Summary Basis of Decision for Ozempic
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Ozempic is located below.
Recent Activity for Ozempic
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 Ozempic
Updated: 2024-01-09
The following table describes post-authorization activity for Ozempic, a product which contains the medicinal ingredient semaglutide. 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 02471469 - 1.34 mg/mL, semaglutide, solution, pen dispenses 1 mg dose, subcutaneous administration
- DIN 02471477 - 1.34 mg/mL, semaglutide, solution, pen dispenses 0.25 or 0.5mg dose, subcutaneous administration
-
DIN 02523930 – 2.68 mg/mL, semaglutide, solution, pen dispenses 2 mg dose, subcutaneous administration
DIN 02540258 – 0.68 mg/mL, semaglutide, solution, pen dispenses 0.25 or 0.5 mg dose, subcutaneous administration
Post-Authorization Activity Table (PAAT)
|
Activity/Submission Type, Control Number |
Date Submitted |
Decision and Date |
Summary of Activities |
|
Drug product (DIN 02540258) market notification |
Not applicable |
Date of first sale: 2023-12-22 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NC # 281617 |
2023-11-30 |
Issued NOL 2023-12-06 |
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. |
|
New safety and effectiveness review |
Not applicable |
Started between 2023-11-01 to 2023-11-30 |
Health Canada started a new safety and effectiveness review for glucagon-like peptide-1 (GLP-1) receptor agonists related to suicide, self-harm, suicidal ideation (thoughts of suicide) and self-injurious ideation (thoughts of self-harm). |
|
NC # 279245 |
2023-09-20 |
Issued NOL 2023-11-24 |
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 # 273877 |
2023-03-30 |
Issued NOC 2023-11-15 |
Submission filed as a Level I – Supplement for a change involving a new drug product manufacturing site and a change to the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 271108 |
2023-01-04 |
Issued NOC 2023-08-04 |
Submission filed as a Level I – Supplement for the introduction of a new drug product concentration of 0.68 mg/mL for the dual-dose (0.25 mg and 0.5 mg) PDS290 pre-filled, disposable, multi-dose pen-injector. The submission was reviewed and considered acceptable, and an NOC was issued. A new DIN (02540258) was issued for the new strength. A Regulatory Decision Summary was published. |
|
NC # 273634 |
2023-03-23 |
Issued NOL 2023-06-12 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change involving a drug product manufacturer/manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 268322 |
2022-09-29 |
Issued NOC 2023-04-06 |
Submission filed as a Level I – Supplement for a new drug product manufacturing site. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
NC # 272089 |
2023-02-06 |
Issued NOL 2023-03-01 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for change involving a drug product manufacturer/manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 260299 |
2022-01-12 |
Issued NOL 2022-04-04 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change involving a drug product manufacturer/manufacturing facility. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
NC # 260457 |
2022-01-14 |
Issued NOL 2022-02-14 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in product‐contact equipment/material used in the drug substance manufacturing process. The submission was considered acceptable, and an NOL was issued. |
|
SNDS # 248754 |
2021-01-25 |
Issued NOC 2022-01-04 |
Submission filed as a Level I – Supplement to seek market authorization for Ozempic at a higher maintenance dose of 2 mg once weekly, in a pre-filled syringe at a higher strength of 2.68 mg/mL, for adult patients with type 2 diabetes who may benefit from additional glucose-lowering and body weight loss as the disease progresses. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions; Adverse Reactions; Drug Interactions; Dosage and Administration; Dosage Forms, Strengths, Composition and Packaging; Clinical Pharmacology; Clinical Trials; and Non-Clinical Toxicology sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the package inserts. An NOC was issued. A new DIN (02523930) was issued for the new presentation. A Regulatory Decision Summary was published. |
|
NC # 258726 |
2021-11-16 |
Issued NOL 2021-11-19 |
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 # 252312 |
2021-05-03 |
Issued NOC 2021-10-20 |
Submission filed as a Level I – Supplement for changes in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 245932 |
2020-10-30 |
Issued NOC 2021-10-13 |
Submission filed as a Level I – Supplement for a new indication: the reduction in risk of major adverse cardiovascular events in patients with type 2 diabetes mellitus with cardiovascular disease and/or chronic kidney disease. Health Canada considered the evidence to be insufficient on its own to support a cardiovascular risk reduction indication for Ozempic, and did not authorize a new indication. Instead, as a result of the SNDS, modifications were made to the Clinical Trials section of the PM. An NOC was issued. |
|
SNDS # 242719 |
2020-08-13 |
Issued NOC 2021-01-22 |
Submission filed as a Level I – Supplement to revise the outer carton and labels. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 231580 |
2019-09-13 |
Issued NOC 2020-07-31 |
Submission filed as a Level I – Supplement for a new indication. The indication authorized was: Ozempic to be used in combination with metformin or a sulfonylurea and a sodium-glucose cotransporter 2 inhibitor (SGLT2i) when diet and exercise plus metformin or a sulfonylurea, in addition to an SGLT2i, do not achieve adequate glycemic control. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Indications; Warnings and Precautions; Adverse Reactions; Dosage and Administration; and Clinical Trials sections of the PM, and corresponding changes were made to Part III: Patient Medication Information and to the outer label and package inserts. An NOC was issued. A Regulatory Decision Summary was published. |
|
Health product advertising incident |
Not applicable |
Date received: 2021-06-01 |
A health product advertising incident was received regarding direct-to-consumer advertising of unauthorized claims. A Compliance letter was sent to request correction of non-compliance. Material was modified/removed/discontinued. |
|
Health product advertising incident |
Not applicable |
Date received: 2021-04-13 |
A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized claims. An Explanatory letter was sent. |
|
Health product advertising incident |
Not applicable |
Date received: 2021-04-09 |
A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized claims. An Explanatory letter was sent. |
|
Health product advertising incident |
Not applicable |
Date received: 2021-03-29 |
A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized claims. An Explanatory letter was sent. |
|
Health product advertising incident |
Not applicable |
