indeed been attained and the European VOD Registry can be discontinued, the sponsor will provide Health Canada with the report on the final data from the Registry. Additionally, the sponsor will submit to Health Canada the totality of data to be provided from experience with Defitelio to date, including data from the European registry studies, PBRERs, and final 2006-05 study, in addition to the data to be gained from the ongoing global 15-007 study on prevention of VOD (with sites in Canada).

 

5 What post-authorization activity has taken place for Defitelio?

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 decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

The PAAT for Defitelio 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

The mechanism of action of defibrotide (defibrotide sodium), the medicinal ingredient in Defitelio, has not been fully elucidated. In vitro data support a role for defibrotide sodium in both endothelial cell protection and the restoration of the thrombo-fibrinolytic balance. In vitro, defibrotide sodium enhances the enzymatic activity of plasmin to hydrolyze fibrin clots. Studies evaluating the pharmacological effects of defibrotide sodium on endothelial cells were conducted primarily in the human microvascular endothelial cell line. In vitro, defibrotide sodium increased tissue plasminogen activator and thrombomodulin expression, and decreased von Willebrand factor and plasminogen activator inhibitor-1 expression, thereby reducing endothelial cell activation and increasing endothelial cell-mediated fibrinolysis. Defibrotide sodium protected endothelial cells from damage caused by chemotherapy, tumor necrosis factor-α, serum starvation, and perfusion.

The clinical pharmacological data support the use of Defitelio for the specified indication.

The pharmacokinetic characterization of defibrotide was based on the following information:

  • Data from a radiolabelled study in healthy subjects using [125I]-defibrotide (Study IRI-151612), in vitro studies using human biomaterial, and information presented in the literature to support the absorption, distribution, metabolism and excretion profile of defibrotide.
  • Results from three studies with pharmacokinetic data collected (Studies R09-1425, DFPK 99-118, and DF VOD-2012-03-PKRen).
  • A population analysis for covariates effect on defibrotide pharmacokinetics.

Literature information and the sponsor's in vivo and in vivo data suggest that defibrotide is highly bound to human plasma proteins and has a volume of distribution similar to plasma volume. Defibrotide does not undergo hepatic metabolism, and it does not interact with the known drug metabolizing enzymes or uptake transporters. Defibrotide is mainly eliminated through degradation by exonucleases, with only 10% to 14% of the administered dose excreted as parent drug. The elimination half-life of defibrotide is less than 2 hours.

Pharmacokinetic results from the Phase II dose-finding study (Study DFPK 99-118, number of patients, n = 49) showed that the exposure of defibrotide increased in a less than dose-proportional manner in patients with severe hepatic veno-occlusive disease (VOD) after hematopoietic stem-cell transplantation (HSCT) within an intravenous dose range of 2.5 mg/kg to 10 mg/kg (administered via 2-hour infusion, every 6 hours). Following a 2-hour infusion of 6.25 mg/kg defibrotide (Study VOD-2012-03-PKRen, n = 18), defibrotide exposure (area under the concentration-time curve to the time of the last quantifiable plasma concentration, AUC0-t, and AUC extrapolated to infinity, AUC0-∞ was approximately 50% to 60% greater in patients with severe end-stage renal disease (ESRD) than that observed in healthy matching subjects. The elimination half-life of defibrotide was 0.5 hours and 0.2 hours for the ESRD patients and subjects with normal renal function, respectively. No accumulation of defibrotide was observed following repeated infusion administrations in renally impaired subjects (Study DF VOD-2012-03 PKRen) or patients with hepatic VOD following HSCT (Study DFPK 99-118). Results from the electrocardiogram (ECG) trial (Study R09-1425, n = 52) showed that defibrotide has no effect on heart rate, atrioventricular conduction, or cardiac depolarization following a single therapeutic (6.25 mg/kg) or supratherapeutic (15 mg/kg) dose of defibrotide in healthy subjects.

A population pharmacokinetic analysis was conducted by the sponsor based on pooled data comprising 1,360 concentrations determined in 83 subjects from the three pharmacokinetic studies. However, the data was not sufficient to assess the effect of factors such as disease status, age, race, and organ impairment on the pharmacokinetics of defibrotide. No pharmacokinetic data was collected from the pivotal trial 2005-01. Formal pharmacokinetic exposure-response relationship could not be assessed due to limited defibrotide concentration data available for patients with hepatic VOD.

