Summary Basis of Decision (SBD) for Axberi/Axberi HP

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Axberi/Axberi HP is located below.

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. At this time, no PAAT is available for Axberi/Axberi HP. When the PAAT for Axberi/Axberi HP becomes available, it will be incorporated into this SBD.

Date SBD Issued: 2024-01-26

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

Enoxaparin sodium

Drug Identification Number (DIN):

• DIN 02539977 (Axberi) - 30 mg/0.3 mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

• DIN 02539985 (Axberi) - 40 mg/0.4 mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

• DIN 02540002 (Axberi) - 60 mg/0.6 mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

• DIN 02540010 (Axberi) - 80 mg/0.8 mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

• DIN 02540045 (Axberi) - 100 mg/mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

• DIN 02540029 (Axberi HP) - 120 mg/0.8 mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

• DIN 02540037 (Axberi HP) - 150 mg/mL, solution, subcutaneous or intravenous administration (single‑use prefilled syringe)

Baxter Corporation

New Drug Submission Control Number: 266545

Submission Type: New Drug Submission

Therapeutic Area (Anatomical Therapeutic Chemical [ATC] Classification, second level): B01 Antithrombotic agents

Date Filed: 2022-07-29

Authorization Date: 2023-07-27

On July 27, 2023, Health Canada issued a Notice of Compliance (NOC) to Baxter Corporation for Axberi/Axberi HP, a biosimilar to Lovenox/Lovenox HP (the reference biologic drug). 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. Axberi/Axberi HP contains the medicinal ingredient enoxaparin sodium, which has been demonstrated to be highly similar to enoxaparin sodium contained in the reference biologic drug, Lovenox/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 biologic drug to be considered a biosimilar, the weight of evidence is provided by the structural and functional studies, whereas 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, pharmacokinetic and pharmacodynamic, 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.

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

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 Axberi/Axberi HP (hereafter referred to as Axberi) is considered to be similar to the benefit‑risk profile of the reference biologic drug, and 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, Axberi 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 (DVT) 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 (ASA).

• The treatment of acute ST‑segment elevation myocardial infarction, including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI).

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

Axberi is an anticoagulant/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, Axberi 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 (DVT) 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 (ASA).

• The treatment of acute ST‑segment elevation myocardial infarction, including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI).

Both Axberi 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 Axberi and Lovenox has been established on the basis of comparative structural and functional studies, comparative non‑clinical studies, and two comparative clinical pharmacodynamic studies in healthy volunteers in accordance with the Guidance Document: Information and Submission Requirements for Biosimilar Biologic Drugs.

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.

Axberi is contraindicated for use in:

• patients who are hypersensitive to this drug, other low molecular weight heparins and/or heparin, or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

• 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).

• patients with

  • 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 Axberi (1 mg/kg every 12 hours or 1.5 mg/kg once daily) are required, due to an increased risk of bleeding.

Axberi was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with its administration. The Axberi/Axberi HP Product Monograph is available through the Drug Product Database.

Axberi/Axberi HP is presented as a solution with two different concentrations: 100 mg/mL enoxaparin sodium (Axberi) and 150 mg/mL (high potency) enoxaparin sodium (Axberi HP). In addition to the medicinal ingredient, the solution in the single‑dose prefilled syringe contains water for injection.

For more information about the rationale for Health Canada's decision, refer to the Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

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

Axberi (enoxaparin sodium) is the sodium salt of enoxaparin, a mixture of low molecular weight fragments of heparin sodium, obtained by controlled depolymerization of natural heparin 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 Axberi, in conjunction with comparative non‑clinical data and comparative clinical pharmacodynamic data, the sponsor sought authorization for each of the indications held by the reference biologic drug, 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. One pivotal clinical comparative pharmacodynamic study (Study NKF‑2012‑001) demonstrated pharmacodynamic similarity between Axberi and the reference biologic drug Lovenox in healthy volunteers. Data from another comparative pharmacodynamic study (Study VEN‑ENO100‑SF‑15) conducted in healthy adult subjects was also provided as supportive evidence.

The safety profile of Axberi (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 Axberi/Axberi HP Product Monograph is based on the clinical experience with the reference biologic drug. Appropriate warnings and precautions are in place in the Axberi/Axberi HP Product Monograph to address the identified safety concerns.

A Risk Management Plan (RMP) for Axberi was submitted by Baxter Corporation 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, Axberi and Axberi HP, were accepted.

Based on an assessment of the relevant information provided in the submission, Axberi is considered to have a benefit‑risk profile similar to that established for the claimed indications, which are currently held by the reference biologic drug, Lovenox. Therefore, the benefit‑risk balance for Axberi 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 Basis for Decision sections.

Submission Milestones: Axberi/Axberi HP

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

Requirements for post‑market commitments are outlined in the Food and Drugs Act and Food and Drug Regulations.

The onus is on the Axberi/Axberi HP sponsor to monitor the post-market safety profile of this biosimilar as well as the Product Monograph of the reference biologic drug for safety signals that could impact the biosimilar, and make safety updates to the Axberi/Axberi 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 Biosimilar Biologic Drugs in Canada: Fact Sheet.

Summary Basis of Decision documents (SBDs) for eligible drugs (as outlined in the Guidance Document: Information and Submission Requirements for Biosimilar Biologic 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.

At this time, no PAAT is available for Axberi/Axberi HP. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

Up-to-date information on drug products can be found at the following links:

• See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.

• See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.

• See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.

• See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the , if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.

• See the Patent Register for patents associated with medicinal ingredients, if applicable.

• See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.