Date received: 2021-03-22 |
A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized claims. An Explanatory letter was sent. |
|
Health product advertising incident |
Not applicable |
Date received: 2021-03-17 |
A health product advertising incident was received regarding the direct-to-consumer advertising of unauthorized claims. An Explanatory letter was sent. |
|
NC # 241535 |
2020-07-10 |
Issued NOL 2020-07-17 |
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 # 227387 |
2019-05-01 |
Cancellation Letter Received 2020-03-06 |
Submission filed as a Level I – Supplement for a new indication: to reduce the risk of major cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in adults with type 2 diabetes and established cardiovascular disease and/or chronic kidney disease. The sponsor cancelled the submission and a Summary of Cancellation was published. |
|
NC # 225014 |
2019-03-04 |
Issued NOL 2019-05-07 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for the modification of a primary container closure system. The submission was reviewed and considered acceptable, and an NOL was issued. |
|
SNDS # 215900 |
2018-04-30 |
Issued NOC 2018-11-05 |
SNDS was filed subsequent to NC # 215548. Submission filed as a Level I – Supplement to add a new pen presentation and to update the labelling. There were no changes to the drug substance or to the composition of the drug product as a result of this change. The submission was reviewed and considered acceptable, and an NOC was issued. |
|
SNDS # 214679 |
2018-03-20 |
Issued NOC 2018-09-04 |
Submission filed as a Level I – Supplement to update the PM. The sponsor submitted clinical data from an open-label clinical study (SUSTAIN 7) in which the two therapeutic dose levels of Ozempic (0.5 mg once weekly [OW] and 1.0 mg OW) were compared to the two therapeutic dose levels of a comparator GLP-1 receptor agonist drug, dulaglutide, 0.75 mg OW and 1.5 mg OW, in terms of glycemic control and other diabetes-related endpoints. The efficacy of both dose levels of Ozempic were statistically superior in glycemic control when compared to corresponding dose levels of dulaglutide, though the absolute magnitude of the treatment difference was relatively small. Appropriate changes were made to the PM. The data were reviewed and considered acceptable. An NOC was issued. |
|
NC # 218582 |
2018-07-25 |
Cancellation Letter Received 2018-08-10 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to transfer a quality control test. The changes were found to be Level III in nature and thus, the sponsor decided to withdraw this submission and re-file the proposed changes as Level III as part of their annual notification. |
|
NC # 215548 |
2018-04-18 |
Cancellation Letter Received 2018-04-27 |
Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add a new pen presentation. The submission exceeded the scope of an NC. The submission was therefore cancelled administratively by the sponsor, so as to be filed as an SNDS. |
|
Drug product (DIN 02471469, 02471477) market notification |
Not applicable |
Date of first sale: 2018-02-22 |
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
|
NDS # 202059 |
2017-01-19 |
Issued NOC 2018-01-04 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Ozempic
Date SBD issued: 2018-04-04
The following information relates to the New Drug Submission for Ozempic.
Semaglutide
1.34 mg/mL solution, subcutaneous
Drug Identification Number (DIN):
- DIN 02471469 - 1.34 mg/mL solution, pen dispenses 1 mg dose
- DIN 02471477 - 1.34 mg/mL solution, pen dispenses 0.25 mg or 0.5 mg dose
Novo Nordisk Canada Inc.
New Drug Submission Control Number: 202059
On January 4, 2018, Health Canada issued a Notice of Compliance to Novo Nordisk Canada Inc. for the drug product Ozempic.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-risk profile of Ozempic is favourable for the once-weekly treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with:
- diet and exercise in patients for whom metformin is inappropriate due to a contraindication or intolerance.
- metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
- metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
- basal insulin with metformin, when diet and exercise plus basal insulin with metformin do not achieve adequate glycemic control.
1 What was approved?
Ozempic, an antihyperglycemic agent, belongs to a class of drugs called glucagon-like peptide-1 (GLP-1) receptor agonists. Ozempic was authorized for the once-weekly treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with:
- diet and exercise in patients for whom metformin is inappropriate due to a contraindication or intolerance.
- metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
- metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
- basal insulin with metformin, when diet and exercise plus basal insulin with metformin do not achieve adequate glycemic control.
Ozempic has not been studied in combination with prandial insulin (short acting). Ozempic is not a substitute for insulin.
Ozempic should not be used in patients with type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus) or for the treatment of diabetic ketoacidosis.
Ozempic was studied in a limited number of patients 75 years of age or older.
The safety and efficacy of Ozempic have not been studied in pediatric (<18 years of age) populations. Ozempic is not indicated for use in pediatric patients.
Ozempic is contraindicated in patients with
- a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2.
- a hypersensitivity to Ozempic or to any of the product components.
Ozempic should also not be used during pregnancy or breastfeeding.
Ozempic 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.
Ozempic (1.34 mg/mL semaglutide) is presented as a solution. In addition to the medicinal ingredient, the solution contains disodium phosphate dihydrate, propylene glycol, phenol, and water for injection.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Ozempic Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Ozempic approved?
Health Canada considers that the benefit-risk profile of Ozempic is favourable for the once-weekly treatment of adult patients with type 2 diabetes mellitus (T2DM) to improve glycemic control, in combination with:
- diet and exercise in patients for whom metformin is inappropriate due to a contraindication or intolerance.
- metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
- metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
- basal insulin with metformin, when diet and exercise plus basal insulin with metformin do not achieve adequate glycemic control.
Type 2 diabetes mellitus is a progressive and chronic metabolic disorder with significant risks associated with failure to manage the disease, including cardiovascular disease. It arises from deficient insulin activity due to decreased insulin secretion, decreased insulin sensitivity/insulin resistance, or a combination of these.
