Mounjaro Product Monograph

Recent Major Label Changes

Table of Contents

Sections or subsections that are not applicable at the time of authorization are not listed.

Recent Major Label Changes ..................................................................................................... 2

Table of Contents ........................................................................................................................ 2

Part 1: Healthcare Professional Information ............................................................................ 5

1. 1.

   Indications ....................................................................................................................... 5

   1.1. Pediatrics ............................................................................................................... 5

   1.2. Geriatrics ............................................................................................................... 5

2. 2. Contraindications ............................................................................................................ 6
3. 3. Serious Warnings and Precautions Box ....................................................................... 6
4. 4.

   Dosage and Administration ........................................................................................... 6

   4.1. Dosing Considerations .......................................................................................... 6

   4.2. Recommended Dose and Dosage Adjustment ..................................................... 6

   4.4. Administration ........................................................................................................ 7

   4.5. Missed Dose .......................................................................................................... 7

5. 5. Overdose .......................................................................................................................... 8
6. 6. Dosage Forms, Strengths, Composition, and Packaging ........................................... 8
7. 7.

   Warnings and Precautions ............................................................................................. 9

   General ............................................................................................................................. 9

   Carcinogenesis and Genotoxicity ...................................................................................... 9

   Cardiovascular .................................................................................................................. 9

   Driving and Operating Machinery .................................................................................... 10

   Endocrine and Metabolism .............................................................................................. 10

   Gastrointestinal ............................................................................................................... 10

   Hepatic/Biliary/Pancreatic ............................................................................................... 10

   Immune ........................................................................................................................... 11

   Monitoring and Laboratory Tests .................................................................................... 11

   Ophthalmologic ............................................................................................................... 11

   Perioperative Considerations .......................................................................................... 12

   Psychiatric ....................................................................................................................... 12

   Renal ............................................................................................................................... 12

   Reproductive Health ........................................................................................................ 12

   7.1. Special Populations ............................................................................................. 12

   7.1.1. Pregnancy ........................................................................................................ 12

   7.1.2. Breastfeeding ................................................................................................... 13

   7.1.3. Pediatrics .......................................................................................................... 13

   7.1.4. Geriatrics .......................................................................................................... 13

   7.1.5. Hepatic Impairment .......................................................................................... 13

   7.1.6. Renal Impairment ............................................................................................. 13

8. 8.

   Adverse Reactions ........................................................................................................ 13

   8.1. Adverse Reaction Overview ................................................................................ 13

   8.2. Clinical Trial Adverse Reactions .......................................................................... 14

   8.2.1. Clinical Trial Adverse Reactions – Pediatrics .................................................. 17

   8.3. Less Common Clinical Trial Adverse Reactions .................................................. 18

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ................................................................................................. 18

   8.5. Post-Market Adverse Reactions .......................................................................... 18

9. 9.

   Drug Interactions .......................................................................................................... 19

   9.2. Drug Interactions Overview ................................................................................. 19

   9.4. Drug-Drug Interactions ........................................................................................ 19

   9.5. Drug-Food Interactions ........................................................................................ 20

   9.6. Drug-Herb Interactions ........................................................................................ 20

   9.7. Drug-Laboratory Test Interactions ....................................................................... 20

10. 10.

    Clinical Pharmacology .................................................................................................. 20

    10.1. Mechanism of Action ....................................................................................... 20

    10.2. Pharmacodynamics ......................................................................................... 21

    10.3. Pharmacokinetics ............................................................................................ 22

    10.4. Immunogenicity ............................................................................................... 23

11. 11. Storage, Stability, and Disposal .................................................................................. 24
12. 12. Special Handling Instructions ...................................................................................... 24

Part 2: Scientific Information ................................................................................................... 25

1. 13. Pharmaceutical Information ......................................................................................... 25
2. 14.

   Clinical Trials ................................................................................................................. 26

   14.1. Clinical Trials by Indication .............................................................................. 26

   14.2. Comparative Bioavailability Studies ................................................................ 37

3. 15. Microbiology .................................................................................................................. 38
4. 16. Non-Clinical Toxicology ............................................................................................... 38

Patient Medication Information ............................................................................................... 40

Part 1: Healthcare Professional Information

1. Indications

MOUNJARO (tirzepatide injection) is indicated for once-weekly administration as an adjunct to diet and exercise to improve glycemic control for the treatment of:

• Adult patients with type 2 diabetes mellitus.

  • As monotherapy when metformin is inappropriate due to contraindication or intolerance.

  • In combination with:

    ○ metformin, or

    ○ metformin and a sulfonylurea (see 4.1 Dosing Considerations and 7 Warnings and Precautions), or

    ○ metformin and a sodium-glucose cotransporter 2 inhibitor (SGLT2i), or

    ○ basal insulin with or without metformin (see 4.1 Dosing Considerations and 7 Warnings and Precautions).

• Pediatric patients aged 10 to less than 18 years with type 2 diabetes mellitus in combination with:

  • metformin, or
  • basal insulin with or without metformin

Limitations of Use

MOUNJARO has not been studied in combination with short-acting, medium-acting, or dual formulation insulins.

MOUNJARO is not a substitute for insulin.

MOUNJARO should not be used in patients with type 1 diabetes mellitus (formerly known as insulin-dependent diabetes mellitus or IDDM).

MOUNJARO should not be used for the treatment of diabetic ketoacidosis.

1.1. Pediatrics

Pediatrics (≥10 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of MOUNJARO in combination with metformin and/or basal insulin in pediatric patients aged 10 years of age and older with type 2 diabetes mellitus as an adjunct to diet and exercise has been established. Therefore, Health Canada has authorized an indication for pediatric use in patients aged 10 to less than 18 years.

Pediatrics (<10 years of age): The safety and efficacy of MOUNJARO have not been studied in pediatric patients less than 10 years of age. MOUNJARO is not indicated for use in pediatric patients less than 10 years of age.

1.2. Geriatrics

Geriatrics (≥65 years of age): No overall differences in safety or efficacy were observed in clinical trial patients ≥65 years of age compared to younger patients (see 4 Dosage and Administration, 7.1.4 Geriatrics, and 10.3 Pharmacokinetics).

2. Contraindications

MOUNJARO is contraindicated:

• in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient (including benzyl alcohol when using MOUNJARO KwikPen), or component of the container (see 7 Warnings and Precautions). (For a complete listing of the ingredients, see 6 Dosage Forms, Strengths, Composition, and Packaging).
• in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (see 7 Warnings and Precautions).
• during pregnancy (see 7.1.1 Pregnancy).

3. Serious Warnings and Precautions Box

RISK OF THYROID C-CELL TUMORS

• Tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and carcinomas) at clinically relevant exposures in male and female rats (see 16 Non-Clinical Toxicology). It is unknown whether MOUNJARO causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC) in humans. The human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined (see 7 Warnings and Precautions).
• MOUNJARO is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors (see 2 Contraindications, 7 Warnings and Precautions, 8 Adverse Reactions and 16 Non-Clinical Toxicology).

