Summary Basis of Decision for Myxredlin

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 Myxredlin is located below.

Recent Activity for Myxredlin

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 Myxredlin

Updated: 2024-06-19

The following table describes post-authorization activity for Myxredlin, a product which contains the medicinal ingredient insulin (human). 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 02529602 – 1 unit/mL insulin (human), solution, intravenous administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02529602) market notification Not applicable Date of first sale: 2023-07-28 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NC # 268496 2022-10-14 Issued NOL
2023-01-10

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to modify a primary container closure system for the drug product. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 251360 2021-04-13 Issued NOC
2022-08-03

NOC issued for New Drug Submission.
Summary Basis of Decision (SBD) for Myxredlin

Date SBD issued: 2023-01-26

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

Insulin (human)

Drug Identification Number (DIN):

  • DIN 02529602 - 1 unit/mL insulin (human), solution, intravenous administration

Baxter Corporation

New Drug Submission Control Number: 251360

 

On August 3, 2022, Health Canada issued a Notice of Compliance (NOC) to Baxter Corporation for Myxredlin, a biosimilar to Novolin ge Toronto (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. Myxredlin contains the medicinal ingredient insulin (human), which has been demonstrated to be highly similar to insulin (human) contained in the reference biologic drug, Novolin ge Toronto.

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. To be considered 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, 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, Novolin ge Toronto is the reference biologic drug. Similarity between Myxredlin and Novolin ge Toronto was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document. Within this drug submission, the sponsor requested the authorization of Myxredlin for all of the indications that are currently authorized for Novolin ge Toronto which are applicable to the intravenous route of administration.

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 Myxredlin is considered to be similar to the benefit-risk profile of the reference biologic drug, and is therefore considered favourable for the treatment of patients with diabetes mellitus who require insulin by intravenous administration for the control of hyperglycemia.

Myxredlin, using intravenous administration, should be used for the treatment of emergencies, such as diabetic coma and pre‑coma, and in diabetics undergoing surgery.

 

1 What was approved?

 

Myxredlin, an antidiabetic agent, was authorized for the treatment of patients with diabetes mellitus who require insulin by intravenous administration for the control of hyperglycemia.

Myxredlin, using intravenous administration, should be used for the treatment of emergencies, such as diabetic coma and pre‑coma, and in diabetics undergoing surgery.

No data regarding the use of Myxredlin in pediatric patients (<18 years of age) or geriatric patients (≥65 years of age) were available to Health Canada at the time of authorization.

Myxredlin is a biosimilar to Novolin ge Toronto. Both drugs contain the medicinal ingredient, insulin (human), which is produced in yeast cells using recombinant deoxyribonucleic acid (DNA) technology.

Similarity between Myxredlin and the reference biologic drug, Novolin ge Toronto, has been established on the basis of comparative structural and functional studies, comparative non‑clinical studies, comparative bioavailability studies, comparative immunogenicity studies, and comparative clinical pharmacokinetic and pharmacodynamic studies in healthy adult male subjects, in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Myxredlin (1 unit/mL insulin [human]) is presented as a solution. In addition to the medicinal ingredient, the solution contains dibasic sodium phosphate anhydrous, monobasic sodium phosphate monohydrate, sodium chloride, and water for injection.

The use of Myxredlin is contraindicated 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. Additionally, Myxredlin is contraindicated during episodes of hypoglycemia.

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

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.

 

2 Why was Myxredlin approved?

 

Based on Health Canada's review, the benefit–risk profile of Myxredlin is considered to be similar to that of the reference biologic drug, and is therefore considered favourable for the treatment of patients with diabetes mellitus who require insulin by intravenous administration for the control of hyperglycemia.

Myxredlin, using intravenous administration, should be used for the treatment of emergencies, such as diabetic coma and pre–coma, and in diabetics undergoing surgery.

Similarity between Myxredlin and Novolin ge Toronto was established in accordance with the Information and Submission Requirements for Biosimilar Biologic Drugs Guidance Document.

Myxredlin is considered to be biosimilar to Novolin ge Toronto, which is authorized for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia.

The New Drug Submission (NDS) filed for Myxredlin requested authorization for all of the indications that are currently authorized for Novolin ge Toronto which are applicable to the intravenous route of administration. The indications have been authorized on the basis of demonstrated similarity between Myxredlin and the reference biologic drug.