Ozempic (semaglutide) is a glucagon-like peptide-1 (GLP-1) receptor agonist similar to other approved products in this class (e.g., Victoza, Eperzan, Trulicity). The GLP-1 receptor agonists act in glycemic control through several mechanisms, including glucose-dependent release of insulin, up-regulation of insulin biosynthesis, and lowering of glucagon secretion. Ozempic and other GLP-1 receptor agonists have been shown to decrease blood glucose over extended periods of time as measured by hemoglobin A1c (HbA1c) levels.
First-line therapy for T2DM is lifestyle and diet modification to reduce weight and manage blood sugar. First-line pharmaceutical treatment is metformin, followed by the addition of second-line medications to the regimen until adequate glycemic control is attained. Second-line treatments include sulfonylurea, insulin, dipeptidyl peptidase-4 inhibitors, thiazolidinedione or GLP-1 receptor agonists similar to Ozempic.
Ozempic has been shown to be efficacious in patients with T2DM. The market authorization was based on five pivotal studies which had primary endpoints of reduction in HbA1c from baseline compared to placebo or comparators. Ozempic administered with other antidiabetic drugs or as monotherapy provided statistically significant improvements in HbA1c over placebo and each comparator (insulin glargine, extended-release exenatide, sitagliptin). The magnitude of change in HbA1c from baseline was 1.21 to 1.45% for Ozempic 0.5 mg, 1.54 to 1.85% for Ozempic 1.0 mg, 0.02 to 0.09% for placebo, and 0.55 to 0.95% for the comparators. In the Ozempic 0.5 mg and 1.0 mg groups respectively, 47 to 66% and 57 to 74% of the patients achieved a target HbA1c of <7% with no severe or blood glucose confirmed events of hypoglycemia and no weight gain. Ozempic also showed secondary-endpoint improvements in all of the studies. A cardiovascular outcome trial (CVOT) showed no increase in major adverse cardiac event (MACE) risk with long-term treatment with Ozempic.
The most frequently reported adverse reactions in clinical studies were gastrointestinal (GI) disorders, including nausea, diarrhea and vomiting. In general, these reactions were mild or moderate in severity. Patients who received Ozempic had more adverse events (AEs) than placebo-treated patients but there was a similar incidence to those on comparator drugs. However, Ozempic-treated patients had significantly more GI-related AEs, and in many cases this was the cause of early discontinuation from the studies. In the CVOT, there was a significantly increased incidence of diabetic retinopathy complications in Ozempic patients. Given the lack of similar findings in the other pivotal studies, the labelling was updated to include these findings. In patients that were also receiving sulfonylurea or basal insulin in addition to Ozempic, hypoglycemic events were more common. In terms of known risks associated with the GLP-1 receptor agonist drug class, the Ozempic clinical program did not demonstrate an increased risk of pancreatitis or malignancies (including medullary thyroid carcinoma). However, the risk of thyroid C-cell tumours (including medullary thyroid carcinoma) is stated in a Serious Warnings and Precautions box in the Ozempic Product Monograph.
A Risk Management Plan (RMP) for Ozempic was submitted by Novo Nordisk 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Ozempic Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Ozempic was accepted.
Overall, the benefits of Ozempic as an add-on treatment for glycemic control in adult patients with T2DM outweigh the risks, assuming adequate labelling and risk management plans are implemented to address the safety concerns noted above.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Ozempic?
Submission Milestones: Ozempic
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2016-09-22 |
| Submission filed: | 2017-01-19 |
| Screening | |
| Screening Acceptance Letter issued: | 2017-03-10 |
| Review | |
| Biostatistics Evaluation complete: | 2017-11-03 |
| Review of Risk Management Plan complete: | 2017-11-06 |
| Quality Evaluation complete: | 2017-12-22 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-01-02 |
| Clinical Evaluation complete: | 2018-01-03 |
| Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate: | 2018-01-04 |
The Canadian regulatory decision on the non-clinical and clinical review of Ozempic was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
Questions raised by the EMA and FDA were reviewed and considered during the quality evaluation and recommendation for Ozempic.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Ozempic, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) providing Health Canada with:
- Periodic Safety Update Reports/Periodic Benefit Risk Evaluation Reports for Ozempic every 6 months as per the pharmacovigilance plan. The reports should include information which may potentially be related to the safety profile of Ozempic (e.g., gastrointestinal adverse drug reactions, malignancies, serious infections, diabetic retinopathy, cardiovascular adverse events, as well as laboratory abnormalities [neutrophils, platelet count, liver enzymes, lipids]).
- An updated Canadian Risk Management Plan in accordance with Canadian labelling in order to capture the post-approval commitments to Health Canada and other regulatory agencies.
- Ozempic medical educational materials for review prior to the launch of the product.
- All of the reports/correspondence pertaining to post-approval commitments from the other major regulatory authorities.
6 What other information is available about drugs?
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 Notice of Compliance with Conditions (NOC/c) Guidance Document, 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.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
The medicinal ingredient of Ozempic, semaglutide, acts as a glucagon-like peptide-1 (GLP-1) receptor agonist that selectively binds to and activates the GLP-1 receptor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells.
Semaglutide stimulates insulin secretion in a glucose-dependent manner. Simultaneously, semaglutide lowers glucagon secretion, also in a glucose-dependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, when the blood glucose is low semaglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of blood glucose lowering also involves a delay in gastric emptying.
The clinical pharmacology program included 16 studies that were conducted to evaluate the pharmacokinetic/pharmacodynamic (PK/PD) properties of semaglutide and to assess potential drug interactions and the impact on the QTc interval. The program was supported by in vitro studies and population PK modelling. The clinical pharmacology studies were conducted in healthy subjects, patients with type 2 diabetes mellitus (T2DM), subjects with obesity, and subjects with renal and hepatic impairment. These studies were performed with single doses (majority used 0.5 mg dose) or multiple doses (1.0 mg steady state). Overall, compared to placebo, semaglutide reduced both fasting and postprandial blood glucose levels.