4. Dosage and Administration

4.1. Dosing Considerations

An increased risk of hypoglycemia was seen with concomitant use of a sulfonylurea or basal insulin with MOUNJARO. To reduce the risk of hypoglycemia, a reduction in the dose of insulin secretagogue or insulin should be considered when MOUNJARO is added to either of these existing therapies. In a clinical trial in patients with a baseline HbA1c ≤8%, the basal insulin dose was decreased by 20% when treatment with MOUNJARO was initiated (see 7 Warnings and Precautions and 8 Adverse Reactions).

4.2. Recommended Dose and Dosage Adjustment

• The recommended starting dose of MOUNJARO is 2.5 mg injected subcutaneously only once weekly. The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control. After 4 weeks, increase the dose to 5 mg injected subcutaneously once weekly.
• If additional glycemic control is needed, increase the dosage in 2.5 mg increments after no less than 4 weeks on the current dose.
• The adult maximum dose is 15 mg injected subcutaneously once weekly.
• The maximum dose for pediatric patients aged 10 to <18 years is 10 mg injected subcutaneously once weekly. Caution is advised when dosing beyond 5 mg in patients weighing ≤60 kg, since safety data are lacking and exposure is predicted to exceed adult dosage (see 10.3 Pharmacokinetics, Pediatrics).
• Renal Insufficiency: No dose adjustment is required in patients with renal impairment (see 10.3 Pharmacokinetics).
• Hepatic Insufficiency: No dose adjustment is recommended in patients with hepatic insufficiency (see 10.3 Pharmacokinetics).
• Geriatrics (≥65 years): No dose adjustment is required in patients over 65 years of age (see 7.1.4 Geriatrics and 10.3 Pharmacokinetics).
• Pediatrics (<10 years): The safety and effectiveness of MOUNJARO have not been studied in patients under 10 years of age. MOUNJARO is not indicated for the treatment of pediatric patients under 10 years of age (see 7.1.3 Pediatrics).

4.4. Administration

• Prior to initiation of MOUNJARO, train patients or caregivers on proper injection technique. Advise the patient or caregiver to carefully read the Instructions for Use included with the Patient Medication Information leaflet before administering the medicinal product.
• A caregiver may give injections or a patient may self-inject if a healthcare provider determines that it is appropriate.
• Patients using the single-dose vial must be instructed to use a syringe equipped with a needle appropriate for subcutaneous injection (for example, a tuberculin or insulin syringe with a 28- to 31-gauge needle more than 2.1 mm in length that is capable of measuring a 0.5 mL dose volume).
• Administer MOUNJARO once weekly, any time of day, with or without meals. MOUNJARO should not be administered daily.
• MOUNJARO is to be injected subcutaneously in the abdomen, in the thigh, or another person should inject in the back of the upper arm. Rotate injection sites with each dose.
• Visually inspect MOUNJARO before use. It should appear clear and colourless to slightly yellow. Do not use MOUNJARO if particulate matter or discoloration is seen.
• When using MOUNJARO with insulin, administer as separate injections and never mix. It is acceptable to inject MOUNJARO and insulin in the same body region, but the injections should not be adjacent to each other.
• MOUNJARO should not be administered intramuscularly or intravenously.
• Patients using the single-dose prefilled pen or vial go through 4 different pens or vials per month.
• Patients using the multi-dose prefilled pen (MOUNJARO KwikPen) go through 1 MOUNJARO KwikPen per month as one pen delivers 4 doses of the same concentration of tirzepatide.

4.5. Missed Dose

If a dose is missed, instruct patients to administer as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once-weekly dosing schedule.

Changing Weekly Dosing Schedule

The day of weekly administration can be changed, if necessary, as long as the time between two doses is at least 3 days (72 hours).

5. Overdose

Potential symptoms from an overdose could be gastrointestinal related (e.g., nausea). In the event of overdose, appropriate supportive care (including frequent blood glucose monitoring) should be initiated according to the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of MOUNJARO.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

MOUNJARO is a clear and colourless to slightly yellow solution that is free of particles. Table 1 lists the dosage forms, strengths, composition, and packaging for each presentation.

Table 1 - Dosage Forms, Strengths, and Composition

MOUNJARO is packaged in a cardboard outer carton and is available in packs of 4 single-dose prefilled pens, or individual single-dose vial.

MOUNJARO KwikPen is packaged in a cardboard outer carton and is available as an individual multi-dose prefilled pen.

7. Warnings and Precautions

See 3 Serious Warnings and Precautions Box.

General

MOUNJARO KwikPen contains 5.4 mg benzyl alcohol in each 0.6 mL dose. Patients with hepatic or renal impairment should be informed of the potential risk of metabolic acidosis due to accumulation of benzyl alcohol over time. Benzyl alcohol may cause allergic reactions (see 2 Contraindications).

Carcinogenesis and Genotoxicity

Risk of Thyroid C-Cell Tumors

Tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) in both sexes of rats in a two-year study at clinically relevant plasma exposures (see 16 Non-Clinical Toxicology). It is unknown whether MOUNJARO causes thyroid C-cell tumors, including MTC, in humans as human relevance could not be determined. Thyroid C-cell tumors in rodents are a known effect for GLP-1 receptor agonists.

MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of MOUNJARO and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness).

In registration clinical trials, there were no cases of MTC observed in patients treated with MOUNJARO.

It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity of serum calcitonin and a high background incidence of thyroid disease. However, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. Similarly, patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation.

Cardiovascular

Heart Rate Increase

MOUNJARO causes an increase in heart rate. Caution should be observed in patients who have cardiac conditions that might be worsened by an increase in heart rate (see 9.4 Drug-Drug Interactions).

Heart Failure

There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV.

Driving and Operating Machinery

No studies on the effects of the ability to drive and use machines have been performed. When MOUNJARO is used in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycemia while driving and using machines.

Endocrine and Metabolism

Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin

Patients receiving MOUNJARO in combination with an insulin secretagogue (e.g., a sulfonylurea) or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of the insulin secretagogue or insulin (see 8.2 Clinical Trial Adverse Reactions and 9.2 Drug Interactions Overview).

Other Incretin Drugs

The use of MOUNJARO in combination with other incretin drugs (e.g., GLP-1 receptor agonists or DPP-4 inhibitors) has not been studied and MOUNJARO should not be used in combination with those drugs. It is unknown if concomitant use of drugs acting via similar pathways affects the efficacy and safety of MOUNJARO.

Gastrointestinal

Use of MOUNJARO has been associated with gastrointestinal adverse reactions, sometimes severe (see 8.2 Clinical Trial Adverse Reactions). MOUNJARO has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and therefore should be used with caution in these patients. Events related to impaired gastric emptying, including severe gastroparesis, have been reported. Monitor and consider dose modification or discontinuation in patients who develop severe gastrointestinal symptoms while on treatment.

Malnutrition

Malnutrition has been reported in patients receiving MOUNJARO, including severe, serious and fatal events. Nutritional guidance and supplementation should be considered for patients receiving MOUNJARO. Discontinuation should be considered for severe or persistent cases of malnutrition.

Hepatic/Biliary/Pancreatic

Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist clinical trials and post-marketing.

In MOUNJARO placebo-controlled trials, acute gallbladder disease (i.e., acute cholecystitis, biliary colic, and cholecystectomy) was reported by 0.6% of MOUNJARO-treated patients and 0% of placebo-treated patients.