Diabetes mellitus is a metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion and/or the development of insulin resistance. The chronic hyperglycemia of diabetes mellitus is associated with significant long–term sequelae; particularly damage, dysfunction, and failure of various organs (especially the kidneys, eyes, nerves, heart, and blood vessels).

Rarely, in the setting of critical illnesses (including but not limited to events of diabetic ketoacidosis and hyperglycemic hyperosmolar state), diabetic coma/pre-coma, or surgery, glycemic control of diabetic patients is achieved through the highly monitored and carefully titrated intravenous administration of insulin. Specifically, intravenous insulin therapy is used when a rapid method of getting insulin into the bloodstream is required. This is the standard treatment modality for hyperglycemia in intensive care units (ICUs).

At the time of authorization of Myxredlin, the marketed insulin products indicated for intravenous administration include Novolin ge Toronto and Humulin–R. Both require admixture with infusion fluids prior to intravenous administration. Dilution must occur on site in the hospital or ICU, which introduces opportunities for dosage error. Prior to the authorization of Myxredlin, a pre–diluted insulin solution for intravenous infusion was not commercially available in Canada.

Myxredlin (insulin [human] in 0.9% sodium chloride) is a novel, ready–to–use (i.e., pre–diluted) insulin solution for intravenous use. At the time of the submission, no ready–to–use 1 unit/mL insulin solution was authorized in Canada to serve as the reference biologic drug. As such, Novolin ge Toronto, a human insulin product available at a concentration of 100 units/mL which is indicated for IV use after suitable admixture, served as the designated Canadian reference product to which Myxredlin was compared as a candidate biosimilar.

Two foreign–sourced products, Actrapid sourced from the European Union (Actrapid–EU) and Novolin R sourced from the United States (Novolin R–US), were used as reference products in the Myxredlin development program. The sponsor declared foreign-sourced Canadian reference product, Actrapid–EU, was found to be a suitable proxy to the Canadian reference product, Novolin ge Toronto, due to adequate similarity between the two products.

The quality attributes of the biosimilar and the reference biologic drug were determined to be highly similar based on evidence from comparative structural and functional studies. A comparative pharmacokinetic and pharmacodynamic study in healthy adult male subjects provided the main clinical basis to support the biosimilarity (quality) assessment. The demonstration of similarity enables the biosimilar assessment to rely on the safety and efficacy information of the reference biologic drug for the authorized indication.

Myxredlin has demonstrated a comparable safety profile with Actrapid–EU, which serves as a proxy to the Canadian reference product, Novolin ge Toronto. Therefore, the Adverse Reactions section of the Myxredlin Product Monograph is based on the clinical experience with the reference biologic drug when administered intravenously. As with Novolin ge Toronto, the major identified safety concerns include hypoglycemia and hyperglycemia. These risks have been listed in the Serious Warnings and Precautions box in the Myxredlin Product Monograph, as can be found in the Novolin ge Toronto Product Monograph.

A Risk Management Plan (RMP) for Myxredlin was submitted by Baxter Corporation to Health Canada. 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. Upon review, the RMP was considered to be acceptable.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Myxredlin Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

The sponsor submitted a brand name assessment that included testing for look–alike sound–alike attributes. Upon review, the proposed name Myxredlin was accepted.

Overall, Myxredlin is considered to have a benefit–risk profile comparable to that which has been established for the claimed indications for its reference biologic drug Novolin ge Toronto. The benefits of Myxredlin are considered to outweigh the potential risks.

The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Myxredlin 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 Quality (Chemistry and Manufacturing), Non-clinical, and Clinical Basis for Decision sections.

 

3 What steps led to the approval of Myxredlin?

 

The review of the quality, non‑clinical, and clinical components of the New Drug Submission (NDS) for Myxredlin was based on a critical assessment of the data package submitted to Health Canada. The reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references, as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada. The Canadian regulatory decision on the Myxredlin NDS was made independently based on the Canadian review.