The PK properties of semaglutide were compatible with the once-weekly dosing, with a time to maximum serum concentration (tmax) of 1 to 3 days at steady state and a time of approximately 1 week for one half of the total amount to be degraded by biological processes (t1/2). Steady-state exposure was comparable between patients with T2DM and healthy volunteers. The population PK analysis indicated that body weight is the only covariate of importance for semaglutide exposure; with higher weight resulting in lower exposure. No clinically relevant drug-drug interactions were observed between semaglutide and any of the other products tested. The results obtained from the study pertaining to the impact on the QTc interval are described in the Ozempic Product Monograph.
In conclusion, the PK and PD properties of semaglutide have been adequately characterised. From the clinical pharmacology point of view and as labelled, there are no outstanding issues that preclude market authorization of semaglutide (Ozempic), at the recommended dose and dosing, for the specified indications.
For further details, please refer to the Ozempic Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Ozempic (semaglutide) in patients with T2DM was evaluated in five pivotal studies SUSTAIN 1-5; i.e., Studies 3623, 3626, 3624, 3625 and 3627 respectively.
Study 3623 (SUSTAIN 1)
Study 3623 (SUSTAIN 1) was designed to test the efficacy and safety of two doses of Ozempic (0.5 mg and 1.0 mg injections weekly) compared to placebo in drug-naïve patients with T2DM. The study was 30 weeks and had a primary endpoint of change in hemoglobin A1c (HbA1c). A dose of 0.5 mg was received by 128 patients, 1.0 mg by 130 patients, and placebo was received by 129 patients.
At Week 30, a reduction in HbA1c from baseline was seen with both doses of Ozempic ( 1.45% with 0.5 mg and 1.55% with 1.0 mg), while a smaller drop in levels was seen with placebo ( 0.02%). The proportion of patients who achieved a target HbA1c of <7% without severe or symptomatic hypoglycemia (confirmed by blood glucose levels) and no weight gain was 66% for the 0.5 mg Ozempic group, 65% for the 1.0 mg Ozempic group, and 19% with placebo. The confirmatory secondary endpoint, change in body weight, was clinically significant. Differences between the two Ozempic groups were not analyzed in the study report and often there did not appear to be any added benefit to the 1.0 mg Ozempic dose when compared to the 0.5 mg dose, including the primary endpoint.
Study 3626 (SUSTAIN 2)
Study 3626 (SUSTAIN 2) was designed to test the efficacy and safety of two doses of Ozempic (0.5 mg and 1.0 mg injections weekly) compared to sitagliptin (100 mg tablets daily) when added on to T2DM treatment with metformin and/or thiazolidinedione. In this 56-week, double-blind study, 409 patients received Ozempic 0.5 mg (plus sitagliptin placebo), 409 patients received Ozempic 1.0 mg (plus sitagliptin placebo), and 407 patients received sitagliptin (plus either 0.5 mg or 1.0 mg semaglutide placebo). While the study allowed the use of thiazolidinedione, only about 5-6% of the patients were on pioglitazone in addition to metformin and their assigned study drug.
Patients in the sitagliptin group were more likely to require rescue medications due to hyperglycemic episodes. The primary endpoint was met, with a significant decrease in HbA1c levels in both Ozempic groups ( 1.32% and 1.61%) compared to sitagliptin ( 0.55%) at Week 56. When the proportion of patients reaching target HbA1c levels was analyzed, it was found that 74% patients treated with Ozempic 1.0 mg and 63% of patients treated with Ozempic 0.5 mg reached the composite target of <7% without severe or blood glucose-confirmed hypoglycemic episodes or weight gain ; whereas 27% of patients treated with sitagliptin met this target. Secondary analyses found that a greater proportion of patients treated with Ozempic reached the desired treatment targets for HbA1c and weight loss responses than patients treated with sitagliptin. Supportive secondary endpoints favoured Ozempic, though the 0.5 mg dose showed no difference from sitagliptin for blood lipids and 7-point self-monitored plasma glucose (SMPG) increment.
Study 3624 (SUSTAIN 3)
Study 3624 (SUSTAIN 3) compared only the 1.0 mg dose of Ozempic to the active comparator exenatide in T2DM patients taking oral antidiabetic drugs. In this 56-week randomized open-label, active-controlled study, 813 patients who were on metformin alone (49%) or metformin with sulfonylurea (45%) were randomized 1:1 to Ozempic 1.0 mg once-weekly or extended-release exenatide 2.0 mg once-weekly. Patients were to continue pre-trial background medication throughout the entire study. The primary objective was to compare the effect of Ozempic 1.0 mg once-weekly vs. extended-release exenatide 2.0 mg once-weekly on glycemic control after 56 weeks of treatment.
The mean decrease of HbA1c from baseline at Week 56 was 1.54% for the Ozempic group and 0.92% for the exenatide group. The difference between the two treatment groups was significant and remained so after all sensitivity analyses. At Week 56, significantly more Ozempic patients had achieved the target of <7.0% with no severe or BG-confirmed symptomatic hypoglycemia and no weight gain (56.9% vs. 28.6%), and an odds ratio of 4.03 (95% confidence interval [CI] 2.90; 5.59). At Week 56, the mean weight loss in the Ozempic group was 5.63 kg (6% of body weight) compared to 1.85 kg in the exenatide group (1.8% of body weight). More than half of the patients treated with Ozempic achieved a weight loss of ≥5%.
Study 3625 (SUSTAIN 4)
Study 3625 (SUSTAIN 4) was a 30-week open-label study that compared the two doses of Ozempic (0.5 mg and 1.0 mg) to daily insulin glargine injections in 1,089 T2DM patients. There were approximately 360 patients per treatment group. All patients were also taking baseline metformin (48%), or metformin and sulfonylurea (51%). Patients were to continue pre-trial background medication throughout the entire study. Patients on insulin glargine started on 10 U injected once-daily. The insulin dose adjustment was intended to reach a pre-breakfast fasting plasma glucose of 4.0 to <5.5 mmol/L (71 to <100 mg/dL), with no maximum dose specified. The mean daily insulin dose at the end of the study was 29 U per day. The primary objective was to compare the effect of once-weekly dosing of the two dose levels of Ozempic vs. insulin glargine once-daily on glycemic control after 30 weeks of treatment.
