Summary Basis of Decision for Redesca/Redesca HP

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 Redesca/Redesca HP is located below.

Recent Activity for Redesca/Redesca HP

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 Redesca/Redesca HP

Updated: 2024-05-22

The following table describes post-authorization activity for Redesca/Redesca HP, which contain the medicinal ingredient enoxaparin 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 Number (DIN):

DIN 02509075 (Redesca) - 30 mg/0.3 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
DIN 02509083 (Redesca) - 40 mg/0.4 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
DIN 02509091 (Redesca) - 60 mg/0.6 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
DIN 02509105 (Redesca) - 80 mg/0.8 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
DIN 02509113 (Redesca) - 100 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)
DIN 02509121(Redesca) - 300 mg/3 mL (100 mg/mL), solution, subcutaneous or intravenous administration (multiple-dose vial)
DIN 02509148 (Redesca HP) - 120 mg/0.8 mL (150 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
DIN 02509156 (Redesca HP) - 150 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 282598

2024-01-05

Issued NOL 2024-04-05

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the supplier for a primary container closure component and a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 279592

2023-10-03

Issued NOL 2024-02-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in specification for the materials. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 270468

2022-12-07

Issued NOL 2023-04-03

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 266014

2022-07-12

Issued NOL 2022-10-17

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 259929

2021-12-23

Issued NOC 2022-08-11

Submission filed as a Level I – Supplement for the addition of a drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 259505

2021-12-13

Issued NOC 2022-05-31

Submission filed as a Level I – Supplement for labelling updates to the blister pack containing the pre-filled syringe. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 254498

2021-07-07

Issued NOC 2022-02-22

Submission filed as a Level I – Supplement for the addition of an alternate drug substance manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued.

Drug product (DINs 02509075, 02509083, 02509091, 02509105, 02509113, 02509121, 02509148, 02509156) market notification

Not applicable

Date of first sale:

2021-04-09

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NDS No. 231767

2019-09-20

Issued NOC:

2020-12-07

NOC issued for New Drug Submission.
 
Summary Basis of Decision (SBD) for Redesca/Redesca HP

Date SBD issued: 2021-07-12

The following information relates to the New Drug Submission for Redesca/Redesca HP.

Enoxaparin sodium

Drug Identification Number (DIN):

  • DIN 02509075 (Redesca) 30 mg/0.3 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02509083 (Redesca) 40 mg/0.4 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02509091 (Redesca) 60 mg/0.6 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02509105 (Redesca) 80 mg/0.8 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02509113 (Redesca) 100 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02509121(Redesca) 300 mg/3 mL (100 mg/mL), solution, subcutaneous or intravenous administration (multiple-dose vial)
  • DIN 02509148 (Redesca HP) 120 mg/0.8 mL (150 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02509156 (Redesca HP) 150 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)

Shenzhen Techdow Pharmaceutical Co., Ltd.

New Drug Submission Control Number: 231767

 

On December 7, 2020, Health Canada issued a Notice of Compliance to Shenzhen Techdow Pharmaceutical Co., Ltd for Redesca and Redesca HP, biosimilar biologic drugs to Lovenox and Lovenox HP (the reference biologic drugs). The terms “biosimilar biologic drug” and “biosimilar” are used by Health Canada to describe subsequent entry versions of a Canadian approved innovator biologic drug with demonstrated similarity to a reference biologic drug. Biosimilars were previously referred to as subsequent entry biologics in Canada. Redesca and Redesca HP contain the medicinal ingredient enoxaparin sodium, which has been demonstrated to be highly similar to enoxaparin sodium contained in the reference products, Lovenox and Lovenox HP.

Authorization of a biosimilar means that it is highly similar to the reference biologic drug in terms of quality and that there are no clinically meaningful differences in efficacy and safety between the two products. For a biosimilar, the weight of evidence is provided by the structural and functional studies. The non-clinical and clinical programs are designed to address potential areas of residual uncertainty. A final determination of similarity is based on the entire submission, including data derived from comparative structural, functional, non-clinical, pharmacodynamic and pharmacokinetic, and clinical studies. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug in the indications being sought.