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

Clinical Efficacy

The clinical efficacy of Defitelio for the treatment of severe hepatic VOD with renal or pulmonary dysfunction following HSCT therapy was evaluated in one pivotal study (Study 2005-01) and three supportive studies (Study 99-118, Study 2006-05, and a Center for International Blood and Marrow Transplant Research [CIBMTR] Registry Study).

Pivotal Study

The pivotal Study 2005-01 was an open-label, historical control study used to determine the safety and efficacy of 25 mg/kg/day Defitelio in patients with severe hepatic VOD with renal or pulmonary dysfunction following HSCT therapy. The study was conducted worldwide in 35 bone marrow transplantation institutes, including four in Canada. Patients in the Defitelio group received Defitelio at a dose of 6.25 mg/kg every 6 hours, with a total daily dose of 25 mg/kg for a minimum of 21 days or until resolution of the hepatic VOD. The study enrolled 102 patients with hepatic VOD with multi-organ failure in the Defitelio group. There were 44 pediatric patients who were older than one month and younger than 16 years of age. The historical control group was comprised of 32 patients selected from a time period 5 to 10 years before the treatment period. While the use of a historical control is common in cases of rare diseases where a control group cannot be established (as it is the case with the severe hepatic VOD), the Health Canada review noted that this historical control group was subject to multiple potential sources of bias, and differed from the treatment group in baseline demographics and the required sample size.

The primary endpoint for Study 2005-01 was survival rate at Day +100 following HSCT in patients who received Defitelio compared to the historical control group. Secondary and supportive endpoints included the complete response (CR) rate by Day +100 post-HSCT (defined as total bilirubin <2 mg/dL, with resolution of associated organ dysfunction by Day +100 post-HSCT), survival at Day +180 post-HSCT, and overall survival post-HSCT (defined as mortality status at the date of last contact).

The observed survival rate at Day +100 after HSCT in the Defitelio group was 38.2% as compared to 25% in the historical control group. The study report showed a clinically meaningful 23% difference in rate using the propensity score and weighted estimate. Of note, the Health Canada biostatistical review of the submitted pivotal study data does not concur with the methodology used for data analysis (see Overall Conclusions on Clinical Efficacy Data).

The CR rate in the Defitelio group was 25.5% as compared to 12.5% in the historical control group. The survival rates at Day +180 after HSCT were 32% in the Defitelio group and 25.0% in the historical control group.

Subgroup analyses, which are generally considered exploratory and not used for confirmatory results, showed that pediatric patients had a higher percentage of survival at Day +100 after HSCT than adults (50% vs. 29%, respectively) as well as a higher percentage of CR than adults (36.4% vs. 17.2%, respectively). Children between ages 2 and 12 years had a better CR compared to infants/toddlers and adolescents (58.8%, 11.8% and 40.0%, respectively).

Supportive Studies

Three supportive studies, Study 99-118, Study 2006-05, and a Center for International Blood and Marrow Transplant Research (CIBMTR) Registry Study were included in the efficacy analysis.

Study 99-118 was a randomized, open-label, dose-finding, multicentre Phase II study to determine the efficacy and safety of two dose levels of defibrotide in adult and pediatric patients with severe hepatic VOD following HSCT. The study also examined pharmacokinetic and pharmacodynamic parameters in a subset of patients treated with defibrotide.

Study 2006-05 is an ongoing Phase III, multicentre, single-arm, open-label expanded access study designed to collect additional usage, tolerability, and safety data from patients with a diagnosis of hepatic VOD with or without organ dysfunction.

The CIBMTR Registry Study was an analysis from patient records in 54 transplant centers in the Unites States designed to provide additional, supportive efficacy data independent of Study 2005-01.

Results from the three supportive studies align with the results from the pivotal study. Study 99-118 showed a Day +100 post-HSCT survival rate of 44%. In Study 2006-05, the Day +100 post-HSCT survival rate was 45%. The CIBMTR Registry Study demonstrated a survival rate of 39% in the Defitelio group and 31% in the supportive care group at Day +100 after HSCT. Across all four studies, the survival rates at Day +100 following HSCT were higher than the survival rates in the historical control group, the CIBMTR Registry Study supportive care group, and those reported in the literature (<20%).

Overall Conclusions on Clinical Efficacy Data

Given the particular design of the pivotal trial, which included historical controls, Health Canada's biostatistics evaluation raised concerns regarding the validity of the propensity score adjusted analysis used by the sponsor. The evaluation also underlined the uncertainty of the treatment effect estimates when varying propensity defined methods were used to analyze the primary efficacy results. Consequently, Health Canada's biostatistics evaluation considers the biostatistics results of the pivotal trial inconclusive.