For the Ozempic 0.5 mg dose, the decreases in HbA1c and body weight ( 1.21% and 3.47 kg) were marginally lower than in other studies with this dose, while the differences achieved with the 1.0 mg dose ( 1.64% and 5.17kg) were similar and of larger magnitude than the 0.5 mg dose. All three treatment groups saw a decrease from baseline HbA1c, but Ozempic patients were more likely to achieve a target of HbA1c <7% with no severe hypoglycemic episodes and no weight gain (47% and 64% vs. 16%). Superiority of Ozempic 0.5 mg and 1.0 mg compared to insulin glargine was also shown for the key secondary endpoint, weight loss. Weight loss of ≥5% was achieved by 37.0%, 50.8% and 4.7% of subjects in the three groups respectively. Interestingly, patients in the insulin glargine group gained weight during this study (+1.15 kg). Primary and key secondary endpoints remained significant after sensitivity analyses. Blood glucose and lipid parameters as well as other endpoints (systolic blood pressure, waist circumference, high-sensitivity C-reactive protein, plasminogen activator inhibitor-1) tended to show better results in the Ozempic groups, though changes were more frequently significant in the 1.0 mg group.
Study 3627 (SUSTAIN 5)
Study 3627 (SUSTAIN 5) was a 30-week blinded study that compared the two doses of Ozempic (0.5 mg and 1.0 mg) to placebo in T2DM patients who were already taking basal insulin with or without metformin. There were approximately 130 T2DM patients per treatment group. In patients with a baseline HbA1c between 7% and 8%, their basal insulin dose was reduced by 20% prior to the onset of the study medication. They were allowed to increase their dose up to baseline again if needed between Weeks 10 and 16. All patients were allowed to decrease their basal insulin dose. Treatment was completed by 89.1% of the patients, and there were more patients in the Ozempic groups (87% in both) than the placebo group (76%) that completed treatment without the use of rescue medications.
The baseline HbA1c was similar across all groups. At Week 30, the change from baseline was 1.45% in the Ozempic 0.5 mg group, 1.85% in the Ozempic 1.0 mg group, and 0.09% in the placebo group. At Week 30, patients in the 0.5 mg group had a decrease in body weight of 3.67 kg (4.21% of body weight), patients in the 1.0 mg group had a decrease in body weight of 6.42 kg (7.27% of body weight) and patients that received placebo had a decrease in body weight of 1.36 kg (1.3% of body weight). Both the primary and key secondary endpoints were statistically significant compared to placebo for both dose levels of Ozempic and remained so after sensitivity analyses. Ozempic-treated patients were much more likely to achieve HbA1c <7% without severe or blood glucose confirmed symptomatic hypoglycemia and no weight gain. Weight loss of at least 5% body mass was achieved by 42%, 66% and 11% of patients in the Ozempic 0.5 mg and 1.0 mg groups and the placebo group, respectively.
Patients with an HbA1c between 7 and 8% at baseline had a reduction in basal insulin dose prior to starting study medications. After Week 10, when patients were allowed to have their insulin dose altered according to glycemic needs, the placebo patients increased their dose to slightly below baseline (7% less than baseline) while the Ozempic groups kept their insulin dose near the reduced level (0.5 mg patients at 18% less than baseline and 1.0 mg patients at 24% less than baseline). In patients who did not have their basal insulin adjusted at baseline (HbA1c >8%), marginal decreases in baseline dose were seen in the 0.5 mg group (~5% dose reduction) and more so in the 1.0 mg group (~10% reduction).
Overall Analysis of Efficacy
All five pivotal studies had the same primary endpoint of change from baseline HbA1c after a period of either 30 or 56 weeks. Four of the 5 studies tested both the Ozempic 0.5 mg and 1.0 mg subcutaneous weekly dose levels. Two studies compared Ozempic to placebo and three studies compared Ozempic to active comparators (insulin glargine, extended-release exenatide, sitagliptin). In 4 of the 5 studies, T2DM patients were also taking their baseline anti-diabetic medications (e.g., metformin, sulfonylurea, thiazolidinediones, basal insulin).
All of the studies demonstrated superiority of both dose levels of Ozempic over the placebo or comparator groups in terms of reduction in HbA1c from baseline. With the Ozempic 0.5 mg dose, patients had a reduction from baseline HbA1c of 1.21 to 1.45%. With the Ozempic 1.0 mg dose, patients demonstrated a reduction from baseline HbA1c of 1.54 to 1.85%. The proportion of patients who reached a target of HbA1c <7% with no episodes of severe or blood glucose-confirmed symptomatic hypoglycemia and no weight gain was 47 to 66% for the 0.5 mg dose and 57 to 74% for the 1.0 mg dose. In each study, patients with unacceptably high blood glucose levels were allowed to receive rescue medication to lower their blood glucose, after which they were excluded from the primary analysis. Among placebo patients, 69 to 76% of patients completed the study without the need for rescue medications, compared to 69 to 91% of patients on active comparators, 82 to 87% of patients on Ozempic 0.5 mg, and 74 to 87% of patients on Ozempic 1.0 mg. Across the pivotal studies, significant improvements were demonstrated in fasting plasma glucose, mean 7-point self-measured plasma glucose, body weight, body mass index, waist circumference, C-reactive protein, and systolic blood pressure, and in some studies there were improvements in other endpoints such as blood lipids.
For more information, refer to the Ozempic Product Monograph, approved by Health Canada and available through the Drug Product Database.
Indication
The New Drug Submission for Ozempic was filed by the sponsor with the following indication:
- Monotherapy: Ozempic is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
- Add-on Combination with one or more antidiabetic drugs: when diet and exercise do not achieve adequate glycemic control.