For more information on the authorization of biosimilars, refer to the Health Canada website on Biosimilar Biologic Drugs.

Within this drug submission, the sponsor requested authorization of Redesca and Redesca HP for all of the indications that are currently authorized for Lovenox and Lovenox HP, the reference biologic drugs. Similarity between Redesca/Redesca HP and Lovenox/Lovenox HP was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The market authorization was based on the quality (chemistry and manufacturing) package submitted, as well as demonstrated similarity between the biosimilar and the reference biologic drug. Similarity was established through data derived from comparative structural, functional, non-clinical, and clinical studies. Based on Health Canada’s review, the benefit-risk profile of Redesca/Redesca HP is considered to be similar to the benefit-risk profile of the reference products, and it is therefore considered favourable for the following indications:

  • The prophylaxis of thromboembolic disorders (deep vein thrombosis) in patients undergoing:
    • orthopedic surgery of the hip or knee. In addition, Redesca is indicated in hospital or after hospital discharge for long-term prevention of venous thromboembolic diseases following hip replacement surgery.
    • high-risk abdominal, gynecological, or urological surgeries.
    • colorectal surgery.
  • The prophylaxis of deep vein thrombosis in medical patients who are at moderate risk of deep vein thrombosis and who are bedridden due to moderate to severe acute cardiac insufficiency (New York Heart Association [NYHA] class III or IV heart failure), acute respiratory failure revealing or complicating chronic respiratory insufficiency not requiring ventilatory support and acute respiratory infections (excluding septic shock), who require short-term prophylaxis of deep vein thrombosis.
  • The prevention of thrombus formation in the extracorporeal circulation during hemodialysis.
  • The treatment of deep vein thrombosis, with or without pulmonary embolism.
  • The treatment of unstable angina or non-Q-wave myocardial infarction, concurrently with acetylsalicylic acid.
  • The treatment of acute ST-segment elevation myocardial infarction, including patients to be managed medically or with subsequent percutaneous coronary intervention.

 

1 What was approved?

 

Redesca and Redesca HP are biosimilars to Lovenox and Lovenox HP (hereafter referred to as Redesca and Lovenox, respectively).

Redesca is an antithrombotic agent authorized for the following indications:

  • The prophylaxis of thromboembolic disorders (deep vein thrombosis) in patients undergoing:
    • orthopedic surgery of the hip or knee. In addition, Redesca is indicated in hospital or after hospital discharge for long-term prevention of venous thromboembolic diseases following hip replacement surgery.
    • high-risk abdominal, gynecological, or urological surgeries.
    • colorectal surgery.
  • The prophylaxis of deep vein thrombosis in medical patients who are at moderate risk of deep vein thrombosis and who are bedridden due to moderate to severe acute cardiac insufficiency (New York Heart Association [NYHA] class III or IV heart failure), acute respiratory failure revealing or complicating chronic respiratory insufficiency not requiring ventilatory support and acute respiratory infections (excluding septic shock), who require short-term prophylaxis of deep vein thrombosis.
  • The prevention of thrombus formation in the extracorporeal circulation during hemodialysis.
  • The treatment of deep vein thrombosis, with or without pulmonary embolism.
  • The treatment of unstable angina or non-Q-wave myocardial infarction, concurrently with acetylsalicylic acid.
  • The treatment of acute ST-segment elevation myocardial infarction, including patients to be managed medically or with subsequent percutaneous coronary intervention.

Both Redesca and the reference biologic drug, Lovenox, contain the medicinal ingredient enoxaparin sodium. Enoxaparin sodium is the sodium salt of enoxaparin, a mixture of low molecular weight fragments of heparin sodium obtained by alkaline depolymerization of the benzyl ester of heparin sodium. The heparin sodium is obtained from porcine intestinal mucosa.

