Summary Basis of Decision for Inclunox/Inclunox 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 Inclunox/Inclunox HP is located below.

Recent Activity for Inclunox/Inclunox 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.

AnchorThe following table describes post-authorization activity for Inclunox/Inclunox HP, a product which contains 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 that are found in PAATs.

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

Updated: 2023-10-11

Drug Identification Number (DIN):

DIN 02507501 (Inclunox) ‑ enoxaparin sodium 30 mg/0.3 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)

DIN 02507528 (Inclunox) ‑ enoxaparin sodium 40 mg/0.4 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)

DIN 02507536 (Inclunox) ‑ enoxaparin sodium 60 mg/0.6 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)

DIN 02507544 (Inclunox) ‑ enoxaparin sodium 80 mg/0.8 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)

DIN 02507552 (Inclunox) ‑ enoxaparin sodium 100 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)

DIN 02507560 (Inclunox HP) ‑ enoxaparin sodium 120 mg/0.8 mL (150 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)

DIN 02507579 (Inclunox HP) ‑ enoxaparin sodium 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

SNDS # 260589

2022-01-20

Issued NOC 2022-08-18

Submission filed as a Level I – Supplement to add a new alternate drug substance manufacturing facility. The submission was reviewed and considered acceptable, and an NOC was issued.

SNDS # 256235

2021-08-30

Issued NOC 2022-01-27

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.

Drug product (DIN 02507501) market notification

Not applicable

Date of first sale: 2021-06-09

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

Drug product (DINs 02507528, 02507536, 02507544, 02507552, 02507560, 02507579) market notification

Not applicable

Date of first sale: 2021-05-04

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

NDS # 233987

2019-11-26

Issued NOC 2020-11-05

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

Date SBD issued: 2021-02-08

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

Enoxaparin sodium

Drug Identification Number (DIN):

  • DIN 02507501 (Inclunox) - 30 mg/0.3 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02507528 (Inclunox) - 40 mg/0.4 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02507536 (Inclunox) - 60 mg/0.6 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02507544 (Inclunox) - 80 mg/0.8 mL (100 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02507552 (Inclunox) - 100 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02507560 (Inclunox HP) - 120 mg/0.8 mL (150 mg/mL), solution, subcutaneous or intravenous administration (prefilled syringe)
  • DIN 02507579 (Inclunox HP) - 150 mg/mL, solution, subcutaneous or intravenous administration (prefilled syringe)

Sandoz Canada Inc.

New Drug Submission Control Number: 233987

 

On November 5, 2020, Health Canada issued a Notice of Compliance to Sandoz Canada Inc. for Inclunox and Inclunox 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. Inclunox and Inclunox 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 Inclunox and Inclunox HP for all of the indications that are currently authorized for Lovenox and Lovenox HP, the reference biologic drugs. Similarity between Inclunox/Inclunox 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 Inclunox/Inclunox 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, Inclunox 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?

 

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

Inclunox 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, Inclunox 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 Inclunox 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, obtained by alkaline depolymerization of the benzyl ester of heparin sodium derived from porcine intestinal mucosa.

Similarity between Inclunox and Lovenox has been established on the basis of comparative structural and functional studies, comparative non-clinical studies, and a comparative 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. Evidence from clinical studies and experience suggests that use of enoxaparin sodium in the geriatric population is associated with differences in safety.

The use of Inclunox is contraindicated in patients with:

  • hypersensitivity to Inclunox (enoxaparin); or any of its constituents or to other low molecular weight heparins and/or heparin
  • 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 treatment doses of Inclunox (1 mg/kg every 12 hours or 1.5 mg/kg once daily) are required, due to an increased risk of bleeding.

Inclunox 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 (Inclunox) and 150 mg/mL (high potency) enoxaparin sodium (Inclunox HP). In addition to the medicinal ingredient, the solution contains water for injection.

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

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

 

2 Why was Inclunox/Inclunox HP approved?

 

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

Inclunox (enoxaparin sodium) is the sodium salt of enoxaparin, which is a mixture of low molecular weight fragments of heparin, obtained by alkaline depolymerization of the benzyl ester of heparin sodium derived from porcine intestinal mucosa. It has antithrombotic properties. Enoxaparin 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 Inclunox in conjunction with comparative non-clinical data and comparative pharmacodynamic data, the sponsor sought authorization for each of the indications held by the Canadian reference product, Lovenox.