- In patients with established cardiovascular disease: Ozempic is indicated as adjunct to standard treatment of cardiovascular risk factors to reduce the risk of myocardial infarction or stroke in adults with type 2 diabetes mellitus and high cardiovascular risk.
Following the review of the submission, Health Canada revised the indication to:
Ozempic is indicated for the once-weekly treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with:
- diet and exercise in patients for whom metformin is inappropriate due to a contraindication or intolerance.
- metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
- metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
- basal insulin with metformin, when diet and exercise plus basal insulin with metformin do not achieve adequate glycemic control.
Because clinical practice in Canada does not recommend the use of incretin drugs such as GLP-1 receptor agonists as first-line treatment, the labelling indicated that monotherapy with Ozempic should be confined to patients with T2DM for which metformin is not tolerated or is contraindicated.
Also, the sponsor included a two-year cardiovascular outcomes trial (CVOT) in order to support an indication of cardiovascular (CV) risk reduction in T2DM patients with CV risk. The trial showed a significant reduction in MACE (a composite endpoint that included CV death, non-fatal myocardial infarction [MI] and non-fatal stroke) when the results of the two dose levels were pooled, as compared to placebo (hazard ratio [HR] 0.74, 95% CI 0.58; 0.95). While the study was not powered to assess components or individual dose levels (0.5 mg or 1.0 mg), the risk reductions were not significant for CV death or non-fatal MI, and the composite endpoint showed a significant risk reduction only when the two dose levels were combined. At this time, the evidence from the CVOT is adequate to negate the need for a post-market CVOT, but inadequate to support an indication of CV risk reduction.
Clinical Safety
The clinical safety of Ozempic was evaluated in seven randomized, placebo- or active-controlled Phase IIIa studies of 30 or 56 weeks duration designed to evaluate the efficacy and safety of Ozempic (0.5 mg and 1.0 mg) in patients with T2DM. A total of 3,150 patients with T2DM were treated with Ozempic; 1,373 patients with 0.5 mg, and 1,777 with 1.0 mg Ozempic, and 1,657 patients were treated with comparators or placebo. The mean duration of exposure among the Ozempic and comparator treatment groups was approximately 10 months. Across the treatment groups, the mean age of patients was 57 years, 3.2% were 75 years or older and 57% were male. In these studies, 60% of the patients were White, 6% were Black or African American, 31% were Asian, and 16% were identified as having Hispanic or Latino ethnicity. At baseline, patients had T2DM for an average of 8.2 years and had a mean HbA1c of 8.2%.
Adverse events (AEs) were reported by 1,015 patients (73.4%) in the 0.5 mg Ozempic group, 1,301 patients (72.7%) in the 1.0 mg Ozempic group, and 1,136 patients (68.7%) in the comparator/placebo group. Common AEs that were reported more frequently with Ozempic than with the comparator were gastrointestinal (GI) disorders (nausea, diarrhea, vomiting and constipation), decreased appetite, and increased levels of lipase. The proportion of patients with serious adverse events (SAEs) was higher with Ozempic (0.5 mg: 6.6%; 1.0 mg: 6.7%) than with comparator products (5.8%).
The proportion of patients who discontinued treatment prematurely due to AEs and SAEs was higher with Ozempic (0.5 mg: 6.0% and 1.0 mg: 9.1%) than with comparators/placebo (3.4%). Among the patients treated with Ozempic that discontinued due to AEs and SAEs, 29% withdrew due to nausea, 15% due to vomiting, and 18% due to diarrhea. A total of 37 patients had SAEs that led to premature treatment discontinuation.
The sponsor included a two-year cardiovascular outcome trial (CVOT) to study the CV risk of Ozempic compared to placebo in adults with T2DM. A total of 3,297 patients were randomized to receive treatment, 823 to Ozempic 0.5 mg, 819 to Ozempic 1.0 mg, and 1,644 to placebo. A larger proportion of patients prematurely discontinued treatment with Ozempic than with placebo. The Ozempic 0.5 mg group had a 19.9% discontinuation rate, 22.6% from the Ozempic 1.0 mg group, and 18.8% from the placebo group. Adverse events were reported by 88.9% of patients treated with Ozempic 0.5 mg, 88.2% of patients treated with Ozempic 1.0 mg and 88.4% of patients treated with placebo. The most commonly reported AEs in the trial were nausea, diarrhea vomiting, constipation, dyspepsia, increased lipase, and increased amylase levels. Serious adverse events were reported by 264 patients (32.1%) treated with Ozempic 0.5 mg, 240 patients (29.3%) treated with Ozempic 1.0 mg, and 574 patients (34.9%) treated with placebo; 106 patients permanently discontinued the trial due to the SAEs.
Adverse Events of Special Interest
Pancreatitis: Specific labelling regarding the risk of pancreatitis exists for all drugs that are in the class of drugs for GLP-1 receptor agonists. In glycemic control trials, acute pancreatitis was confirmed by the Event Adjudication Committee (EAC) in 7 patients treated with Ozempic (0.3 cases per 100 patient-years of observation) vs. 3 patients treated with another GLP-1 receptor agonist (0.2 cases per 100 patient-years of observation); no cases were reported with placebo or other drug classes. One case of chronic pancreatitis was confirmed in an Ozempic-treated patient. In the 2-year CVOT, acute pancreatitis was confirmed by adjudication in 8 Ozempic-treated patients (0.27 cases per 100 patient-years of observation) and in 10 placebo-treated patients (0.33 cases per 100 patient-years of observation), both on a background of standard of care. There were no cases of chronic pancreatitis. Ozempic-treated patients did have an increased incidence of elevated pancreatic enzymes (amylase and lipase) but these did not appear to be associated with symptoms and the increases were often transient.