Similarity between Redesca and Lovenox has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, and a comparative clinical pharmacodynamic study in healthy volunteers in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

The safety and effectiveness of enoxaparin sodium in children have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

Evidence from clinical studies and experience suggests that use of enoxaparin sodium in the geriatric population is associated with differences in safety or effectiveness.

Redesca is contraindicated for use in:

  • patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container
  • newborns or premature neonates, because the drug product in a multiple-dose vial contains benzyl alcohol as a preservative
  • patients with
    • history of confirmed or suspected immunologically mediated heparin-induced thrombocytopenia (delayed-onset severe thrombocytopenia), within the past 100 days, or in patients in whom an in vitro platelet-aggregation test in the presence of enoxaparin is positive (circulating antibodies)
    • acute or subacute bacterial endocarditis
    • active bleeding
    • major blood clotting disorders
    • active gastric or duodenal ulcer
    • hemorrhagic cerebrovascular accident (except if there are systemic emboli)
    • severe uncontrolled hypertension
    • diabetic or hemorrhagic retinopathy
    • other conditions or diseases involving an increased risk of hemorrhage
    • injuries to and operations on the brain, spinal cord, eyes and ears

Furthermore, spinal/epidural anesthesia is contraindicated where repeated doses of Redesca (1 mg/kg every 12 hours or 1.5 mg/kg once daily) are required, due to an increased risk of bleeding.

Redesca 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.

This biosimilar biologic drug is presented as a solution with two different concentrations: 100 mg/mL enoxaparin sodium (Redesca) and 150 mg/mL (high potency) enoxaparin sodium (Redesca HP). In addition to the medicinal ingredient, the solution in the single-dose prefilled syringe contains water for injection. The solution in the multiple-dose vial contains 300 mg of enoxaparin sodium in 3 mL of water for injection (concentration 100 mg/mL) and 45 mg (15 mg/mL) of benzyl alcohol as a preservative.

For more information, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.

Additional information may be found in the Redesca/Redesca HP Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Redesca/Redesca HP approved?

 

Health Canada considers that the benefit-risk profile of Redesca/Redesca HP (hereafter referred to as Redesca) is similar to that of the reference biologic drug, Lovenox/Lovenox HP (hereafter referred to as Lovenox). Therefore, the benefit-risk profile of Redesca is favourable for the prevention of venous thromboembolic disease, treatment of deep vein thrombosis, treatment of unstable angina and non-Q-wave myocardial infarction concurrently with acetylsalicylic acid, and treatment of acute ST-segment elevation myocardial infarction. Similarity between Redesca and Lovenox was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Redesca (enoxaparin sodium) is the sodium salt of enoxaparin, a mixture of low molecular weight fragments of heparin sodium, obtained by alkaline depolymerization of the benzyl ester of heparin sodium. The heparin sodium is obtained from porcine intestinal mucosa. Enoxaparin has antithrombotic properties. It potentiates preferentially the inhibition of coagulation factors Xa and IIa and only slightly affects other hemostatic mechanisms such as clotting time. The antithrombotic effect of enoxaparin is well correlated to the inhibition of coagulation factor Xa.

Based on an extensive analytical and biological similarity assessment of Redesca, in conjunction with comparative non-clinical data and comparative clinical pharmacodynamic data, the sponsor sought authorization for each of the indications held by the Canadian reference product, Lovenox.

Following review of the submitted data, the biosimilar and the reference enoxaparin sodium were judged highly similar in terms of quality attributes as assessed in the comparative structural and functional studies. A single-dose comparative pharmacodynamic study demonstrated pharmacodynamic similarity between Redesca and the reference enoxaparin sodium in healthy volunteers.