As clinical evidence to support authorization, the sponsor provided a single-dose comparative pharmacodynamic study demonstrating pharmacodynamic similarity between Inclunox and the reference enoxaparin sodium in healthy volunteers. The results of this study, in combination with the results of extensive comparative physicochemical and functional assessments, provide sufficient evidence of similarity to support the authorization of Inclunox for the indications being sought.

The safety profile of Inclunox is considered to be comparable to that which has been established for the reference biologic drug, Lovenox. The Adverse Reactions section of the Inclunox/Inclunox HP Product Monograph is based on the clinical experience with the reference biologic drug. Appropriate warnings and precautions are in place in the Inclunox/Inclunox 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 Inclunox/Inclunox HP Product Monograph.

A Risk Management Plan (RMP) for Inclunox was submitted by Sandoz Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed names, Inclunox and Inclunox HP, were accepted.

Based on an assessment of the relevant information provided in the submission, Inclunox 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 Inclunox is considered favourable for the prevention of venous thromboembolic disease, treatment of deep vein thrombosis, treatment of unstable angina and non-Q-wave myocardial infarction and treatment of acute ST-segment elevation myocardial infarction.

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 Basis for Decision sections.

 

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

 

Submission Milestones: Inclunox/Inclunox HP

Submission Milestone Date
Pre-submission meeting 2019-02-05
Submission filed 2019-11-26
Screening  
Screening Acceptance Letter issued 2020-01-10
Review  
Review of Risk Management Plan complete 2020-08-18
Quality Evaluation complete 2020-11-02
Clinical Evaluation complete 2020-11-02
Labelling Review complete, including Look-alike Sound-alike brand name assessment 2020-11-04
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2020-11-05

 

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 Inclunox/Inclunox 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 Inclunox/Inclunox 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 Inclunox/Inclunox 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

 

Inclunox and Inclunox HP (hereafter referred to as Inclunox) 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 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.

The quantitative ranges for the quality attributes in the comparability study were established according to well-defined rationales and, where applicable, appropriate statistical calculations. Most of the experiments in the extensive comparability exercise were carried out with the drug substance, whereas some used the drug product.

The results of the comparability study met the acceptance criteria established for demonstrating biosimilarity between Inclunox and Clexane. Adequate data have been provided to support the sponsor's conclusion that Inclunox is highly similar to Clexane in terms of physicochemical properties, heparin source material and mode of depolymerization, disaccharide building blocks, fragment mapping and sequence of oligosaccharide species, and in vitro biological and biochemical assays.

Characterization of the Drug Substance

Enoxaparin sodium is the sodium salt of enoxaparin, which is a mixture of low molecular weight fragments of heparin, obtained by alkaline depolymerization of the benzyl ester of heparin sodium derived from porcine intestinal mucosa. Enoxaparin consists of a complex set of oligosaccharides that have not yet been completely characterized. Based on current knowledge, 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 molecular weight of enoxaparin ranges from 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. Adequate 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 the established and acceptable limits.

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

Enoxaparin sodium is produced from heparin sodium obtained from porcine intestinal mucosa.

The manufacturing process of enoxaparin sodium involves four stages: formation of heparin benzethonium salt, formation of heparin benzyl ester, depolymerization, and purification.

The drug product manufacturing process consists of the following six phases: weighing of drug substance, compounding and first filtration of the bulk solution, sterile filtration of the bulk solution, aseptic syringe filling and stoppering, 100% inspection for detection of visible particles and other defects, and secondary packaging of completed syringes.

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 adequate data or rationales, and the test methods used are either compendial or validated. Batch analysis data met specifications and were consistent between lots.

Inclunox and Inclunox 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 Inclunox and Inclunox HP drug products, when stored at room temperature of 15°C to 25°C.

Facilities and Equipment

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

Based on risk assessment scores determined by Health Canada, on-site evaluations of the drug substance and drug product manufacturing facilities were not deemed necessary for all but one of the manufacturing sites. Due to the coronavirus disease 2019 (COVID-19) pandemic and travel restrictions at the time of the review, an on-site evaluation could not be conducted at this site. An evaluation of the suitability of the facility was conducted by a thorough review of additional documentation provided upon Health Canada's request. This evaluation was considered adequate to support the final quality review recommendation.