If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Acute Pancreatitis

Acute pancreatitis has been observed in patients treated with GLP-1 receptor agonists. In MOUNJARO clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 (0.2%) MOUNJARO-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 (0.1%) comparator-treated patients (0.11 patients per 100 years of exposure).

After initiation of MOUNJARO, observe patients carefully for signs and symptoms of pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis. In the absence of other signs and symptoms of pancreatitis, elevations in pancreatic enzymes alone are not predictive of pancreatitis. If pancreatitis is suspected, MOUNJARO should be discontinued and appropriate management initiated; if confirmed, MOUNJARO should not be restarted. MOUNJARO has not been evaluated in patients with a prior history of pancreatitis and should be used with caution in these patients.

Immune

Hypersensitivity Reactions

Hypersensitivity reactions have been reported with MOUNJARO in clinical trials. There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylactic reactions and angioedema) in patients treated with MOUNJARO. If hypersensitivity reactions occur, discontinue use of MOUNJARO; treat promptly per standard of care, and monitor until signs and symptoms resolve. Do not use in patients with a previous hypersensitivity to tirzepatide or any of the excipients in MOUNJARO (see 2 Contraindications).

Anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. Use MOUNJARO with caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist or related products because it is unknown whether such patients will be predisposed to anaphylaxis with MOUNJARO.

Monitoring and Laboratory Tests

Regular self-monitoring of blood glucose is not needed in order to adjust the dose of MOUNJARO. However, when initiating treatment with MOUNJARO in combination with a sulfonylurea or insulin, self-monitoring of blood glucose may become necessary to reduce the dose of the sulfonylurea or insulin in order to reduce the risk of hypoglycemia.

Patients should be informed that response to all diabetic therapies should be monitored by periodic measurement of HbA1c levels, with a goal of decreasing these levels towards the normal range. HbA1c is useful for evaluating long-term glycemic control.

Ophthalmologic

Diabetic Retinopathy Complications

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. MOUNJARO has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema, and should be used with caution in these patients, with appropriate monitoring.

Non-arteritic anterior ischemic optic neuropathy (NAION)

Events of non-arteritic anterior ischemic optic neuropathy (NAION) have been reported in patients treated with GLP-1 receptor agonist products. There is no identified time interval for when NAION may develop following treatment start. Patients reporting a sudden loss of vision (including partial loss) should be urgently referred for ophthalmological examination and treatment with tirzepatide should be discontinued if NAION is confirmed.

Perioperative Considerations

Aspiration during General Anesthesia or Deep Sedation

MOUNJARO delays gastric emptying. Pulmonary aspiration has been reported in patients receiving long-acting GLP-1 receptor agonists undergoing general anesthesia or deep sedation. For the safe management of patients, consider the benefits and risks, and advise patients of these, prior to such procedures.

Psychiatric

Suicidal Ideation and Behaviour

Monitor patients treated with MOUNJARO for the emergence or worsening of depression, suicidal thoughts or behaviours, and/or any unusual changes in mood or behaviour. Consider the benefits and risks to individual patients prior to initiating or continuing therapy in patients with suicidal thoughts or behaviours, or those who have a history of suicidal attempts.

Renal

Acute Kidney Injury

MOUNJARO has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhea (see 8 Adverse Reactions). These events may lead to dehydration, which could cause a deterioration in renal function including acute renal failure.

In patients treated with GLP-1 receptor agonists, there have been post-marketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of MOUNJARO in patients reporting severe adverse gastrointestinal reactions.

Reproductive Health

Women of childbearing potential are recommended to use contraception when treated with tirzepatide. MOUNJARO is contraindicated during pregnancy (see 2 Contraindications, 7.1.1 Pregnancy, and 16 Non-Clinical Toxicology).

Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO (see 9.4 Drug-Drug Interactions).

7.1. Special Populations

7.1.1. Pregnancy

No clinical trials have been conducted in pregnancy. Studies in animals (i.e., rats and rabbits) have shown reproductive and developmental toxicity, including harm to fetal development and maternal weight loss (see 16 Non-Clinical Toxicology). The extent of exposure in pregnancy during clinical trials is very limited and has been reported in individual cases only.

MOUNJARO is contraindicated during pregnancy (see 2 Contraindications). If a patient wishes to become pregnant, MOUNJARO should be discontinued at least 1 month before a planned pregnancy due to the long half-life of MOUNJARO.

7.1.2. Breastfeeding

In a 5 mg single-dose clinical lactation study, the concentration of tirzepatide in breast milk was found to be either undetectable (limit of detection in breastmilk 4 ng/mL) to very low compared to maternal administered dose and maternal plasma concentrations (see 10.3 Pharmacokinetics). There are no available data on the effects of tirzepatide on the breastfed infant, or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for MOUNJARO and any potential adverse effects on the breastfed infant from MOUNJARO or from the underlying maternal condition.

7.1.3. Pediatrics

MOUNJARO can be used as an add-on to metformin and/or basal insulin in children and adolescents 10 to less than 18 years of age with type 2 diabetes mellitus as an adjunct to diet and exercise.

Safety and effectiveness of MOUNJARO have not been established in children below 10 years of age or weighing <50 kg. MOUNJARO is not indicated for use in patients younger than 10 years.

7.1.4. Geriatrics

No dose adjustment is required in patients over 65 years of age (see 10.3 Pharmacokinetics).

In clinical trials, 1539 (30.1%) MOUNJARO-treated patients were 65 years of age or older and 212 (4.1%) MOUNJARO-treated patients were 75 years of age or older at baseline.

No overall differences in safety or efficacy were detected between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

7.1.5. Hepatic Impairment

In a clinical pharmacology study in adult subjects with varying degrees of hepatic impairment, no change in tirzepatide pharmacokinetics (PK) was observed (see 10.3 Pharmacokinetics). However, there is limited clinical experience in patients with mild, moderate, or severe hepatic impairment; therefore, use MOUNJARO with caution in these patient populations.

7.1.6. Renal Impairment

In clinical trials, 2140 (39.5%) of MOUNJARO-treated patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73 m²), 393 (7.3%) MOUNJARO-treated patients had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73 m²) and 12 (0.2%) had severe renal impairment (eGFR <30 mL/min/1.73 m²) at baseline. MOUNJARO is not recommended in patients with end stage renal impairment due to very limited clinical experience with MOUNJARO in this population (see 10.3 Pharmacokinetics).

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea, diarrhea and vomiting. In general, these reactions were mild or moderate in severity. Gastrointestinal adverse reactions (4.2%) were the most common reasons for treatment discontinuation (see 8.2 Clinical Trial Adverse Reactions). The following serious adverse reactions are described below or elsewhere in the Product Monograph: (see 7 Warnings and Precautions)

• Risk of Thyroid C-cell Tumors
• Gastrointestinal Adverse Reactions
• Acute Pancreatitis
• Diabetic Retinopathy Complications
• Hypersensitivity Reactions
• Use with Medications Known to Cause Hypoglycemia
• Acute Kidney Injury
• Suicidal Ideation and Behaviour
• Aspiration during General Anesthesia or Deep Sedation
• Malnutrition

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in practice and should not be compared to frequencies reported in clinical trials of another drug.

All adult phase 3 studies assessed MOUNJARO 5 mg, 10 mg and 15 mg.