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

 

Submission Milestones: Myxredlin

Submission Milestone Date
Pre-submission meeting 2018-02-01
Pre-submission meeting 2020-10-27
New Drug Submission filed 2021-04-13
Screening  
Screening Acceptance Letter issued 2021-05-28
Review 1  
Review of Risk Management Plan completed 2022-07-07
Quality evaluation completed 2022-07-13
Non-clinical evaluation completed 2022-07-21
Clinical/medical evaluation completed 2022-07-25
Labelling review completed 2022-08-02
Notice of Compliance issued by Director General, Biologic and Radiopharmaceutical Drugs Directorate 2022-08-03

 

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 Myxredlin 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 Myxredlin 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 Myxredlin?

 

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 Myxredlin 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

 

As described above, the review of the quality component of the New Drug Submission for Myxredlin was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Myxredlin was developed as a biosimilar to the reference biologic drug Novolin ge Toronto. 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.

The biological activity of Myxredlin is considered to be representative of the mechanism of action and pharmacological effect of Novolin ge Toronto.

Comparative Structural and Functional Studies

The biosimilarity assessment for Myxredlin was performed with Actrapid‑EU, the declared foreign‑sourced proxy to the Canadian reference product (CRP), Novolin ge Toronto. Supporting data were also provided from Novolin R, the equivalent product marketed in the United States. Both Actrapid‑EU and Novolin R are considered representative of the CRP based on Health Canada guidelines.

The quality target product profile (QTPP) of Myxredlin was established using lots of Novolin R. The quality attributes were classified based on criticality risk rankings, factoring in potential impacts on efficacy, immunogenicity, safety, and/or pharmacokinetics and pharmacodynamics. The pivotal biosimilarity assessment was conducted using batches of Myxredlin drug substance and drug product and batches of Actrapid‑EU. Given formulation differences between the biosimilar and the reference biologic drug, efforts were made to match concentrations and formulation matrices when possible.

Overall, Myxredlin was shown to be highly similar to Actrapid‑EU with respect to primary structure and higher order structures, molecular mass, and charge. No new impurities or product‑related substances were identified in Myxredlin when compared to the reference biologic drug. No differences in levels of impurities or product‑related substances were observed. However, while Myxredlin had lower levels of desamidos when compared to Actrapid‑EU, it also had a higher degradation rate under stability. The control strategy was revised to ensure safety and efficacy. Certain differences were observed with respect to functional activity, which have been attributed to the inherent matrix differences between Myxredlin and Actrapid‑EU. The results of the assessment between Myxredlin and Novolin R were comparable to those obtained for Actrapid‑EU. Overall, the results of the biosimilarity assessment and comparative stability study support the biosimilarity claim between Myxredlin and Actrapid‑EU. Where differences were observed, the sponsor provided acceptable evidence to conclude that these differences are unlikely to translate into any clinically meaningful differences.

Characterization of the Drug Substance

The medicinal ingredient in Myxredlin, insulin (human), is a polypeptide hormone composed of 51 amino acids forming two chains (Chains A and B) linked by disulfide bonds.

Detailed characterization studies demonstrated that the insulin (human) in Myxredlin consistently exhibits the desired characteristic structure and biological activity. The primary and higher order structures, process‑ and product‑related impurities, and biological activity were all confirmed through appropriately qualified methods.

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

The drug substance, insulin (human), is produced in Pichia pastoris (yeast) cells which have been genetically engineered to express this hormone using recombinant deoxyribonucleic acid (DNA) technology. The four‑part manufacturing process consists of an upstream process and three downstream processes. In the upstream process, a cell culture is initiated from a working cell bank vial and allowed to expand to commercial scale. The downstream processes involve harvest, cell separation, chromatography, crystallization, and centrifugation steps, followed by trypsinization, coupling, crystallization and centrifugation steps, and then a series of chromatography steps (including a deblocking step), crystallization, and freeze drying.

Manufacturing of the drug product, Myxredlin, involves formulation, bioburden reduction and sterile filtrations, and filling steps.