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

Adventitious Agents Safety Evaluation

Adequate 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 and 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.

Non-clinical studies were conducted to compare the biological and biochemical properties as well as the pharmacodynamic activity of Inclunox with those of the reference products, Clexane (authorized in the European Union) or Lovenox (authorized in the United States, Lovenox-US). The primary pharmacodynamic effect of enoxaparin sodium, i.e., its inhibitory activity against the coagulation factor Xa (anti-FXa activity), is considered a surrogate for the biologic drug exposure (pharmacokinetics) since plasma concentrations of enoxaparin sodium cannot be measured.

In an in vitro study, comparable anti-FXa and anti-coagulation factor IIa (anti-FIIa) activities between Inclunox and Clexane were demonstrated. Comparable anti-FXa and anti-FIIa activity levels between Inclunox and Clexane (or Lovenox-US) were also demonstrated in two in vivo studies conducted in rabbits.

The immunogenic potential of Inclunox and Clexane (or Lovenox-US) was indirectly predicted by in vitro studies, showing similar binding affinities to platelet factor 4 (PF4) and similar structural changes in the heparin-PF4 complexes. These heparin-PF4 complexes undergo a conformational change that may trigger a rare immunogenic response in patients known as heparin-induced thrombocytopenia (HIT), where anti-heparin-PF4 antibodies may activate platelet aggregation. In an in vitro assay using anti-heparin-PF4 antibodies obtained from human sera, similar frequencies in the formation of antibody-complex aggregates were observed with each of the three products.

In view of the intended use of Inclunox, no pharmacological or toxicological issues were identified within this submission to preclude authorization of the product.

The non-clinical dataset submitted for Inclunox 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 Inclunox/Inclunox 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 Pharmacodynamic Study in Healthy Volunteers

A pivotal comparative pharmacodynamic study (ROV-RO20-2015-01) was conducted in healthy volunteers. The study established comparability in the pharmacodynamic parameters between Inclunox and the reference product Clexane (authorized in the European Union). Clexane 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.

No Phase III clinical efficacy and safety studies were submitted.

Pivotal Study (ROV-RO20-2015-01)

Study ROV-RO20-2015-01 was a single-dose, randomized, double-blind, two-way crossover study in healthy volunteers to evaluate the pharmacodynamic comparability of Inclunox to Clexane, following subcutaneous administration of a single dose of 100 mg of the assigned study drug. The anti-coagulation factor Xa (anti-FXa) and anti-coagulation factor II (anti-FIIa) activities were selected as the primary pharmacodynamic endpoints of the study. The study evaluated 46 healthy adult subjects (23 subjects in each treatment sequence: Inclunox/Clexane or Clexane/Inclunox). Two subjects from the Inclunox/Clexane treatment sequence and one subject from the Clexane/Inclunox treatment sequence did not complete the study, which resulted in 43 subjects being included in the statistical comparisons.

The study met its primary objective of demonstrating pharmacodynamic comparability of Inclunox and Clexane. The primary pharmacodynamic parameters evaluated were maximum activity (Amax) and area under the effect curve (AUEC) from time 0 to the last measured activity (AUEC0-t) and AUEC from time 0 to infinity (AUEC0-inf) of anti-FXa activity, and Amax and AUEC0-t of anti-FIIa activity. The 95% confidence intervals of the ratios of the geometric least squares means between Inclunox and Clexane for the AUEC0-t, AUEC0-inf, and Amax of anti-FXa activity, and AUEC0-t and Amax of anti-FIIa activity were completely within the equivalence interval of 80% to 125%, thereby demonstrating pharmacodynamic biosimilarity of Inclunox to Clexane.

Comparative Safety Assessments in Healthy Volunteers

In Study ROV-RO20-2015-01 (described in Comparative Pharmacodynamic Study in Healthy Volunteers), the safety profile of Inclunox was similar to that of Clexane. The most frequently occurring treatment-emergent adverse events were consistent with those reported in the Product Monograph for the Canadian reference product, Lovenox. The incidences of treatment-emergent adverse events were similar for both treatments. None of the treatment-emergent adverse events was of severe, significant, or serious nature.

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

Indications

Similarity between Inclunox/Inclunox 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, Inclunox/Inclunox 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, Inclunox 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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