Gastrointestinal Disorders: Gastrointestinal (GI) AEs consistently occurred in more patients and with a higher frequency in the Ozempic groups than in the placebo or active comparator groups. Ozempic-treated patients also had higher incidences of serious and/or severe GI AEs than patients taking comparators or placebo, and were more likely to discontinue from the studies due to GI events. In the CVOT, three patients had GI AEs that were fatal, 1 event in 1 patient treated with Ozempic 0.5 mg and 3 events in 2 patients treated with placebo.
Malignancies: No overall increased risk for malignancy was reported with the use of Ozempic, and there did not appear to be an increased risk for individual cancer types, including thyroid neoplasms. However, the Warnings and Precautions section of the Ozempic Product Monograph was updated to include the risk of thyroid C-cell tumours. The warning in the Serious Warnings and Precautions box was included as part of the class-labelling for all GLP-1 receptor agonists.
Cardiovascular Events: In the placebo-controlled studies, Ozempic 0.5 mg and 1 mg resulted in a mean increase in heart rate of 2 to 3 beats per minute. There was a mean decrease in heart rate of 0.3 beats per minute in placebo-treated patients. The Ozempic Product Monograph was updated to reflect this observation.
The general CV safety of Ozempic was evaluated in the CVOT with T2DM patients at high CV risk. It was demonstrated that Ozempic is not associated with increased CV events. The primary objective was to test whether the upper limit of the 95% CI for the hazard ratio (HR) of major adverse cardiac events (MACE) associated with Ozempic was below the pre-specified non-inferiority margin of 1.8. A total of 254 adjudicated primary MACE events were reported during the trial; 108 MACE were observed in the Ozempic group (3.2 per 100 patient-years), and 146 in the placebo group (4.3 per 100 patient-years). The stratified Cox proportional hazards model for the primary analysis estimated an HR of 0.74 (95% CI 0.58; 0.95) associated with Ozempic, corresponding to an estimated 26% risk reduction. The upper bound of 0.95 ruled out the risk margin of 1.8, confirming the non-inferiority of Ozempic vs. placebo.
Diabetic Retinopathy: In the CVOT, a significantly increased risk of EAC-confirmed events of diabetic retinopathy complications was observed with Ozempic (50 [3.0%] patients) compared with placebo (29 [1.8%] patients) (HR: 1.76, 95% CI 1.11; 2.78). The patient population enrolled in the CVOT was at high risk of having diabetic retinopathy complications. The mean age was 64.6 years, the mean diabetes duration was 13.89 years, the mean HbA1c was 8.70%, 58.0% of the patients used insulin and 29.4% of the patients had pre-existing diabetic retinopathy (non-proliferative in the majority of the cases). In contrast to the other Phase IIIa studies, no exclusion criteria regarding proliferative diabetic retinopathy or maculopathy were implemented in the CVOT. Post-hoc analysis was conducted to identify the population for which the risk might be higher. Compared to the overall population, the patients who had EAC-confirmed events of diabetic retinopathy complications during the trial were characterised by longer diabetes duration (17.53 years), had higher baseline HbA1c (9.37%), were receiving insulin at baseline (75.9%), and had pre-existing diabetic retinopathy (83.5%). In the Phase IIIa studies (excluding CVOT), AEs of diabetic retinopathy were reported in a similar proportion of patients treated with Ozempic (1.7%) and comparator products (2.0 %).
Overall Analysis of Safety
The safety profile for Ozempic demonstrated an increased risk of many GI symptoms, particularly nausea, diarrhea and vomiting. The dose escalation protocol in which subjects received an introductory period of 0.25 mg and 0.5 mg was intended to decrease the GI symptoms associated with the drug. The majority of GI events occurred in the first weeks or months of treatment and abated thereafter, and most events were mild or moderate. However, there were increased incidences of GI SAEs and discontinuations due to GI AEs. Other prevalent AEs of interest included reduced appetite and increased lipase. In terms of hypoglycemic episodes, there was an increased risk of events when Ozempic was given in conjunction with sulfonylurea or insulin. An additional finding of interest in the CVOT was an increased risk of diabetic retinopathy complications with Ozempic treatment in patients with pre-existing retinopathy. This increased risk was associated with patients on insulin, with pre-existing diabetic retinopathy, and with a long duration of T2DM. Increased risk of cholelithiasis was also seen with Ozempic in the Phase IIIa program. The sponsor monitored trials for events of pancreatitis and medullary thyroid carcinoma which had been identified as risks based on other drugs in the same class and on animal studies, respectively. There were no findings indicating increased risk of pancreatitis and no cases of medullary thyroid carcinoma.
Appropriate warnings and precautions are in place in the approved Ozempic Product Monograph to address the identified safety concerns.
For more information, refer to the Ozempic Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The results of the non-clinical in vitro and in vivo primary pharmacodynamic studies demonstrated proof of concept for the indicated clinical use of Ozempic. Ozempic was shown to be a potent and selective GLP-1 receptor agonist that binds to the receptor with high affinity. Ozempic also binds to human albumin with high affinity, which is anticipated to prolong the half-life of the drug substance. In an established mouse model of T2DM Ozempic dose-dependently decreased blood glucose concentrations, systemic exposure, and HbA1c levels.
In all of the animal species tested, Ozempic administration resulted in decreased food consumption leading to reduced body weight gain and body weight.
Repeat-dose toxicity studies were conducted in mice, rats, and monkeys using subcutaneous administration. In mice, thyroid-cell hyperplasia was observed at all doses tested. A no-observed-adverse-effect-level (NOAEL) could therefore not be identified in mice. Two-year carcinogenicity studies were conducted in mice and rats in which compound-related increases in the rates of focal/multifocal C-cell hyperplasia, C-cell adenoma, and C-cell carcinoma of the thyroid were observed. A NOAEL for the carcinogenicity of Ozempic could not be identified in either mice or rats. Thyroid C-cell tumours in rodents are a class effect for GLP-1 receptor agonists. The human relevance of the thyroid C-cell tumours observed in these species is unknown and could not be determined based on the results of the clinical or non-clinical studies. No other compound-related tumours were observed in the carcinogenicity studies.