The safety profile of Redesca (including the risk of bleeding-related adverse events) is considered to be comparable to that which has been established for the reference biologic drug, Lovenox. The Adverse Reactions section of the Redesca/Redesca HP Product Monograph is based on the clinical experience with the reference biologic drug. Appropriate warnings and precautions are in place in the Redesca/Redesca HP Product Monograph to address the identified safety concerns.

Adverse reactions reported during the post-marketing use of enoxaparin sodium (including heparin-induced thrombocytopenia, a severe immune-mediated thrombocytopenia) are also listed in the Redesca/Redesca HP Product Monograph.

A Risk Management Plan (RMP) for Redesca was submitted by Shenzhen Techdow Pharmaceutical Co., 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 names, Redesca and Redesca HP, were accepted.

Based on an assessment of the relevant information provided in the submission, Redesca is considered to have a benefit-risk profile similar to that established for the claimed indications, which are currently held by the reference product, Lovenox. Therefore, the benefit-risk balance for Redesca is considered favourable for the same indications, doses, and routes of administration authorized for Lovenox.

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 Quality (Chemistry and Manufacturing), Non-clinical, and Clinical and Basis for Decision sections.

 

3 What steps led to the approval of Redesca/Redesca HP?

 

Submission Milestones: Redesca/Redesca HP

Submission Milestone Date
Submission filed 2019-09-20
Screening  
Screening Acceptance Letter issued 2019-11-07
Review  
Quality Evaluation complete 2020-08-31
Review of Risk Management Plan complete 2020-10-27
Non-Clinical Evaluation complete 2020-12-02
Clinical/Medical Evaluation complete 2020-12-07
Labelling Review complete 2020-12-07
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2020-12-07

 

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

The onus is on the sponsor to monitor the post-market safety profile of this biosimilar product as well as the Product Monograph of the reference biologic drug for safety signals that could affect the biosimilar and to make safety updates to the Redesca/Redesca HP Product Monograph as appropriate. New safety issues that are first identified with the biosimilar, the reference biologic drug, or other biologics that share a common medicinal ingredient may or may not have relevance to both the biosimilar and the reference biologic drug. For more information, refer to the Fact Sheet: Biosimilars.

 

5 What post-authorization activity has taken place for Redesca/Redesca HP?

 

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 life cycle.

The PAAT for Redesca/Redesca HP 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 Quality Basis for Decision

 

Redesca and Redesca HP (hereafter referred to as Redesca) were developed as biosimilars to the reference biologic drugs, Lovenox and Lovenox HP (hereafter referred to as Lovenox). For biosimilars, the weight of evidence is provided by structural and functional studies. Biosimilars are manufactured to the same regulatory standards as other biologic drugs. In addition to a typical chemistry and manufacturing data package that is submitted for a standard new biologic drug, biosimilar submissions include extensive data demonstrating similarity with the reference biologic drug.

Comparative Structural and Functional Studies

The reference product chosen for the biosimilarity assessment was Clexane, authorized in the European Union. Clexane is the same enoxaparin sodium product as Lovenox, and both are produced by the same manufacturer. Clexane was considered a suitable proxy for the reference product Lovenox as it met all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Adequate data have been provided to support the sponsor’s conclusion that Redesca is highly similar to Clexane with respect to the heparin sodium source material and mode of depolymerization, general physicochemical properties, structural characteristics, impurities profile, in vitro biological activity, and stability profile.

Characterization of the Drug Substance

Enoxaparin sodium is the sodium salt of enoxaparin, a mixture of low molecular weight fragments of heparin sodium, obtained by alkaline depolymerization of the benzyl ester of heparin sodium. The heparin sodium is obtained from porcine intestinal mucosa. Enoxaparin sodium consists of a complex set of oligosaccharides that have not yet been completely characterized. The majority of the components have a 4-enopyranose uronate structure at the non-reducing end of their chain. About 15% to 25% of the components have a 1,6-anhydro structure at the reducing end of their chain. The average molecular weight of enoxaparin sodium is approximately 4,500 daltons (range: 3,800 to 5,000 daltons).