The drug substance manufacturing process has been optimized and scaled up during development. The changes introduced at each generation of the process were adequately described and comparatively assessed. Lot release, stability, and characterization data have also been used to support the comparability assessment. Overall, the process validation data provided demonstrate that the manufacturing processes are well‑controlled and can produce drug substance and drug product that consistently meet predetermined quality criteria.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. The compatibility of insulin (human) with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The overall control strategy for Myxredlin incorporates control of materials/excipients, critical steps within the manufacturing processes, and release and stability specifications. Process parameter ranges and in‑process control limits are well defined and justified to ensure process and product consistency. The specification limits set for compendial methods comply with European Pharmacopeia standards. The limits for non‑compendial methods were established based on manufacturing experience and stability data, and were revised over the course of the review to ensure product consistency. The non‑compendial methods were appropriately validated and deemed suitable for their intended purpose.

Myxredlin is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. The consistency test results support the suitability of the selected methods for their intended purpose and the consistency of the manufacturing process. For post‑approval monitoring, Myxredlin has been assigned to Lot Release Evaluation Group 3, as it is considered to require a moderate level of assessment. Before each lot is sold, a formal Release Letter from Health Canada is required to approve the sale of the lot in Canada. This assessment level also involves the review of testing protocols, and samples may be requested periodically. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

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 24‑month shelf life at 2 °C to 8 °C for Myxredlin is considered acceptable. The product must be stored in the original carton to protect from light. If needed, Myxredlin may be removed from the original carton and stored at room temperature up to 25 °C for up to 25 days, but not exceeding the original expiry date. Additional storage and special handling instructions are included in the Myxredlin Product Monograph.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, an on‑site evaluation (OSE) was not warranted for the drug product manufacturing site, but an OSE was warranted for the drug substance manufacturing site.

An OSE of the drug substance manufacturing site could not be conducted due to the coronavirus disease 2019 (COVID‑19) pandemic. However, an OSE was conducted for the site within the last 7 years, during which it was issued a compliant rating. The information obtained during the previous OSE was considered to support the issuance of a Notice of Compliance (NOC) for Myxredlin.

Adventitious Agents Safety Evaluation

The master and working cell banks were extensively characterized and confirmed to be free of adventitious agents.

The drug substance and drug product are tested at defined steps of production to measure bioburden and confirm that they are free of bacterial endotoxins. The Pichia pastoris host cell line used for the production of the drug substance is a yeast cell line, which does not support viral transmission. Microbiological controls are in place during drug substance and drug product production, and routine testing for microbiological contamination is performed at defined stages of drug substance and drug product operations.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy agents or other human pathogens.

Overall, the approaches used to minimize the risk of contamination from adventitious agents are suitable.

 

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.

The non‑clinical pharmacodynamic data package reviewed for Myxredlin evaluated various aspects relative to Actrapid‑EU, the declared foreign‑sourced proxy to the Canadian reference product (CRP), Novolin ge Toronto. Collectively, the in vitro assessment of the pharmacodynamics of Myxredlin showed that the binding profiles to the insulin receptors A and B and the insulin‑like growth factor 1 (IGF‑1) receptor, biological activity (adipogenesis, inhibition of lipolysis, and glucose uptake), and mitogenic activity were similar relative to the reference biologic drug.

The Myxredlin insulin preparation contains a higher level of desamido impurities compared to the reference biologic drug, because it is a diluted and ready‑to‑use form of insulin. Desamido impurities are insulin‑related substances that form slowly in aqueous solutions during storage and are classified as degradation products. In the pivotal in vivo non‑clinical study, rats were administered Myxredlin containing 2%, 5%, or 10% desamido degradants, vehicle control (saline), or the reference biologic drug (Novolin R‑US, diluted in saline; 1.8% desamido degradants) as a single two‑week continuous intravenous infusion. No new toxicities or tolerability concerns were observed when rats were administered Myxredlin containing up to 10% desamido degradation products. This is equal to the expected amount of desamidos in a clinical dose when the specification limits of total desamidos is 7.2% for Myxredlin, after correction for body surface area.

The results of the comparative non‑clinical studies as well as the potential risks to humans have been included in the Myxredlin Product Monograph. Considering the intended use of Myxredlin, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

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

 

 

7.3 Clinical basis for decision

 

As described above, the review of the clinical component of the New Drug Submission for Myxredlin was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The purpose of the clinical program for a biosimilar 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. The clinical program is designed to complement the structural and functional studies and address potential areas of residual uncertainty.