Pool of Placebo-Controlled Trials

The placebo-controlled data in Table 2 are derived from 2 trials (1 monotherapy trial and 1 trial in combination with basal insulin with or without metformin) in patients with type 2 diabetes mellitus (see 14 Clinical Trials). These data reflect exposure of 718 patients to MOUNJARO and a mean duration of exposure to MOUNJARO of 36.6 weeks.

Pool of Phase 3 Placebo and Active-Controlled Trials

The MOUNJARO data for all phase 3 trials in Table 2 are derived from a pool of patients with type 2 diabetes mellitus participating in 7 placebo- or active-controlled Phase 3 glycemic control trials (see 14 Clinical Trials) evaluating the use of MOUNJARO as monotherapy and add-on therapy to oral glucose-lowering medications or insulin. In this pool, a total of 5119 patients with type 2 diabetes mellitus were treated with MOUNJARO for a mean duration of 48.1 weeks.

Common Adverse Reactions

Table 2 shows common adverse reactions, excluding hypoglycemia (shown in Table 3), associated with the use of MOUNJARO in the pool of placebo-controlled and pool of phase 3 placebo- and active-controlled trials in adults. These adverse reactions occurred more commonly with MOUNJARO than with placebo and occurred in at least 1% of patients treated with MOUNJARO.

Table 2 - Adverse Reactions in Phase 3 Trials Reported in ≥1% of MOUNJARO-Treated Adult Patients with Type 2 Diabetes Mellitus

Gastrointestinal Adverse Reactions

In the pool of phase 3 placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving MOUNJARO than patients receiving placebo: MOUNJARO 5 mg (37.1%), MOUNJARO 10 mg (39.6%), MOUNJARO 15 mg (43.6%), (placebo 20.4%). These events were typically mild or moderate in severity. More patients receiving MOUNJARO 5 mg (3.0%), MOUNJARO 10 mg (5.4%), and MOUNJARO 15 mg (6.6%) discontinued treatment due to gastrointestinal adverse reactions compared to patients receiving placebo (0.4%). The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation and decreased over time.

In the pool of 7 phase 3 registration studies (placebo-controlled plus active comparator), gastrointestinal events occurred in 38.0% of patients on MOUNJARO 5 mg, 43.8% of patients on MOUNJARO 10 mg, and 48.8% of patients on MOUNJARO 15 mg. For patients who reported gastrointestinal adverse reactions, investigators graded the maximum severity of gastrointestinal adverse reactions occurring on MOUNJARO 5 mg, 10 mg, and 15 mg as "mild" in 66%, 66%, and 65% of patients, “moderate” in 29%, 30%, 32%, or "severe" in 5%, 4%, and 3% of patients, respectively.

Other Adverse Reactions in Adults

Hypoglycemia

Table 3 summarizes the incidence of hypoglycemic events in the placebo-controlled trials in adults.

Table 3 - Hypoglycemia Adverse Reactions in Placebo-Controlled Trials in Adult Patients with Type 2 Diabetes Mellitus

* Data includes events occurring during 4 weeks of treatment-free safety follow-up. Events after the introduction of a new glucose-lowering treatment are excluded.

** Episodes requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

Hypoglycemia was more frequent when MOUNJARO was used in combination with a sulfonylurea or basal insulin than when used with non-secretagogues (see 7 Warnings and Precautions). In study SURPASS-4, severe hypoglycemia occurred in 0.5%, 0.0%, 0.6% and 1.1% of patients when MOUNJARO 5 mg, 10 mg, 15 mg or insulin glargine, respectively, was co-administered with a sulfonylurea. Severe hypoglycemia or hypoglycemia with glucose <3.0 mmol/L occurred in 13.8%, 9.9%, 12.9% and 21.6% of adult patients when MOUNJARO 5 mg, 10 mg, 15 mg or insulin glargine, respectively, was co-administered with a sulfonylurea.

In the SURPASS-2 study, severe hypoglycemia or hypoglycemia with glucose <3.0 mmol/L occurred in 0.9%, 0.2%, 1.7% and 0.4% of patients when MOUNJARO 5 mg, 10 mg, 15 mg or semaglutide 1 mg, respectively, was co-administered with metformin.

In the SURPASS-3 study, no cases of severe hypoglycemia occurred when MOUNJARO 5 mg, 10 mg, 15 mg or insulin degludec, was co-administered with a SGLT2i. Severe hypoglycemia or hypoglycemia with glucose <3.0 mmol/L occurred in 1.8%, 1.7%, 2.7% and 8.6% of patients when MOUNJARO 5 mg, 10 mg, 15 mg or insulin degludec, respectively, was co-administered with a SGLT2i.

Hypersensitivity Reactions

Hypersensitivity reactions, sometimes severe (e.g., urticaria and eczema), have been reported in clinical trials with MOUNJARO.

In the pool of placebo-controlled trials, hypersensitivity reactions were reported in 3.2% of MOUNJARO-treated patients compared to 1.7% of placebo-treated patients.

In the pool of seven clinical trials, hypersensitivity reactions occurred in 106/2,570 (4.1%) of MOUNJARO-treated patients with anti-tirzepatide antibodies and in 73/2,455 (3.0%) of MOUNJARO-treated patients who did not develop anti-tirzepatide antibodies (see 7 Warnings and Precautions).

Injection Site Reactions

In the pool of placebo-controlled trials, injection site reactions were reported in 3.2% of MOUNJARO-treated patients compared to 0.4% of placebo-treated patients. In the pool of seven clinical trials, injection site reactions occurred in 119/2,570 (4.6%) of MOUNJARO-treated patients with anti-tirzepatide antibodies and in 18/2,455 (0.7%) of MOUNJARO-treated patients who did not develop anti-tirzepatide antibodies.

8.2.1. Clinical Trial Adverse Reactions – Pediatrics

MOUNJARO was administered to 97 pediatric patients 10 years of age and older with type 2 diabetes mellitus for a mean duration of 39.9 weeks. The mean age was 15 years and 61% of patients were female. At baseline, the mean duration of diabetes was 2.4 years, with a mean HbA1c of 8.0% and a mean BMI of 35 kg/m².

The incidence of adverse reactions reported in pediatric patients treated with MOUNJARO 5 mg and 10 mg subcutaneously once-weekly was generally consistent with that described above for adult patients with type 2 diabetes mellitus with the exception of a higher incidence of vomiting, abdominal pain, and hypoglycemia. During the 30-week placebo-controlled period of the study, vomiting occurred in 3%, 16% and 12% of patients and abdominal pain occurred in 9%, 22% and 15% of patients treated with placebo, MOUNJARO 5 mg and 10 mg, respectively. Table 4 summarizes the incidence of hypoglycemic events with blood glucose <3 mmol/L in the trial. No severe hypoglycemia episodes were reported during the trial.

Table 4 - Hypoglycemia Adverse Reactions in the 30 Week Placebo-Controlled Trial in Pediatric Patients 10 to <18 Years of Age with Type 2 Diabetes Mellitus

^a Events after introduction of a new glucose-lowering treatment are excluded.

^b Hypoglycemia reactions reflect the number of patients who reported at least 1 episode of blood glucose <3.0 mmol/L.