Detailed characterization studies were performed to provide assurance that enoxaparin sodium consistently exhibits the desired characteristic structure and biological activity. Sufficient data have been provided to demonstrate comparability of enoxaparin sodium produced on each of the drug substance manufacturing lines.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established and acceptable limits.

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

The starting material for the drug substance manufacturing process is heparin sodium, which is prepared from crude heparin derived from pooled porcine intestinal mucosa. Following salification and esterification steps, the resulting heparin benzyl ester undergoes depolymerization by alkaline hydrolysis to yield crude enoxaparin sodium. Subsequently, the crude enoxaparin sodium is purified and lyophilized to obtain the final drug substance.

The drug product manufacturing process involves dissolving the drug substance in water for injection, sterile filtration, aseptic filling into syringes and vials using isolator technology, visual inspection, and secondary packaging. The manufacturing of multi-dose vials includes the extra step of adding benzyl alcohol as a preservative at the outset of production.

Sufficient data were provided from the process validation studies to demonstrate that the manufacturing processes are consistent, reproducible, and generate a drug substance and a drug product that are uniform in quality and in compliance with a defined quality profile.

Control of the Drug Substance and Drug Product

The release specifications for the drug substance are supported by sufficient data and the test methods used are either compendial or validated. Batch analysis data met specifications and were consistent among the process validation lots.

Redesca and Redesca HP are Schedule D (biologic) drugs and are, therefore, subject to Health Canada’s Lot Release Program as per Health Canada’s Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

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 satisfactory.

The stability data support the proposed shelf life of 36 months for the Redesca and Redesca HP drug products, when stored below 25 °C.

Facilities and Equipment

Due to the coronavirus disease 2019 (COVID-19) pandemic and travel restrictions at the time of the review, Health Canada could not conduct an on-site evaluation of the drug substance and drug product manufacturing facilities. Therefore, the suitability of the facilities was evaluated by a thorough review of additional documentation provided upon Health Canada’s request.

The design, operations, and controls of the facilities and equipment involved in production are considered suitable for the activities and products manufactured. The sites involved in production are compliant with Good Manufacturing Practices.

Adventitious Agents Safety Evaluation

Acceptable control measures are incorporated in the manufacturing process of enoxaparin sodium to prevent contamination and maintain microbial control. Purification process steps designed to inactivate any potential viral contaminants are adequately validated. Bioburden testing and bacterial endotoxin testing are integrated in the control strategy and meet relevant guidelines and requirements.

No animal-derived raw material other than the heparin sodium from porcine intestinal mucosa is used for the production of enoxaparin sodium. According to the published literature, pigs are not naturally susceptible to transmissible spongiform encephalopathy (TSE) infection via the oral route. Therefore, they are not considered a TSE-relevant animal species. The sourcing of porcine intestinal mucosa is controlled to prevent cross-contamination of the starting material with bovine, ovine or caprine tissues.

 

7.2 Non-Clinical Basis for Decision

 

For biosimilars, the degree of similarity at the quality level determines the scope and the breadth of the required non-clinical data. Non-clinical studies serve to complement the structural and functional studies and address potential areas of residual uncertainty.

In the submitted non-clinical dataset for Redesca, Clexane (authorized in the European Union) was used as the reference product. Clexane is considered a suitable proxy for the reference product Lovenox as per the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Results of an in vitro comparative study showed that both the inhibitory activity against the coagulation factor Xa (anti-FXa activity) and the anti-FIIa activity generally overlapped between Redesca and Clexane.

The immunogenic comparability of Redesca with Clexane was indirectly evaluated in five in vitro antigenicity studies, which compared Redesca and Clexane in terms of platelet factor 4 (PF4)-enoxaparin binding, PF4-enoxaparin complex particle size, PF4 antiparallel β-sheet structure contents, and peripheral blood mononuclear cells (PBMC) activation. Redesca and Clexane showed similar in vitro binding affinity to PF4 and similar in vitro immune activation using human PBMC. Based on these results, the immunogenicity potential of Redesca is expected to be similar to that of Clexane.