The pivotal study, CEL–HI–203, was a double–blind, randomized, two–treatment, two–period, crossover hyperinsulinemic euglycemic clamp trial conducted in 60 healthy adult male subjects between 19 and 50 years of age (mean age: 33.4 years). All subjects received single intravenous infusions of Myxredlin and Actrapid–EU, the declared foreign–sourced proxy to Novolin ge Toronto, the Canadian reference product (CRP).

Study drug was administered as an intravenous infusion at a dose of 0.36 units (U)/kg over a 6–hour period (rate of infusion: 1.0 mU/kg/min), concurrent with an 8–hour euglycemic clamp procedure. Following the start of infusion, blood glucose concentration was clamped at 9 mg/dL below the individual fasting blood glucose level of the subject. This was achieved through a constant intravenous infusion of 20% glucose by a Biostator (a glucose controlled insulin infusion system), which automatically calculated the appropriate glucose infusion rate (GIR). Data related to clinical pharmacokinetics, pharmacodynamics, and safety were collected in this study.

Comparative Pharmacokinetic and Pharmacodynamic Studies

The primary activity of Myxredlin (insulin human in 0.9% sodium chloride injection) is the regulation of glucose metabolism. The blood glucose–lowering effect of insulins, including Myxredlin, is due to the facilitated uptake of glucose following binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.

Pharmacokinetic and pharmacodynamic data were collected in the pivotal study, CEL–HI–203 (described above). The primary pharmacokinetic endpoints were the area under the curve (AUC) measuring insulin concentration over time and the maximum concentration (Cmax), both measured at steady state from 300 to 360 minutes (AUCINS–SS 300–360min and Cmax INS–SS 300–360 min, respectively). Pharmacokinetic similarity between Myxredlin and Actrapid–EU was assessed by constructing the 90% confidence intervals (CIs) for the geometric least–squares (LS) mean ratios (Myxredlin/Actrapid–EU) for these endpoints.

A pharmacodynamic evaluation utilizing the hyperinsulinemic clamp technique is considered an adequate proxy to examine the efficacy of insulin action. Therefore, an efficacy study was not conducted for Myxredlin. The primary pharmacodynamic endpoints were the AUC measuring the GIR over time and the maximum GIR, both measured at steady state from 300 to 360 minutes (AUCGIR–SS 300–360 min and GIRmax SS 300–360 min, respectively). Pharmacodynamic similarity between Myxredlin and Actrapid–EU was assessed by constructing the 95% CIs for the geometric LS mean ratios (Myxredlin/Actrapid–EU) for these endpoints.

The pharmacokinetic and pharmacodynamic endpoints were found to be appropriate for a comparative bioavailability study designed to examine a proposed insulin biosimilar administered intravenously and based on the euglycemic clamp procedure. Although the pharmacokinetic endpoints do not align with the current applicable Health Canada guidance, the selected endpoints are considered more appropriate as they allow for the evaluation of insulin pharmacokinetics at steady state.

The 90% CIs of the geometric LS mean ratios of the primary pharmacokinetic endpoints, AUCINS–SS 300–360 min and Cmax INS–SS 300–360 min, were within the prespecified limits of 80% and 125% (100.23–106.50 and 101.8–107.9, respectively), signifying pharmacokinetic similarity. The 90% CIs of geometric LS mean ratios of other AUCINS endpoints (i.e., AUCINS 0–6hrs, AUCINS 0–8hrs, and AUCINS 6–8hrs) were also within the prespecified limits of 80% and 125%. The results of sensitivity analyses and exploratory analyses were further supportive of pharmacokinetic similarity between Myxredlin and Actrapid–EU.

The 95% CIs of the geometric LS mean ratios of the primary pharmacodynamic endpoints, AUCGIR–SS 300–360 min and GIRmax–SS 300–360 min, were within the prespecified limits of 80% and 125% (i.e., 96.60–107.45 and 97.23–107.80, respectively), signifying pharmacodynamic similarity. The 95% CIs of the geometric LS mean ratios of the additional pharmacodynamic endpoints (i.e., AUCGIR 0–6hrs, AUCGIR 0–5hrs, AUCGIR 0–8hrs, and AUCGIR 6–8hrs) were also within the prespecified limits of 80% and 125%. The results of sensitivity analyses were further supportive of pharmacodynamic similarity between Myxredlin and Actrapid–EU.