Despite the limitations in the pivotal study design and the statistical methodologies applied, Health Canada's clinical evaluation concluded that the Day +100 post-HSCT survival rates across all studies in patients treated with Defitelio ranged from 38% to 45%. Such results show a clinically meaningful benefit of Defitelio in the target patient population. This conclusion takes into account the totality of data provided in the submission, and concurs with review conclusions of other major drug regulatory authorities.

Indication

The New Drug Submission for Defitelio was filed by the sponsor with the following indication:

  • Defitelio (defibrotide) solution for intravenous infusion is indicated for the treatment of severe hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), in hematopoietic stem-cell transplantation (HSCT) therapy.
  • It is indicated in adults and in adolescents, children and infants over 1 month of age.

To ensure safe and effective use of the product and accurately reflect the patient target population, Health Canada authorized the following indication:

  • Defitelio (defibrotide sodium) solution for intravenous infusion is indicated for the treatment of adult and pediatric patients with hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), with renal or pulmonary dysfunction following hematopoietic stem-cell transplantation (HSCT) therapy.

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

Clinical Safety

The safety of Defitelio was examined in 176 adult and pediatric patients with hepatic VOD with pulmonary and/or renal dysfunction following HSCT who received the therapy at the recommended dose of 25 mg/kg/day in Study 2005-01 and Study 99-118 (described in the Clinical Efficacy section). The median age of the safety population was 25 years (range: 1 month to 72 years), and 63% were ≥17 years of age. Patients were excluded from these studies if, at time of study entry, they had significant acute bleeding or hemodynamic instability, acute graft-versus-host disease, or required the use of medications that could increase the risk of hemorrhage. At study entry, 13% were dialysis dependent and 18% were ventilator dependent. Defitelio was administered for a median of 21 days (range: 1 to 83 days).

The most common adverse reactions (incidence ≥10% and independent of causality) were hypotension, diarrhea, vomiting, nausea, and epistaxis.

The most common serious adverse reactions (incidence ≥5% and independent of causality) were hypotension (11%) and pulmonary alveolar hemorrhage (7%). Hemorrhage events of any type and any grade were reported for 104 (59%) of the patients, and the events were grade 4-5 in 35 (20%) of the patients.

Less common adverse reactions (incidence <1%) included disorders of the gastrointestinal, nervous, reproductive, and respiratory systems, and of the skin and subcutaneous tissue.

Adverse reactions leading to permanent discontinuation (derived from information available for 102 patients) included: pulmonary alveolar hemorrhage in 5 (5%) patients; pulmonary hemorrhage, hypotension, catheter site hemorrhage, and multi-organ failure, each in 3 (3%) patients; and cerebral hemorrhage and sepsis, each in 2 (2%) patients.

The incidence of both pulmonary alveolar hemorrhage and pulmonary hemorrhage were greater in pediatric patients than in adults (15% and 9% vs. 5% and 1%, respectively). However, the rates for any type of hemorrhage were similar (58.5% for pediatric patients and 56.8% for adults). Hemorrhagic adverse events that led to death occurred in 9% of Defitelio patients and in 6% of historical control patients.

Overall, the safety data support an acceptable safety profile for Defitelio at its recommended dose and schedule in both pediatric and adult patients in the context of the sought indication for the treatment of severe hepatic VOD, with renal or pulmonary dysfunction following HSCT. The identified safety concerns, particularly the increased risk of hemorrhage and the need for closely monitoring of patients for signs and symptoms of hemorrhage during treatment with Defitelio, have been appropriately highlighted in a Serious Warnings and Precautions box and the Warnings and Precautions section of the Defitelio Product Monograph. Furthermore, concomitant administration of Defitelio with systemic anticoagulant or fibrinolytic therapy is contraindicated.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical toxicology studies conducted to support the development of Defitelio include 13-week studies with intravenous infusion of Defitelio in rats and dogs. Study results showed a prolonged activated partial thromboplastin time in dogs and an increased prothrombin time in rats. These findings were observed at doses at least 6 times higher than the clinical dose of 25 mg/kg/day. Based on the dose-dependent response observed, the effects on the activated partial thromboplastin time and prothrombin time may be due to direct effects of Defitelio on coagulation.

Developmental toxicity of Defitelio was assessed in rats and rabbits. Defitelio showed maternal toxicity by inducing a high rate of hemorrhagic abortion when infused intravenously at all dose levels tested, including doses close to the human dose. Additionally, the mean number of implantations was lower and the post-implantation loss was increased in the Defitelio group compared to the control group.