Hypersensitivity reactions

In the clinical trial in pediatric patients 10 years of age and older, hypersensitivity reactions (urticaria, bronchospasm) occurred in 2/50 (4%) of MOUNJARO-treated pediatric patients with anti-tirzepatide antibodies and in 0/43 (0%) of MOUNJARO-treated pediatric patients who did not develop anti-tirzepatide antibodies (see 7 Warnings and Precautions).

Injection Site Reactions

In the clinical trial in pediatric patients 10 years of age and older, injection site reactions occurred in 3/50 (6%) of MOUNJARO-treated pediatric patients with anti-tirzepatide antibodies and in 0/43 (0%) of MOUNJARO-treated pediatric patients who did not develop anti-tirzepatide antibodies.

8.3. Less Common Clinical Trial Adverse Reactions

Hepatobiliary disorders: acute gallbladder disease

Pancreatic disorders: pancreatitis

Nervous System Disorders: dysgeusia

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Pancreatic Enzymes

Amylase and lipase were measured in the clinical trials. Treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33% to 38% and lipase of 31% to 42%. The percentage of patients with values above 3 times the upper limit of normal for amylase or lipase at any timepoint on-treatment after baseline are presented below. The clinical significance of elevations of amylase or lipase in patients without other signs and symptoms of pancreatitis is unknown (see 7 Warnings and Precautions).

Table 5 - Amylase and Lipase

%: percentage of patients; N: number of patients; ULN: upper limit of normal

8.5. Post-Market Adverse Reactions

The following additional adverse reactions have been reported during post-approval use of MOUNJARO. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: ileus

Immune system disorders: anaphylactic reaction

Nervous system disorders: dysesthesia

Skin and subcutaneous tissue disorders: angioedema

Renal: acute kidney injury

Eye disorders: non-arteritic anterior ischemic optic neuropathy (NAION)

9. Drug Interactions

9.2. Drug Interactions Overview

MOUNJARO delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. The impact of tirzepatide on gastric emptying was greatest after a single dose of 5 mg and diminished after subsequent doses. Dose adjustments with concomitant use of insulin secretagogues (e.g., sulfonylurea) or insulin may be necessary (see 7 Warnings and Precautions and 8.2 Clinical Trial Adverse Reactions).

9.4. Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 6 - Established or Potential Drug-Drug Interactions

Drugs that Cause PR Interval or QTc Interval Prolongation

In phase 3 clinical studies, no clinically meaningful treatment-emergent differences in PR interval or QTc duration were noted between placebo, tirzepatide, or comparators.

A dedicated thorough QT study has not been conducted with MOUNJARO.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Tirzepatide is a GIP and a GLP-1 receptor agonist. It is an amino acid sequence with a C20-fatty diacid moiety that enables albumin binding and prolongs the half-life.

Tirzepatide is selective to human GIP and GLP-1 receptors. The activity of tirzepatide on the GIP receptor is similar to native GIP hormone. The activity of tirzepatide on the GLP-1 receptor is lower compared to native GLP-1 hormone.

Tirzepatide enhances first- and second-phase insulin secretion, and reduces plasma glucagon levels, both in a glucose-dependent manner.

10.2. Pharmacodynamics

Tirzepatide lowers fasting and postprandial glucose concentrations through the mechanisms described below, and is associated with reduced food intake, in patients with type 2 diabetes.

Insulin Secretion

In a hyperglycemic clamp study in patients with type 2 diabetes mellitus, tirzepatide 15 mg enhanced the first- and second-phase insulin secretion rate (Figure 1).

Figure 1 - Mean Insulin Concentration at 0-120 Minutes During Hyperglycemic Clamp at Baseline and Week 28

Insulin Sensitivity

In a hyperinsulinemic euglycemic clamp study, tirzepatide 15 mg increased whole-body insulin sensitivity by 63%, as measured by M-value at 28 weeks. The M-value was unchanged for patients receiving placebo. In this study, tirzepatide also lowered body weight in patients with type 2 diabetes.

Glucagon Concentration

Tirzepatide reduces the fasting and postprandial glucagon concentrations. After 28 weeks of treatment, tirzepatide 15 mg reduced fasting glucagon concentration by 28% and glucagon AUC after a mixed meal by 43%, compared with no change for placebo.

Gastric Emptying

Tirzepatide delays gastric emptying. The delay in gastric emptying with tirzepatide is largest after the first dose and diminishes with subsequent doses.

Vital Signs

Blood Pressure

In placebo-controlled Phase 3 trials, treatment with MOUNJARO resulted in a mean decrease in systolic and diastolic blood pressure of 6 to 9 mmHg and 3 to 4 mmHg, respectively. There was a mean decrease in systolic and diastolic blood pressure of 2 mmHg each in placebo-treated patients.

Cardiac Electrophysiology

In phase 3 clinical studies, no clinically meaningful treatment-emergent differences in PR interval or QTc duration were noted between placebo, MOUNJARO, or comparators. A dedicated thorough QT study has not been conducted with MOUNJARO.

QTc and PR interval were evaluated using a population pharmacokinetic model-based analyses utilizing all data from healthy participants and patients with T2DM who were given either placebo or tirzepatide in one phase 1 study and two phase 2 studies. Concentration-QTc analysis and concentration-PR interval analysis based upon these three studies did not suggest an association between tirzepatide and QTc prolongation or PR interval duration.

10.3. Pharmacokinetics

The pharmacokinetics of tirzepatide is similar between healthy subjects and patients with type 2 diabetes mellitus. Steady-state plasma tirzepatide concentrations were achieved following 4 weeks of once-weekly administration. Tirzepatide exposure increases in a dose-proportional manner.

Absorption

Following subcutaneous administration, the time to maximum plasma concentration of tirzepatide ranges from 8 to 72 hours. The mean absolute bioavailability of tirzepatide following subcutaneous administration was 80%. Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm.

Distribution

The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes is approximately 10.3 L. Tirzepatide is highly bound to plasma albumin (99%).

Metabolism

Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20-fatty diacid moiety and amide hydrolysis.

Elimination

The primary excretion routes of tirzepatide metabolites are via urine and feces. Intact tirzepatide is not observed in urine or feces. The apparent population mean clearance of tirzepatide is 0.061 L/h with an elimination half-life of approximately 5 days, enabling once-weekly dosing.

Special populations and conditions

• Pediatrics: A population pharmacokinetic analysis was conducted for tirzepatide 5 mg and 10 mg using data from 93 pediatric patients aged 10 to less than 18 years weighing ≥50 kg with type 2 diabetes mellitus. The systemic exposure of tirzepatide in pediatric patients weighing > 70 kg was comparable to exposures observed in adults. However, due to the influence of body weight on tirzepatide clearance and volume of distribution, higher steady-state exposures are predicted for pediatric patients with lower body weights. Predicted exposure in pediatric patients weighing < 60 kg is approximately 1.5- to 2-fold higher than in the adult population. Tirzepatide has not been studied in children less than 10 years of age or weighing < 50 kg.
• Geriatrics: age had no effect on the pharmacokinetics of tirzepatide.
• Sex: sex had no effect on the pharmacokinetics of tirzepatide.