The results from the pivotal study, CEL–HI–203 demonstrated pharmacokinetic and pharmacodynamic similarity between Myxredlin and Actrapid–EU, a suitable proxy for the CRP, Novolin ge Toronto. A similarly designed supportive study (CEL–HI–200) comparing Myxredlin and Novolin R–US (similar to Actrapid–EU) was also submitted. Findings from this study supported the conclusions drawn from the pivotal study.

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

Comparative Clinical Safety and Immunogenicity

Clinical safety data were provided from healthy subjects in the pivotal study, CEL–HI–203 (described above), and the supportive study, CEL–HI–200. The pivotal study initially included 60 enrolled subjects, with 56 subjects (93.3%) completing the study. Two subjects voluntarily withdrew consent, one subject was withdrawn due to adverse events of vomiting, hypokalaemia, atrial fibrillation, and headache after receiving Myxredlin, and one subject was withdrawn due to multiple haemolysed samples and missed pharmacokinetic timepoints due to difficult sampling after receiving Actrapid–EU. Thirteen of 60 subjects (21.7%; 22 events) reported a treatment–emergent adverse event (TEAE), 7 of 58 subjects (12.1%; 12 events) reported any TEAE following Myxredlin, and 7 of 58 subjects (12.1%; 10 events) reported any TEAE following Actrapid–EU. No serious adverse events or deaths occurred during the study. No changes in laboratory evaluations, vital signs, or findings on physical examinations from baseline to follow–up resulted in an adverse event or were found to be significant. The magnitude of change observed was similar for subjects treated with Myxredlin or Actrapid–EU. Safety data from the supportive study did not raise any concerns.

Notably, immunogenicity was not evaluated as part of this submission. Overall, the absence of immunogenicity data for Myxredlin was found to be acceptable based on a cumulative assessment of three concepts. First, adequate physiochemical and functional similarity between Myxredlin and the CRP, Novolin ge Toronto, was determined in the Quality review. Second, Myxredlin is intended only for acute use. Evaluating the long–term formation of anti–insulin antibodies is of minor importance relative to insulins intended for chronic administration over years. Third, acute hypersensitivity reactions due to insulin administration are very rare, and the risk of hyperglycaemia due to pre–existing (neutralizing) anti–insulin antibodies is even lower for insulins administered intravenously than for subcutaneous formulations.

A Serious Warnings and Precautions box was included in the Myxredlin Product Monograph to highlight the risks of hypoglycemia (the most common adverse event of insulin products) and hyperglycemia. Important instructions for use have also been listed, which include caution if a transfer of insulin products is made, not mixing insulin products with any other insulin products unless clearly indicated and done under medical supervision, and not using the product if particulate matter or colouration is seen in the solution.

Overall, the safety profile of Myxredlin is considered to be comparable to that which has been established for the reference biologic drug, Novolin ge Toronto. The identified safety concerns are appropriately addressed in the Serious Warnings and Precautions Box and the Warning and Precautions section of the Myxredlin Product Monograph, as they are in the Product Monograph for Novolin ge Toronto.

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

Indications

Myxredlin is considered to be biosimilar to Novolin ge Toronto, the reference biologic drug. Novolin ge Toronto is authorized for the treatment of patients with diabetes mellitus who require insulin for the control of hyperglycemia.

Within this drug submission, the sponsor requested the authorization of Myxredlin for all of the indications that are currently authorized for Novolin ge Toronto which are applicable to the intravenous route of administration. To promote safe and effective use of the product, Health Canada approved the following indication for Myxredlin:

  • The treatment of patients with diabetes mellitus who require insulin by intravenous administration for the control of hyperglycemia.

Myxredlin, using intravenous administration, should be used for the treatment of emergencies, such as diabetic coma and pre–coma, and in diabetics undergoing surgery.

Similarity between Myxredlin and Novolin ge Toronto 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. The indications have been authorized on the basis of demonstrated similarity between Myxredlin and the formulation of the reference biologic drug authorized for intravenous administration, in structural and functional studies, mechanism of action, pharmacological effect, pathophysiological mechanisms of the diseases involved, safety profile, dosage regimen, and clinical experience with the reference biologic drug.

 

 

 

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