The non-clinical dataset submitted for Redesca was in compliance with the requirements for non-clinical studies of biosimilars defined in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

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

 

 

7.3 Clinical basis for decision

 

For biosimilars, the purpose of the clinical program is to demonstrate that there are no clinically meaningful differences between the biosimilar and the reference biologic drug. The structural complexity of the biologic drug and availability of a relevant and sensitive pharmacodynamic endpoint determine the scope and the breadth of the required clinical data. Accordingly, the clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

Comparative Pharmacodynamics

A randomized, open-label, single-dose, two-way crossover study was conducted in healthy volunteers to evaluate the pharmacodynamic parameters of Redesca (40 mg/0.4 mL) and Clexane (40 mg/0.4 mL), following subcutaneous administration of a single dose of 40 mg of the assigned study drug. Clexane (authorized in the European Union) met all of the requirements set forth in the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document to be considered a suitable proxy for Lovenox authorized in Canada.

The study included 20 healthy adult subjects (10 subjects in each treatment sequence: Redesca followed by Clexane or Clexane followed by Redesca). A washout period of 8 days separated the two single-dose subcutaneous administrations.

The primary pharmacodynamic parameters of the study were area under the effect curve (AUEC) from time 0 to the last measured activity (AUEC0-t) and maximum activity observed (Amax) of anti-FXa activity and anti-FIIa activity.

The study met its primary objective of demonstrating pharmacodynamic comparability between Redesca and Clexane. The 95% confidence intervals of the ratios of the geometric least squares means between Redesca and Clexane for the AUEC0-t and Amax of anti-FXa activity and anti-FIIa activity were within the equivalence interval of 80% to 125%. In addition, the ratio of anti-FXa activity versus anti-FIIa activity was also within the equivalence interval of 80% to 125%.

Indications

Similarity between Redesca/Redesca HP and the reference biologic drugs, Lovenox/Lovenox HP, was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. The demonstration of similarity between the biosimilar and its reference biologic drug enables the sponsor’s submission for the biosimilar to rely on the safety and efficacy information of the reference biologic drug and therefore clinical trials are not required to support each indication.

Within this drug submission, the sponsor provided an acceptable scientific justification for requesting the authorization of each of the indications currently granted to the reference products, Lovenox and Lovenox HP.

Based on the evidence submitted, Redesca/Redesca HP were authorized for the same indications currently held by Lovenox/Lovenox HP, as follows:

  • The prophylaxis of thromboembolic disorders (deep vein thrombosis) in patients undergoing:
    • orthopedic surgery of the hip or knee. In addition, Redesca is indicated in hospital or after hospital discharge for long-term prevention of venous thromboembolic diseases following hip replacement surgery.
    • high-risk abdominal, gynecological, or urological surgeries.
    • colorectal surgery.
  • The prophylaxis of deep vein thrombosis in medical patients who are at moderate risk of deep vein thrombosis and who are bedridden due to moderate to severe acute cardiac insufficiency (New York Heart Association [NYHA] class III or IV heart failure), acute respiratory failure revealing or complicating chronic respiratory insufficiency not requiring ventilatory support and acute respiratory infections (excluding septic shock), who require short-term prophylaxis of deep vein thrombosis.
  • The prevention of thrombus formation in the extracorporeal circulation during hemodialysis.
  • The treatment of deep vein thrombosis, with or without pulmonary embolism.
  • The treatment of unstable angina or non-Q-wave myocardial infarction, concurrently with acetylsalicylic acid.
  • The treatment of acute ST-segment elevation myocardial infarction, including patients to be managed medically or with subsequent percutaneous coronary intervention.

 

 

 

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