• Pregnancy and breastfeeding: studies characterizing the pharmacokinetics of tirzepatide in pregnant patients have not been performed.

  Following subcutaneous administration of a single 5 mg dose to 11 healthy lactating adult females, the concentration of tirzepatide in breastmilk was found to be undetectable (limit of detection in breastmilk 4 ng/mL) in 164/171 samples assayed. Very low concentrations of tirzepatide (4.6 to 7.2 ng/mL) were detected in 7 breast milk samples and the cumulative amount of tirzepatide detected in the 7 breast milk samples over the 28-day sampling window was equivalent to less than 0.02% of the maternal administered dose, with the last measurable concentrations occurring 5 days post-dose. The AUC of tirzepatide in breastmilk could not be calculated, due to insufficient quantifiable concentrations.

• Ethnic origin: race had no clinically meaningful effect on the pharmacokinetics of tirzepatide.
• Hepatic Insufficiency: hepatic impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with participants with normal hepatic function (see 4 Dosage and Administration and 7.1 Special Populations).
• Renal Insufficiency: renal impairment does not impact the pharmacokinetics of tirzepatide. The pharmacokinetics of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with participants with normal renal function. This was also shown for patients with both T2DM and mild, moderate or severe renal insufficiency based on data from clinical studies (see 4 Dosage and Administration and 7.1 Special Populations).
• Obesity: pharmacokinetic analyses have demonstrated an observed inverse relationship between body weight and tirzepatide exposure, although there was no clinically relevant impact of weight on glycemic control.

10.4. Immunogenicity

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity (including neutralizing antibody) in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to tirzepatide cannot be directly compared with the incidence of antibodies of other products.

Across seven Phase 3 clinical studies, 2,570 (51.1%) MOUNJARO-treated patients developed anti-drug antibodies (ADAs). Of the 2,570 MOUNJARO-treated patients that developed tirzepatide ADAs, 94 (1.9% of the overall population) and 107 (2.1% of the overall population) had neutralizing antibodies against tirzepatide activity on the GIP and GLP-1 receptors, respectively, and 43 (0.9% of the overall population) and 18 (0.4% of the overall population) had neutralizing antibodies against native GIP and GLP-1, respectively.

During the 30-week double-blind placebo-controlled period of the glycemic control trial in pediatric patients 10 to less than 18 years with type 2 diabetes mellitus (see 14 Clinical Trials), 30/61 (49%) of MOUNJARO-treated pediatric patients developed ADAs. Anti-tirzepatide antibodies showed cross reactivity to native GIP or native GLP-1 in 16/61 (26%) and 5/61 (8%) of MOUNJARO-treated pediatric patients positive for post-baseline treatment emergent ADA, respectively. No pediatric patients developed neutralizing antibodies against tirzepatide activity on the GIP or GLP-1 receptors and no pediatric patients developed neutralizing antibodies against native GIP or GLP-1.

There was no evidence of an altered pharmacokinetic profile, or an impact on efficacy associated with the development of ADAs. More MOUNJARO-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies.

1. 11. Storage, Stability, and Disposal

MOUNJARO single-dose prefilled pen and vial:

• Store MOUNJARO in a refrigerator at 2°C to 8°C, up to the expiration date. Do not use MOUNJARO beyond the expiration date.
• Do not freeze MOUNJARO. Do not use MOUNJARO if frozen.
• Store MOUNJARO in the original carton to protect from light.
• If needed, each single-dose pen or vial can be stored unrefrigerated for up to 21 days at temperatures not to exceed 30°C.
• The single-dose prefilled pen must be discarded after use in a puncture-resistant container.
• Throw away all opened vials after use, even if there is medicine left in the vial.

MOUNJARO KwikPen multi-dose prefilled pen:

• Store MOUNJARO KwikPen in a refrigerator at 2°C to 8°C up to the expiration date. Do not use MOUNJARO KwikPen beyond the expiration date.
• Do not freeze MOUNJARO KwikPen. Do not use MOUNJARO KwikPen if frozen.
• Protect MOUNJARO KwikPen from light.
• If needed, each multi-dose prefilled KwikPen can be stored unrefrigerated at temperatures not to exceed 30°C for up to 30 days.
• The MOUNJARO KwikPen must be discarded after four weekly doses in a puncture-resistant container or in accordance with local requirements.

12. Special Handling Instructions

Each single-dose prefilled pen or vial delivers one single dose of tirzepatide only.

Each multi-dose prefilled pen (MOUNJARO KwikPen) delivers four doses of tirzepatide.

MOUNJARO should not be used if the pen, KwikPen, or vial is damaged.

MOUNJARO should not be used if it does not appear clear, free of particles, and colourless to slightly yellow.

If the pen, KwikPen or vial is dropped on a hard surface, it should not be used.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance: tirzepatide

Molecular formula and molecular mass: C₂₂₅H₃₄₈N₄₈O₆₈ and 4813 Dalton

Structural formula:

Physiochemical properties: White to practically white amorphous solid

Table 7 - Tirzepatide Substance Solubility Profile

^a Solubility descriptions are consistent with the USP, Ph.Eur., and Japanese Pharmacopoeias

Product Characteristics:

MOUNJARO (tirzepatide injection), for subcutaneous use, contains tirzepatide, a long-acting once-weekly GIP and GLP-1 receptor agonist. Tirzepatide is based on the GIP sequence and contains aminoisobutyric acid (Aib) in positions 2 and 13, a C-terminal amide, and Lys residue at position 20 is attached to 1,20-eicosanedioic acid via a linker. MOUNJARO has a pH of 6.5-7.5.

14. Clinical Trials

14.1. Clinical Trials by Indication

Glycemic Control in Patients with Type 2 Diabetes

Table 8 - Summary of Patient Demographics for Clinical Trials in Type 2 Diabetes

A total of 6263 adult patients with type 2 diabetes mellitus and inadequate glycemic control were randomized, of whom 4199 received at least one dose of study drug, in 5 placebo- and/or active-controlled, glycemic control global phase 3 studies to evaluate the safety and efficacy of MOUNJARO. Of these, 2082 (33%) patients were ≥65 years and 317 (5%) were ≥75 years. Patients had an overall mean age of 59 years (range 18 to 91 years). 55% were male and 45% were female. The racial distribution of patients in these studies was 81% White, 7% Asian, 4% African American, and 8% other racial origin. The mean body mass index (BMI) overall was 33 kg/m² at baseline, and the duration of diabetes was 9.6 years.

Monotherapy Use of MOUNJARO in Patients with Type 2 Diabetes Mellitus (SURPASS-1)

SURPASS-1 was a 40-week double-blind trial that randomized 478 patients with type 2 diabetes mellitus with inadequate glycemic control with diet and exercise to MOUNJARO 5 mg, 10 mg, or 15 mg once weekly or placebo.

Patients had a mean age of 54 years and 52% were men. The mean duration of type 2 diabetes mellitus was 4.7 years and the mean BMI was 32 kg/m². Overall, 36% were White, 5% were Black or African American, and 35% were Asian; 43% identified as Hispanic or Latino ethnicity.

Monotherapy with MOUNJARO 5 mg, 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 9).

Table 9 - Results at Week 40 in a Trial of MOUNJARO as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control with Diet and Exercise

^a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment due to inadvertent enrollment were excluded. At Week 40, the HbA1c data were missing for 6%, 7%, 14%, and 12% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 2%, 3%, 2%, and 25% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. Missing Week 40 data were imputed using placebo multiple imputation.

^b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.

^c p<0.001 for superiority vs. placebo, controlled for multiplicity.

Combination Therapy Use of MOUNJARO in Patients with Type 2 Diabetes Mellitus

Combination with metformin (SURPASS-2)

SURPASS-2 was a 40-week open-label trial (double-blind with respect to MOUNJARO dose assignment) that randomized 1879 patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin alone to once weekly MOUNJARO 5 mg, 10 mg, or 15 mg or subcutaneous semaglutide 1 mg, all in combination with metformin.

Patients had a mean age of 57 years and 47% were men. The mean duration of type 2 diabetes mellitus was 8.6 years and the mean BMI was 34 kg/m². Overall, 83% were White, 4% were Black or African American, and 1% were Asian; 70% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with semaglutide 1 mg once weekly (see Table 10 and Figure 2).

Table 10 - Results at Week 40 in a Trial of MOUNJARO versus Semaglutide 1 mg in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin

^a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment due to inadvertent enrollment were excluded. At Week 40 the HbA1c endpoint was missing for 4%, 5%, 5%, and 5% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and semaglutide 1 mg, respectively. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 2%, 1%, 1%, and 3% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and semaglutide 1 mg, respectively. Missing Week 40 data were imputed using multiple imputation with retrieved dropout.

^b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.

^c p<0.05 for superiority vs. semaglutide, controlled for multiplicity.

^d p<0.01 for superiority vs. semaglutide, controlled for multiplicity.

^e p<0.001 for superiority vs. semaglutide, controlled for multiplicity.

Note: Displayed results are from modified Intent-to-Treat Full Analysis Set. (1) Observed mean value from Week 0 to Week 40, and (2) least squares mean ± standard error at Week 40 multiple imputation (MI).

Figure 2 - Mean HbA1c (%) Over Time - Baseline to Week 40

Combination with metformin with or without SGLT-2i (SURPASS-3)

SURPASS-3 was a 52-week open-label trial that randomized 1444 patients with type 2 diabetes mellitus with inadequate glycemic control on stable doses of metformin with or without SGLT2i to once weekly MOUNJARO 5 mg, 10 mg, 15 mg, or titrated insulin degludec 100 units/mL once daily. 32% of patients were on SGLT2i. Patients randomized to insulin degludec initially received 10 units once daily. The dose was adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting <5 mmol/L. By the primary endpoint at Week 52, the mean daily insulin degludec dose was 49 U (0.5 U per kilogram) per day.

Patients had a mean age of 57 years and 56% were men. The mean duration of type 2 diabetes mellitus was 8.4 years and the mean BMI was 34 kg/m². Overall, 91% were White, 3% were Black or African American, and 5% were Asian; 29% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with daily insulin degludec (see Table 11 and Figure 3).

Table 11 - Results at Week 52 in a Trial of MOUNJARO versus Insulin Degludec in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin with or without SGLT-2i

^a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment due to inadvertent enrollment were excluded. At Week 52 the HbA1c endpoint was missing for 6%, 10%, 5%, and 9% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and insulin degludec, respectively. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%, 1%, 2%, and 1% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and insulin degludec, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout.

^b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.

^c p<0.001 for superiority vs. insulin degludec, controlled for multiplicity.

Note: Displayed results are from modified Intent-to-Treat Full Analysis Set. (1) Observed mean value from Week 0 to Week 52, and (2) least squares mean ± standard error at Week 52 multiple imputation (MI).

Figure 3 - Mean HbA1c (%) over time - Baseline to Week 52

Combination with metformin, sulfonylurea and/or SGLT-2i (SURPASS-4)

SURPASS-4 was a 104-week open-label trial (52-week primary endpoint) that randomized 2002 patients with type 2 diabetes mellitus with increased cardiovascular risk to MOUNJARO 5 mg, 10 mg, 15 mg once weekly, or insulin glargine 100 units/mL once daily (1:1:1:3 ratio) on a background of metformin (95%) and/or sulfonylureas (54%) and/or SGLT2i (25%) (see Table 12 for further information regarding the number of patients on each combination).

Table 12 - Summary of Baseline Antihyperglycemic Medications in SURPASS-4

Patients had a mean age of 64 years and 63% were men. The mean duration of type 2 diabetes mellitus was 11.8 years and the mean BMI was 33 kg/m². Overall, 82% were White, 4% were Black or African American, and 4% were Asian; 48% identified as Hispanic or Latino ethnicity. Across all treatment groups, 87% of patients had a history of cardiovascular disease as a preexisting condition. At baseline, eGFR was ≥90 mL/min/1.73 m² in 43%, 60 to 90 mL/min/1.73 m² in 40%, 45 to 60 mL/min/1.73 m² in 10%, and 30 to 45 mL/min/1.73 m² in 6% of patients.

Patients assigned to insulin glargine were started on a dose of 10 U once daily. The dose was adjusted weekly throughout the trial using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting <5.6 mmol/L. By the primary endpoint at week 52, the mean daily insulin glargine dose was 44 U (0.5 U per kilogram) per day.

Treatment with MOUNJARO 10 mg and 15 mg once weekly for 52 weeks resulted in a statistically significant reduction in HbA1c compared with insulin glargine once daily (see Table 13 and Figure 4).

Table 13 - Results at Week 52 in a Trial of MOUNJARO versus Insulin Glargine in Adult Patients with Type 2 Diabetes Mellitus in Combination with Metformin and/or Sulfonylurea and/or SGLT-2i

^a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment due to inadvertent enrollment were excluded. At Week 52 the HbA1c endpoint was missing for 9%, 6%, 4%, and 9% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and insulin glargine, respectively. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 0%, 0%, 1%, and 1% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and insulin glargine, respectively. Missing Week 52 data were imputed using multiple imputation with retrieved dropout.

^b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.

^c p<0.001 for superiority vs. insulin glargine, controlled for multiplicity.

Figure 4 - Mean HbA1c (%) Over Time - Baseline to Week 52

Combination with basal insulin with or without metformin (SURPASS-5)

SURPASS-5 was a 40-week double-blind trial that randomized 475 patients with type 2 diabetes mellitus with inadequate glycemic control on insulin glargine 100 units/mL, with or without metformin, to MOUNJARO 5 mg, 10 mg, 15 mg once weekly, or placebo. The dose of background insulin glargine was adjusted using a treat-to-target algorithm based on self-measured fasting blood glucose values, targeting <5.6 mmol/mol.

Patients had a mean age of 61 years and 56% were men. The mean duration of type 2 diabetes mellitus was 13.3 years and the mean BMI was 33 kg/m². Overall, 80% were White, 1% were Black or African American, and 18% were Asian; 5% identified as Hispanic or Latino ethnicity.

The mean starting dose of insulin glargine was 34, 32, 35, and 33 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. At randomization, the initial insulin glargine dose in patients with HbA1c ≤8.0% was reduced by 20%. At week 40, mean dose of insulin glargine was 38, 36, 29, and 59 units/day for patients receiving MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively.

Treatment with MOUNJARO 5 mg, 10 mg and 15 mg once weekly for 40 weeks resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 14).

Table 14 - Results at Week 40 in a Trial of MOUNJARO with Basal Insulin in Adult Patients with Type 2 Diabetes Mellitus with or without Metformin

^a The modified intent-to-treat population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. Patients who discontinued study treatment due to inadvertent enrollment were excluded. At Week 40 the HbA1c endpoint was missing for 6%, 3%, 7%, and 2% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. During the trial, rescue medication (additional antihyperglycemic medication) was initiated by 1%, 0%, 1%, and 4% of patients randomized to MOUNJARO 5 mg, 10 mg, 15 mg, and placebo, respectively. Missing Week 40 data were imputed using placebo multiple imputation.

^b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.

^c p<0.001 for superiority vs. placebo, controlled for multiplicity.

Pediatrics (aged 10 to <18 years)

SURPASS-PEDS was a 30-week double-blind trial, followed by a 22-week open-label extension on active treatment, that randomized 99 patients aged 10 to less than 18 years weighing ≥ 50 kg with type 2 diabetes mellitus and inadequate glycemic control on metformin (68.7%), or basal insulin (8.1%), or both (23.2%) to MOUNJARO 5 mg, MOUNJARO 10 mg, or placebo once weekly.

Patients had a mean age of 15 years, and 61% were female. The mean duration of type 2 diabetes mellitus was 2.4 years, mean HbA1c was 8.0%, mean weight was 97 kg, and the mean baseline BMI was 35 kg/m². There were 5 participants weighing ≤60 kg, including 2 randomized to MOUNJARO at a dose of 5 mg once weekly. Overall, 58% were White, 11% were Black or African American, 6% were Asian, 20% were American Indian or Alaska Native, and 5% were other races; 66% identified as Hispanic or Latino ethnicity.

Treatment with MOUNJARO 5 mg and 10 mg once weekly for 30 weeks, both pooled (primary endpoint) and individually (secondary endpoint), resulted in a statistically significant reduction in HbA1c compared with placebo (see Table 15).

Table 15 - Results at Week 30 in a Trial of MOUNJARO Added to Metformin, or Basal Insulin, or Both in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus

^a The mITT population consists of all randomly assigned participants who were exposed to at least 1 dose of study drug. During the double-blind period, rescue medication was initiated by 6%, 0%, and 0% of patients randomized to placebo, MOUNJARO 5 mg, and 10 mg, respectively. At Week 30 the HbA1c endpoint was missing for 6%, 9% and 18% of patients randomized to placebo, MOUNJARO 5 mg, and 10 mg, respectively. Missing Week 30 data were imputed using multiple imputation with placebo wash-out or with assumption of missing at random.

^b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.

^c p<0.001 (two-sided) for superiority vs. placebo, controlled for multiplicity.

^d Analyzed using logistic regression adjusted for baseline value and other stratification factors.

^e p<0.01 (two-sided) for superiority vs. placebo, controlled for multiplicity.

^f Any missing values at baseline were imputed as missing at random.

14.2. Comparative Bioavailability Studies

A randomized, multicenter, open-label, two-way, single-dose, crossover comparative bioavailability study of MOUNJARO KwikPen (tirzepatide solution in a multi-dose prefilled pen) and MOUNJARO (tirzepatide injection in a single-dose prefilled pen), administered as 0.6 mL x 5 mg/0.6 mL for MOUNJARO KwikPen and as 0.5 mL x 5 mg/0.5 mL for MOUNJARO subcutaneous injection, was conducted in healthy, adult, female and male participants. Comparative bioavailability data from 62 subjects that were included in the statistical analysis are presented in Table 16:

Table 16 - Summary Table of the Comparative Bioavailability Data

¹ MOUNJARO^® KwikPen^® (tirzepatide injection in a multi-dose prefilled pen) Solution, 5 mg/0.6 mL (Eli Lilly Canada Inc.)

² MOUNJARO^® (tirzepatide injection in a single-dose prefilled pen) Solution, 5 mg/0.5 mL (Eli Lilly Canada Inc.)

³ AUC_T= area under the concentration versus time curve from time to t, where t is the last time point with a measurable concentration

⁴ Expressed as the median (range) only

⁵ Expressed as the geometric mean (range)

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology: Tirzepatide was administered twice weekly by subcutaneous injection to rats and cynomolgus monkeys, at doses up to 3 mg/kg (1.96x human exposure based on AUC) and 0.5 mg/kg (1.35x human exposure based on AUC), respectively. Primary findings were consistent with the activity of incretins, including GLP-1R agonists, and included significantly decreased food consumption and body weight loss.

Genotoxicity: Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay at single SC-administered doses up to 3 mg/kg.

Carcinogenicity: A 2-year carcinogenicity study (lifetime exposure) was conducted with tirzepatide in male and female rats, administered twice weekly by subcutaneous injection, at doses of 0.15, 0.5, and 1.5 mg/kg (0.1-, 0.4-, and 1-fold the maximum recommended human dose (MRHD) of 15 mg once weekly based on AUC). Tirzepatide caused an increase in thyroid C-cell tumors (adenomas and carcinomas combined) in both sexes at all dose levels.

In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered twice weekly by subcutaneous injection was not tumorigenic.

Reproductive and developmental toxicology: In fertility and early embryonic development studies, male and female rats were administered tirzepatide twice weekly by subcutaneous injection at doses of 0.5, 1.5, or 3 mg/kg (0.3-, 1-, and 2-fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC). No effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. However, in female rats, an increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food consumption and body weight.

Pregnant rats were given twice weekly subcutaneous doses of 0.02, 0.1, and 0.5 mg/kg tirzepatide (0.03-, 0.1-, and 0.5-fold the MRHD of 15 mg once weekly based on AUC) during organogenesis. Increased incidences of external, visceral, and skeletal malformations, increased incidences of visceral and skeletal developmental variations, and reduced fetal weights were observed, in addition to decreases in maternal body weights and food consumption, at 0.5 mg/kg.

Pregnant rabbits were given tirzepatide once weekly subcutaneous doses of 0.01, 0.03, or 0.1 mg/kg (0.01-, 0.1-, and 0.23-fold the MRHD) during organogenesis. Adverse effects on the gastrointestinal system resulting in maternal mortality or abortion in a few rabbits were observed at all dose levels. Reduced fetal weights, decreased maternal food consumption and decreased maternal body weights were observed at 0.1 mg/kg.

In a prenatal-postnatal study in F₀ maternal rats administered tirzepatide twice weekly by subcutaneous injection at doses of 0.02, 0.10, or 0.25 mg/kg from implantation through lactation, F₁ pups from F₀ maternal rats given 0.25 mg/kg tirzepatide had lower mean body weight from birth through the end of the study for males and postnatal day 56 for females.

Juvenile toxicity: Consistent with adult rats, in a juvenile toxicity study in rats, effects were limited to pharmacological effects of tirzepatide on body weight and food consumption and other reversible effects secondary to tirzepatide pharmacology. Tirzepatide led to a delay in sexual maturity in male and female rats, which was attributed to the reduced body weight gain during treatment. These data indicate that tirzepatide does not have specific toxicities in juvenile animals.