Ozempic was non-genotoxic in a standard battery of genotoxicity tests.
In monkeys, electrocardiogram recordings revealed a continuous left-bundle-branch-block in one female at a dose of 0.36 mg/kg body weight administered twice weekly, the highest dose tested. Histopathology also revealed multifocal myocardial vacuolation, with karyomegaly, in the left ventricle of one male at the same dose. The NOAEL in monkeys was therefore determined to be the next lowest dose of 0.06 mg/kg body weight twice weekly.
In fertility, embryo-fetal development and postnatal development studies in rats, rabbits and monkeys, there was an increased incidence of visceral malformations in all species and skeletal malformations in rats and monkeys beginning at doses below the equivalent maximum recommended human dose. In rats, a decrease in the number of corpora lutea was observed at the two highest doses (0.03 and 0.09 mg/kg body weight/day), leading to fewer implantations and reduced litter size. In rabbits, an increase in post-implantation loss was observed at the two highest doses (0.0025, and 0.0075 mg/kg body weight/day). In monkeys, a higher incidence of pre-natal loss at the two highest doses and a higher incidence of post-natal loss at all doses were observed (0.015, 0.075, and 0.15 mg/kg body weight every 3 days). Infant monkeys were also slightly smaller at delivery at the two highest doses, but recovered during the lactation period.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Ozempic Product Monograph. In view of the intended use of Ozempic, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Ozempic Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
Ozempic contains semaglutide, a GLP-1 receptor agonist (or GLP-1 analog) with a 94% sequence homology to human GLP-1. The peptide backbone is produced by yeast fermentation and includes three amino acid substitutions to allow for attachment of an albumin-binding C-18 fatty diacid with a hydrophilic spacer and to increase stabilization against degradation by the enzyme dipeptidyl-peptidase 4.
Semaglutide specifically binds to and activates the GLP-1 receptor, which leads to an increase in intracellular cyclic adenosine monophosphate. Semaglutide stimulates insulin secretion and lowers glucagon secretion in a glucose-dependent manner.
Ozempic is a clear and colourless solution with a pH of 7.4. Ozempic is provided in a pre-filled multi-dose disposable pen, which contains the drug substance, semaglutide, in a 1.5 mL cartridge, equivalent to 2 mg semaglutide.
Characterization of the Drug Substance
Detailed characterization studies were performed to provide assurance that semaglutide consistently exhibits the desired characteristic structure and biological activity.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
Semaglutide is produced using recombinant deoxyribonucleic acid (DNA) technology in yeast.
The manufacturing process of the drug substance consists of a series of stages which include fermentation of the semaglutide precursor, recovery of this target protein, purification, a modification process to create the semaglutide drug substance, and final purification.
The manufacturing process of the drug product, Ozempic, consists of formulation of the drug substance with excipients to become the drug product. The drug product then undergoes fill and finish operations.
Process validation data demonstrated that the drug substance manufacturing process operates in a consistent manner, yielding product of acceptable quality. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
The drug product manufacturing process has been appropriately validated. Appropriate media fill data was provided to demonstrate that the sponsor is able to manufacture in an aseptic manner. The sponsor also provided acceptable antimicrobial effectiveness data to support that phenol is a suitable preservative over the shelf life specification range.
Batch analysis data for final drug substance and drug product batches were of consistent and comparable quality, and within the specifications. The commercial scale material was evaluated and found to be comparable to material used in non-clinical studies and in clinical trials.
The method of manufacturing and the controls used during the manufacturing process for both the drug substance and drug product are valid and are considered to be adequately controlled within justified limits.
Control of the Drug Substance and Drug Product
The proposed commercial specifications for both the Ozempic drug substance and drug product are appropriately justified. The batch analysis data support the specifications. The specification methods have been appropriately validated or qualified, and are considered acceptable; the shelf life and the release test results, for individual and total degradation products, have been demonstrated to be within acceptable limits.
The sponsor has a comprehensive control strategy using a variety of different approaches to ensure the consistent production of Ozempic. The control strategy includes design control, process control, raw material control, in-process control testing, release testing, stability testing, process performance qualification lot testing and characterization. In addition, continued process verification will be performed to confirm that the process as designed remains in control.
Through Health Canada's lot release testing and evaluation program, consecutively manufactured final product lots were tested using a subset of release methods. The testing process confirmed that the methods used in-house are acceptable for their intended use and positively supported the quality review recommendation.
Stability of the Drug Substance and Drug Product
Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at 2°C to 8°C for Ozempic is considered acceptable.
The container closure system was evaluated for compatibility with the drug product, safety, product protection, performance, and transportation impact. It was demonstrated that the container closure system for the drug product is suitable for its intended use.
The sponsor provided dose accuracy studies that demonstrate that the proposed pen is suitable for use.
Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured.
On-site evaluations of the facilities involved in the manufacture and testing of semaglutide and Ozempic were not recommended based on the compliance history of the manufacturing facilities.
The sites involved in production are compliant with Good Manufacturing Practices.
Adventitious Agents Safety Evaluation
No raw materials or excipients of animal or human origin are used for the manufacture of the semaglutide drug substance or drug product. The semaglutide precursor is produced in yeast, and since yeast is not a natural host for mammalian virus, no testing was performed for either endogenous or adventitious mammalian viruses. For the same reason, the manufacturing process has not been evaluated for its viral clearance capacity.
Based on the safety evaluations, it is concluded that Ozempic is safe with regard to virus, transmissible spongiform encephalopathy (TSE) agents, bacteria, mycoplasma, and fungi.
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| OZEMPIC | 02471469 | NOVO NORDISK CANADA INC | SEMAGLUTIDE 1.34 MG / ML |
| OZEMPIC | 02523930 | NOVO NORDISK CANADA INC | SEMAGLUTIDE 2.68 MG / ML |
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