The embryo-fetal and pre- and postnatal non-clinical findings were addressed in the Special Populations section of the Defitelio Product Monograph to reflect the potential risks to pregnant women. The use of Defitelio during pregnancy is not recommended.

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

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

 

 

7.3 Quality Basis for Decision

 

Defibrotide sodium, the medicinal ingredient of Defitelio, is a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotide sodium salts derived from porcine intestinal tissue. It has a mean weighted molecular weight of 13-20 kDa, and a potency of 27-39 and 28-38 biological units per mg as determined by two separate assays measuring the release of a product formed by contact between defibrotide sodium, plasmin and a plasmin substrate. The chemical name of defibrotide sodium is polydeoxyribonucleotide sodium salt.

The mechanism of action of defibrotide sodium has not been fully elucidated. Non-clinical data suggest that defibrotide stabilizes endothelial cells by reducing endothelial cell activation and by protecting endothelial cells from further damage, which results in the restoration of thrombo-fibrinolytic balance.

Characterization of the Drug Substance

Due to the very large number of individual components of different lengths and sequences in the drug substance, it is not possible to determine the sequence of the collective polydeoxyribonucleotides. The polydisperse nature of the drug substance hampers its characterization by standard methods. For example, when defibrotide is analyzed using sub-2 micron particle reversed-phase high-performance liquid chromatography (RP-HPLC) or by capillary gel electrophoresis, only a smear is produced. In addition, mass spectrometry analysis yields a multitude of peaks that are hard to distinguish from one another. Consequently, the sponsor used alternative methods to characterize the drug substance. The methods focused on demonstrating the structural similarity with deoxyribonucleic acid (DNA) and confirming the predominantly single-stranded nature of the drug substance. Furthermore, the characterization methods confirmed the polydisperse and anionic nature of the drug substance.

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

The manufacture of the drug substance is comprised of two distinct phases. The first phase is the preparation of liquid nucleic acids. The biological starting material for the liquid nucleic acids is porcine mucosa obtained from slaughter houses and preserved in acetic acid. The mucosa is subjected to treatments to remove the fat and insoluble impurities as well as potential adventitious viral contaminants. The DNA fraction is separated out via column chromatography, then washed and concentrated by ultrafiltration. The extracted DNA is then further purified by removing the soluble impurities from the DNA fraction to produce liquid nucleic acids. The second phase involves the conversion of the liquid nucleic acids into defibrotide by depolymerization, additional adventitious agent clearance steps, purification, drying, and declumping.

The drug product is supplied as a sterile aqueous solution in a single-use, clear glass vial. Each single vial contains 200 mg/2.5 mL (concentration of 80 mg/mL) defibrotide sodium. The solution also contains sodium citrate dihydrate and water for injection. Hydrochloric acid and/or sodium hydroxide may have been used for pH adjustment. Prior to infusion, defibrotide needs to be diluted with either 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, to a concentration of 4 mg/mL to 20 mg/mL depending on the individual patient's baseline weight (weight prior to the preparative regimen for the HSCT).

The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are appropriately validated and considered to be adequately controlled within justified limits.

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

Control of the Drug Substance and Drug Product

The majority of the specifications for the drug substance were set based on historical and stability data while taking into consideration manufacturing and analytical variability. The specifications for the drug substance including the biological assays are considered acceptable. The specifications for the drug product were based on historical lots of the drug product and have been updated over the course of time. The specifications are considered acceptable.

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 36-month shelf life at 15ºC-30ºC for the drug product is considered acceptable.

The proposed packaging and components are considered acceptable.

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 facility involved in the manufacture and testing of the drug substance was not conducted as the facility was not in production during the review period.

An On-Site Evaluation (OSE) of the facility involved in the manufacture and testing of the drug product was not warranted since the facility had been previously evaluated and received a satisfactory rating, and there were no issues with the facility, either reported or identified in the review.

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

Adventitious Agents Safety Evaluation

To minimize the potential of adventitious agents being present, only animals from specified slaughterhouses, which comply with local and national regulations for products of animal origin intended for human consumption, may be used to manufacture the porcine intestinal mucosa. Additionally, the animals come from herds that are monitored for signs of disease and testing is performed ante and post-mortem.

The manufacturing process has several steps that have been shown to sufficiently inactivate enveloped viruses, non-enveloped viruses, and viruses known to infect swine. There are two additional steps in the drug substance manufacturing process with the potential to inactivate viruses which have not been formally validated. The validated measures are considered acceptable for the removal of potential viral agents.

 

Date modified: