Type 2 diabetes mellitus

Mounjaro is indicated for the treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise

·       as monotherapy when metformin is considered inappropriate due to intolerance or contraindications

·       in addition to other medicinal products for the treatment of diabetes.

For study results with respect to combinations, effects on glycaemic control and the populations studied, see sections 4.2, 4.5 and 5.1.

Chronic Weight Management

Mounjaro is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:

•     30 kg/m² or greater (obesity) or

•     27 kg/m² or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, prediabetes, type 2 diabetes mellitus, obstructive sleep apnea or cardiovascular disease).

Limitations of Use

•     Mounjaro contains tirzepatide and should not be coadministered with other tirzepatide-containing products or with any GLP‑1 receptor agonist.

•     The safety and efficacy of Mounjaro in combination with other products intended for weight management, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

•     Mounjaro has not been studied in patients with a history of pancreatitis [see Special warnings and precautions for use (4.4)]

Posology

·       The recommended starting dosage of Mounjaro is 2.5 mg injected subcutaneously once weekly. The 2.5 mg dosage is for treatment initiation and is not intended for glycemic control.

·       After 4 weeks, increase the dosage to 5 mg injected subcutaneously once weekly.

·       If needed to achieve individual treatment goals, dose increases can be made in 2.5 mg increments after a minimum of 4 weeks on the current dose, increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose.

·       The maximum dosage of Mounjaro is 15 mg injected subcutaneously once weekly.

·       If a dose is missed, instruct patients to administer Mounjaro 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.

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

When tirzepatide is added to existing metformin and/or sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy, the current dose of metformin and/or SGLT2i can be continued.

When tirzepatide is added to existing therapy of a sulphonylurea and/or insulin, a reduction in the dose of sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea and insulin. A stepwise approach to insulin reduction is recommended (see sections 4.4 and 4.8).

Missed doses

If a dose is missed, it should be administered as soon as possible within 4 days 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 the 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.

Special populations

Elderly, gender, race, ethnicity or body weight

No dose adjustment is needed based on age, gender, race, ethnicity or body weight (see sections 5.1 and 5.2).

Renal impairment

No dose adjustment is required for patients with renal impairment including end stage renal disease (ESRD). Experience with the use of tirzepatide in patients with severe renal impairment and ESRD is limited. Caution should be exercised when treating these patients with tirzepatide (see section 5.2).

Hepatic impairment

No dose adjustment is required for patients with hepatic impairment. Experience with the use of tirzepatide in patients with severe hepatic impairment is limited. Caution should be exercised when treating these patients with tirzepatide (see section 5.2).

Paediatric population

The safety and efficacy of tirzepatide in children aged less than 18 years have not yet been established. No data are available.

Method of administration

Mounjaro is to be injected subcutaneously in the abdomen, thigh or upper arm.

The dose can be administered at any time of day, with or without meals.

Injection sites should be rotated with each dose. If a patient also injects insulin, they should inject Mounjaro into a different injection site.

Patients should be advised to read the instructions for use included with the package leaflet carefully before administering the medicinal product.

For further information before administration see section 6.6

Acute pancreatitis

Tirzepatide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients.

Acute pancreatitis has been reported in patients treated with tirzepatide.

Patients should be informed of the symptoms of acute pancreatitis. If pancreatitis is suspected, tirzepatide should be discontinued. If the diagnosis of pancreatitis is confirmed, tirzepatide should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis (see section 4.8).

Risk of Thyroid C-Cell Tumors

In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C‑cell tumors (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures [see Preclinical safety data (5.3)]. It is unknown whether MOUNJARO causes thyroid C‑cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C‑cell tumors has not been determined.

MOUNJARO is contraindicated in patients with a personal or family history of MTC or in patients with 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).

Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with MOUNJARO. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

Acute Pancreatitis

Type 2 diabetes mellitus

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP1 receptor agonists.

In clinical studies, 14 events of acute pancreatitis were confirmed by adjudication in 13 MOUNJARO-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). MOUNJARO has not been studied in patients with a prior history of pancreatitis and should be used with caution in these patients. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on MOUNJARO. Acute pancreatitis has been reported in patients treated with tirzepatide.

After initiation of MOUNJARO, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting).

Chronic Weight Management

In clinical trials, 0.2% of Mounjaro-treated patients for chronic weight management had acute pancreatitis confirmed by adjudication (0.14 patients per 100 years of exposure) versus 0.2% of placebo-treated patients (0.15 patients per 100 years of exposure). In the absence of other signs and symptoms of pancreatitis, elevations in pancreatic enzymes alone are not predictive of pancreatitis. If pancreatitis is suspected, discontinue Mounjaro and initiate appropriate management. If the diagnosis of pancreatitis is confirmed, Mounjaro should not be restarted.

Hypoglycaemia in Patients with Type 2 Diabetes

Patients receiving tirzepatide in combination with an insulin secretagogue (for example, a sulphonylurea) or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of the insulin secretagogue or insulin (see sections 4.2 and 4.8).

Gastrointestinal effects

Tirzepatide has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhoea (see section 4.8). These adverse reactions may lead to dehydration, which could lead to a deterioration in renal function including acute renal failure. Patients treated with tirzepatide should be advised of the potential risk of dehydration, due to the gastrointestinal adverse reactions and take precautions to avoid fluid depletion and electrolyte disturbances. This should particularly be considered in the elderly, who may be more susceptible to such complications.

Severe gastrointestinal disease

Use of Mounjaro has been associated with gastrointestinal adverse reactions, sometimes severe [see Undesirable effects (4.8)]. Mounjaro has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Diabetic retinopathy

Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy or diabetic macular oedema, and should be used with caution in these patients with appropriate monitoring.

Acute Gallbladder Disease

Type 2 diabetes mellitus

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP1 receptor agonist trials and postmarketing.

In Mounjaro placebo-controlled clinical trials, acute gallbladder disease (cholelithiasis, 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.

Chronic Weight Management

Substantial or rapid weight loss has been associated with risk of acute gallbladder disease.

In clinical trials, cholelithiasis was reported by 1.1% of Mounjaro -treated patients for chronic weight management and 1.0% of placebo-treated patients. Cholecystitis was reported by 0.7% of Mounjaro -treated patients and 0.2% of placebo-treated patients. These acute gallbladder events were positively correlated with weight reduction. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Elderly

Only very limited data are available from patients aged ≥ 85 years.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium‑ free’.

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

Mounjaro lowers blood glucose. When initiating Mounjaro, consider reducing the dose of concomitantly administered insulin secretagogues (e.g., sulfonylureas) or insulin to reduce the risk of hypoglycaemias [see Special warnings and precautions for use (4.4)].

Paracetamol

Following a 5 mg single dose of tirzepatide, the maximum plasma concentration (C_max) of paracetamol was reduced by 50 %, and the median (t_max) was delayed by 1 hour. The effect of tirzepatide on the oral absorption of paracetamol is dose and time dependent. At low doses (0.5 and 1.5 mg), there was only a minor change in paracetamol exposure. After four consecutive weekly doses of tirzepatide (5/5/8/10 mg), no effect on the paracetamol Cmax and tmax was observed. The overall exposure (AUC) was not influenced. No dose adjustment of paracetamol is necessary when administered with tirzepatide.

Oral Medications

Mounjaro delays gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with Mounjaro.

Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with Mounjaro.

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 with Mounjaro and for 4 weeks after each dose escalation. Hormonal contraceptives that are not administered orally should not be affected [see Fertility, pregnancy and lactation (4.6) and Pharmacodynamic properties (5.1))].

Pregnancy

There are no or limited amount of data from the use of tirzepatide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of tirzepatide during pregnancy.

Breast‑feeding

It is unknown whether tirzepatide is excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tirzepatide therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

The effect of tirzepatide on fertility in humans is unknown.

Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility (see section 5.3).

Use During Pregnancy

In animal reproduction studies, tirzepatide caused fetal growth reductions and fetal abnormalities at exposures below the MRHD based on AUC. An increased incidence of external, visceral, and skeletal malformations and visceral and skeletal developmental variations were observed in rats. Fetal growth reductions were observed in rats and rabbits. All developmental effects occurred at maternally toxic doses.

There are no adequate and well-controlled studies of tirzepatide in pregnant women.

Type 2 diabetes mellitus

Administer tirzepatide to pregnant women only if the potential benefit justifies the potential risk to the fetus.

Chronic Weight Management

Tirzepatide should not be used for weight reduction during pregnancy.

Use During Lactation

It is not known whether tirzepatide is excreted in human milk. Administer tirzepatide to nursing women only if the potential benefit to the mother justifies the potential risk to the infant.

Females and Males of Reproductive Potential

Contraception

Use of Mounjaro may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. 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 with Mounjaro and for 4 weeks after each dose escalation [see Interaction with other medicinal products and other forms of interaction (4.5) and Pharmacodynamic properties (5.1)].

Pediatric Use

Safety and effectiveness of Mounjaro have not been established in pediatric patients (younger than 18 years of age).

Tirzepatide has no or negligible influence on the ability to drive or use machines. When tirzepatide is used in combination with a sulphonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines (see section 4.4).

Summary of safety profile

Type 2 diabetes mellitus

In 7 completed phase 3 studies, 5119 patients were exposed to tirzepatide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions were gastrointestinal disorders, including nausea (very common), diarrhoea (very common), constipation (common), and vomiting (common). In general, these reactions were mostly mild or moderate in severity and occurred more often during dose escalation and decreased over time (see sections 4.2, and 4.4).

Tabulated list of adverse reactions

The following related adverse reactions from clinical studies are listed below by system organ class and in order of decreasing incidence (very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1 000 to < 1/100; rare: ≥ 1/10 000 to < 1/1 000; very rare: < 1/10 000). Within each incidence grouping, adverse reactions are presented in order of decreasing frequency.

Table 1: Frequency of Adverse Reactions of Tirzepatide for Type 2 Diabetes Mellitus

^a      Includes the following MedDRA preferred terms:

Diarrhea: diarrhea, frequent bowel movements

Abdominal Pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain

Constipation: constipation, feces hard

Fatigue: asthenia, fatigue, lethargy, malaise

Injection Site Reaction: injection site bruising, injection site dermatitis, injection site eczema, injection site edema, injection site erythema, injection site hemorrhage, injection site hypersensitivity, injection site irritation, injection site mass, injection site pain, injection site pruritus, injection site rash, injection site reaction, injection site swelling

^b      hypoglycemia with blood glucose <54 mg/dL (<3.0 mmol/L) or severe hypoglycemia

^c    sodium-glucose co-transporter 2 inhibitor

Chronic Weight Management

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Mounjaro for chronic weight management was evaluated for safety in 2 randomized, double-blind, placebo-controlled trials that included adult patients with overweight or obesity treated with Mounjaro for up to 72 weeks and a 4-week off drug follow-up period [see Pharmacodynamic properties (5.1)]. These data reflect exposure of 2519 patients to tirzepatide and a mean duration of exposure to tirzepatide of 66.3 weeks. The mean age of patients was 47.3 years, and 36.7% were male. Treatment discontinuation due to an adverse reaction was 4.8%, 6.3%, and 6.7% for the 5 mg, 10 mg, and 15 mg Mounjaro -treated groups respectively and 3.4% for the placebo-treated group across both studies. The majority of patients who discontinued Mounjaro due to adverse reactions did so during the first few months of treatment.

Common Adverse Reactions

Table 2: Frequency of Adverse Reactions of Tirzepatide for Chronic Weight Management (SURMOUNT-1 + SURMOUNT-2)

Injection Site Reaction: injection site bruising, injection site edema, injection site erythema, injection site hematoma, injection site hemorrhage, injection site hypersensitivity, injection site induration, injection site inflammation, injection site irritation, injection site pain, injection site paresthesia, injection site pruritus, injection site rash, injection site reaction, injection site swelling, puncture site reaction, vessel puncture site erythema

^b    hypoglycemia with blood glucose <54 mg/dL (<3.0 mmol/L)

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with tirzepatide in the pool T2DM of placebo-controlled trials, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2 % of tirzepatide-treated patients compared to 1.7 % of placebo-treated patients.

Hypersensitivity reactions have been reported with tirzepatide in the pool of placebo‑controlled trials in patients with BMI ≥ 27 kg/m², sometimes severe (e.g., rash and dermatitis); hypersensitivity reactions were reported in 5.0 % of tirzepatide-treated patients compared to 2.3 % of placebo-treated patients.

Hypoglycaemia in patients with type 2 diabetes

Clinically significant hypoglycaemia (blood glucose < 3.0 mmol/L (< 54 mg/dL) or severe hypoglycaemia (requiring the assistance of another person) occurred in 10 to 14 % (0.14 to 0.16 events/patient year) of patients when tirzepatide was added to sulphonylurea and in 14 to 19 % (0.43 to 0.64 events/patient year) of patients when tirzepatide was added to basal insulin.

The rate of clinically significant hypoglycaemia when tirzepatide was used as monotherapy or when added to other oral antidiabetic medicinal products was up to 0.04 events/patient year (see table 1 and sections 4.2, 4.4 and 5.1).

In phase 3 clinical studies, 10 (0.2 %) patients reported 12 episodes of severe hypoglycaemia. Of these 10 patients, 5 (0.1 %) were on a background of insulin glargine or sulphonylurea who reported 1 episode each.

Hypoglycaemia in patients using Mounjaro for Chronic Weight Management

In a trial of adult patients with type 2 diabetes mellitus and BMI ≥27 kg/m2, clinically significant hypoglycemia (defined as a plasma glucose <54 mg/dL) was reported in 4.2% of Mounjaro-treated patients versus 1.3% of placebo-treated patients. The rate of clinically significant hypoglycemic episodes was similar across Mounjaro 10 mg and 15 mg (4.3, and 6.1 episodes per 100 patient years of exposure, respectively) and the placebo-treated group (9.7 episodes per 100 patient years of exposure). No cases of severe hypoglycemia were reported. The risk of hypoglycemia was increased when Mounjaro was used with a sulfonylurea. Episodes of hypoglycemia have been reported with GLP‑1 receptor agonists in adult patients without type 2 diabetes mellitus. In Mounjaro clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia.

Gastrointestinal adverse reactions

In the placebo-controlled T2DM phase 3 studies, gastrointestinal disorders were dose-dependently increased for tirzepatide 5 mg (37.1 %), 10 mg (39.6 %) and 15 mg (43.6 %) compared with placebo (20.4 %). Nausea occurred in 12.2 %, 15.4 % and 18.3 % versus 4.3 % and diarrhoea in 11.8 %, 13.3 % and 16.2 % versus 8.9 % for tirzepatide 5 mg, 10 mg and 15 mg versus placebo. Gastrointestinal adverse reactions were mostly mild (74 %) or moderate (23.3 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time.

More subjects in the tirzepatide 5 mg (3.0 %), 10 mg (5.4 %) and 15 mg (6.6 %) groups compared to the placebo group (0.4 %) discontinued permanently due to the gastrointestinal event.

In the placebo‑controlled phase 3 studies in patients with BMI ≥ 27 kg/m², gastrointestinal disorders were increased for tirzepatide 5 mg (51.3 %), 10 mg (55.2 %) and 15 mg (55.6 %) compared with placebo (28.5 %). Nausea occurred in 22.1 %, 28.8 % and 27.9 % versus 8.3 % and diarrhoea in 16.9 %, 19.3 % and 21.7 % versus 8.0 % for tirzepatide 5 mg, 10 mg and 15 mg respectively versus placebo. Gastrointestinal adverse reactions were mostly mild (63.0 %) or moderate (32.6 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time.

More subjects in the tirzepatide 5 mg (2.0 %), 10 mg (4.5 %) and 15 mg (4.3 %) groups compared to the placebo group (0.5 %) discontinued permanently due to the gastrointestinal event.

Pancreatic Enzymes

Type 2 diabetes mellitus

Treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33% to 38% and lipase of 31% to 42%.

Chronic Weight Management

Treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 20% to 25% and lipase of 28% to 35%.

Vital Signs

Type 2 diabetes mellitus

Treatment with tirzepatide 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.

Treatment with tirzepatide resulted in a mean increase in heart rate of 2 to 4 beats per minute. There was a mean increase in heart rate of 1 beat per minute in placebo-treated patients.

Chronic Weight Management

Treatment with tirzepatide resulted in a mean decrease in systolic and diastolic blood pressure of 7 to 8 mmHg and 4 to 5 mmHg, respectively. There was a mean decrease in systolic and diastolic blood pressure of 1 mmHg each in placebo-treated patients.

Treatment with tirzepatide resulted in a mean increase in heart rate of 1 to 3 beats per minute. There was a mean increase in heart rate of 0 beats per minute in placebo-treated patients.

Immunogenicity

The pharmacokinetic profile and efficacy were not impacted by the development of ADAs. More tirzepatide-treated patients who developed anti-tirzepatide antibodies experienced hypersensitivity reactions or injection site reactions than those who did not develop these antibodies.

5 025 tirzepatide-treated patients in the T2DM phase 3 clinical studies were assessed for anti-drug antibodies (ADAs). Of these, 51.1 % developed treatment-emergent (TE) ADAs during the on-treatment period. In 38.3 % of the assessed patients, TE ADAs were persistent (ADAs present for a period of 16-weeks or greater). 1.9 % and 2.1 % had neutralizing antibodies against tirzepatide activity on the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, respectively and 0.9 % and 0.4 % had neutralising antibodies against native GIP and GLP-1, respectively.

6 206 tirzepatide-treated patients with BMI ≥ 27 kg/m² were assessed in the phase 3 clinical studies for anti-drug antibodies (ADAs). Of these, 56.1 % developed treatment-emergent (TE) ADAs during the on-treatment period. In 43.1 % of the assessed patients, TE ADAs were persistent (ADAs present for a period of 16‑weeks or greater). 2.2 % and 2.4 % had neutralizing antibodies against tirzepatide activity on the glucose‑dependent insulinotropic polypeptide (GIP) and glucagon-like peptide‑1 (GLP‑1) receptors, respectively and 0.8 % and 0.3 % had neutralising antibodies against native GIP and GLP‑1, respectively.

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

Type 2 diabetes mellitus

Across seven Phase 3 clinical studies, 2 570 (51.1 %) tirzepatide-treated patients developed anti-drug antibodies (ADAs).

Of the 2 570 tirzepatide-treated patients, 1.9 % and 2.1 % had neutralizing antibodies against tirzepatide activity on the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, respectively and 0.9 % and 0.4 % had neutralizing antibodies against native GIP and GLP-1, respectively. There was no evidence of an altered pharmacokinetic profile or an impact on efficacy and safety associated with the development of ADAs.

Chronic Weight Management

Across two Phase 3 clinical studies, 64.5% of tirzepatide-treated patients with obesity or overweight developed ADAs.

Of the overall tirzepatide-treated patients with obesity or overweight, 2.8% and 2.7% had neutralizing antibodies against tirzepatide activity on the GIP and GLP‑1 receptors, respectively.

0.8% and 0.1% had neutralizing antibodies against native GIP and GLP-1, respectively.

Heart rate

In the placebo-controlled T2DM phase 3 studies, treatment with tirzepatide resulted in a maximum mean increase in heart rate of 3 to 5 beats per minute. The maximum mean increase in heart rate in placebo-treated patients was 1 beat per minute.

The incidence of patients who had a change of baseline heart rate of > 20 bpm for 2 or more consecutive visits was 2.1 %, 3.8 % and 2.9 %, for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 2.1 % for placebo.

Small mean increases in PR interval were observed with tirzepatide when compared to placebo (mean increase of 1.4 to 3.2 msec and mean decrease of 1.4 msec respectively). No difference in arrythmia and cardiac conduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mg and placebo (3.8 %, 2.1 %, 3.7 % and 3 % respectively).

In the placebo‑controlled phase 3 studies in patients with BMI ≥ 27 kg/m², treatment with tirzepatide resulted in a maximum mean increase in heart rate of 3 to 5 beats per minute. The maximum mean increase in heart rate in placebo-treated patients was 1 beat per minute.

The incidence of patients who had a change of baseline heart rate of > 20 bpm for 2 or more consecutive visits was 1.0 %, 2.4 % and 3.3 %, for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 0.7 % for placebo.

Small mean increases in PR interval were observed with tirzepatide and placebo (mean increase of 0.3 to 1.3msec and of 0.6 msec respectively). No difference in arrythmia and cardiac conduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mg and placebo (3.9 %, 3.1 %, 3.6 % and 3.3 % respectively).

Injection site reactions

In the placebo-controlled T2DM phase 3 studies, injection site reactions (e.g. erythema and pruritus) were increased for tirzepatide (3.2 %) compared with placebo (0.4 %).

In the placebo-controlled phase 3 studies in patients with BMI ≥ 27 kg/m², injection site reactions were increased for tirzepatide (7.2 %) compared with placebo (1.8 %).

Overall, in the phase 3 studies, the most common signs and symptoms of injection site reactions were erythema and pruritus. The maximum severity of injection site reactions for patients was mild (91 %) or moderate (9 %). No injection site reactions in clinical trials were serious.

Injection site reactions (e.g. injection site pain) has been reported in post marketing by patients receiving tirzepatide.

Pancreatic enzymes

In the placebo-controlled T2DM phase 3 studies, treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33 % to 38 % and lipase of 31 % to 42 %. Placebo treated patients had an increase from baseline in amylase of 4 % and no changes were observed in lipase.

In the placebo‑controlled phase 3 studies in patients with BMI ≥ 27 kg/m², treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 20 % to 24 % and lipase of 29 % to 35 %. Placebo treated patients had an increase from baseline in amylase of 3.8 % and in lipase of 5.3 %.

Postmarketing Data

The following adverse drug reactions are based on postmarketing reports of tirzepatide.

Immune System Disorders:

Anaphylactic Reaction and Angioedema: Rare (≥0.01% - <0.1%)

Gastrointestinal Disorders:

Ileus

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below

In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. Patients may experience gastrointestinal adverse reactions including nausea. There is no specific antidote for overdose of tirzepatide. A prolonged period of observation and treatment of these symptoms may be necessary, taking into account the half-life of tirzepatide (approximately 5 days).

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, ATC code:  A10BX16

Mechanism of action

Tirzepatide is a long acting GIP and GLP-1 receptor agonist.

Both receptors are present on the pancreatic α and β endocrine cells, heart, vasculature, immune cells (leukocytes), gut and kidney. GIP receptors are also present on adipocytes.

In addition, both GIP and GLP‑1 receptors are expressed in the areas of the brain important to appetite regulation.

Tirzepatide is highly selective to human GIP and GLP‑1 receptors. Tirzepatide has high affinity to both the 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 regulates appetite and decreases food intake. Tirzepatide lowers body weight and body fat mass. Animal studies have shown that tirzepatide modulates fat utilization.

Glycaemic control

Tirzepatide improves glycaemic control by lowering fasting and postprandial glucose concentrations in patients with type 2 diabetes through several mechanisms.

Appetite regulation and energy metabolism

Tirzepatide lowers body weight and body fat mass. The mechanisms associated with body weight and body fat mass reduction involve decreased food intake through the regulation of appetite. Clinical studies show that tirzepatide reduces energy intake and appetite by increasing feelings of satiety and fullness, and decreasing feelings of hunger.

Pharmacodynamic effects

Insulin secretion

Tirzepatide increases pancreatic β‑cell glucose sensitivity. It enhances first- and second-phase insulin secretion in a glucose dependent manner.

In a hyperglycaemic clamp study in patients with type 2 diabetes, tirzepatide was compared to placebo and the selective GLP‑1 receptor agonist semaglutide 1 mg for insulin secretion. Tirzepatide 15 mg enhanced the first and second‑phase insulin secretion rate by 466 % and 302 % from baseline, respectively. There was no change in first- and second-phase insulin secretion rate for placebo.

Insulin sensitivity

Tirzepatide improves insulin sensitivity

Tirzepatide 15 mg improved whole body insulin sensitivity by 63 %, as measured by M‑value, a measure of glucose tissue uptake using hyperinsulinemic euglycaemic clamp. The M‑value was unchanged for placebo.

Tirzepatide lowers body weight in patients with obesity and overweight, and in patients with type 2 diabetes (irrespective of body weight), which may contribute to improvement in insulin sensitivity. Reduced food intake with tirzepatide contributes to body weight loss. The body weight reduction is mostly due to reduced fat mass.

Glucagon concentration

Tirzepatide reduced the fasting and postprandial glucagon concentrations in a glucose dependent manner. 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 which may slow post meal glucose absorption and can lead to a beneficial effect on postprandial glycaemia. Tirzepatide slows post-meal glucose absorption, reducing postprandial glucose. The delay is largest after the first dose and this effect diminishes over time.

Clinical efficacy and safety

Type 2 diabetes mellitus

Overview of Clinical Studies

The safety and efficacy of tirzepatide were evaluated in five global randomised, controlled, phase 3 studies (SURPASS 1‑5) assessing glycaemic control as the primary objective. The studies involved 6 263 treated patients with type 2 diabetes (4 199 treated with tirzepatide). The secondary objectives included body weight, fasting serum glucose (FSG) and proportion of patients reaching target HbA1c. All five phase 3 studies assessed tirzepatide 5 mg, 10 mg and 15 mg. All patients treated with tirzepatide started with 2.5 mg for 4 weeks. Then the dose of tirzepatide was increased by 2.5 mg every 4 weeks until they reached their assigned dose.

Across all studies, treatment with tirzepatide demonstrated sustained, statistically significant and clinically meaningful reductions from baseline in HbA1c as the primary objective compared to either placebo or active control treatment (semaglutide, insulin degludec and insulin glargine) for up to 1 year. In 1 study these effects were sustained for up to 2 years. Statistically significant and clinically meaningful reductions from baseline in body weight were also demonstrated. Results from the phase 3 studies are presented below based on the on-treatment data without rescue therapy in the modified intent-to-treat (mITT) population consisting of all randomly assigned patients who were exposed to at least 1 dose of study treatment, excluding patients discontinuing study treatment due to inadvertent enrolment.

SURPASS 1 – Monotherapy

In a 40 week double blind placebo-controlled study, 478 patients with inadequate glycaemic control with diet and exercise, were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or placebo. Patients had a mean age of 54 years and 52 % were men. At baseline the patients had a mean duration of diabetes of 5 years and the mean BMI was 32 kg/m2.

Table 3. SURPASS 1: Results at week 40

^* p < 0.05, ** p < 0.001 for superiority, adjusted for multiplicity.

^† p < 0.05, ^†† p < 0.001 compared to placebo, not adjusted for multiplicity.

^# p < 0.05, ^## p < 0.001 compared to baseline, not adjusted for multiplicity.

Figure 1. Mean HbA_1c (%) and mean body weight (kg) from baseline to week 40

SURPASS 2 - Combination therapy with metformin

In a 40 week active-controlled open-label study, (double-blind with respect to tirzepatide dose assignment) 1 879 patients were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or semaglutide 1 mg once weekly, all in combination with metformin. Patients had a mean age of 57 years and 47 % were men. At baseline the patients had a mean duration of diabetes of 9 years and the mean BMI was 34 kg/m2.

Table 4. SURPASS 2: Results at week 40

^*p < 0.05, ** p < 0.001 for superiority, adjusted for multiplicity.

^†p < 0.05, ^††p < 0.001 compared to semaglutide 1 mg, not adjusted for multiplicity.

^# p < 0.05, ^## p < 0.001 compared to baseline, not adjusted for multiplicity.

Figure 2. Mean HbA_1c (%) mean body weight (kg) from baseline to week 40

SURPASS 3 - Combination therapy with metformin, with or without SGLT2i

In a 52 week active-controlled open-label study, 1 444 patients were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or insulin degludec, all in combination with metformin with or without a SGLT2i. 32 % of patients were using SGLT2i at baseline.

At baseline the patients had a mean duration of diabetes of 8 years, a mean BMI of 34 kg/m2,  a mean age of 57 years and 56 % were men.

Patients treated with insulin degludec started at a dose of 10 U/day which was adjusted using an algorithm for a target fasting blood glucose of < 5 mmol/L. The mean dose of insulin degludec at week 52 was 49 units/day.

Table 5. SURPASS 3: Results at week 52

^*p < 0.05, **p < 0.001 for superiority, adjusted for multiplicity.

^†p < 0.05, ^††p < 0.001 compared to insulin degludec, not adjusted for multiplicity.

^# p < 0.05, ^## p < 0.001 compared to baseline, not adjusted for multiplicity.

Figure 3. Mean HbA_1c (%) and mean body weight (kg) from baseline to week 52

SURPASS 4 – Combination therapy with 1‑3 oral antidiabetic medicinal products: metformin, sulphonylureas or SGLT2i

In an active-controlled open-label study of up to 104 weeks (primary endpoint at 52 weeks), 2 002 patients with type 2 diabetes and increased cardiovascular risk were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or insulin glargine once daily on a background of metformin (95 %) and/or sulphonylureas (54 %) and/or SGLT2i (25 %). At baseline the patients had a mean duration of diabetes of 12 years, a mean BMI of 33 kg/m2, a mean age of 64 years and 63 % were men. Patient treated with insulin glargine started at a dose of 10 U/day which was adjusted using an algorithm with a fasting blood glucose target of < 5.6 mmol/L. The mean dose of insulin glargine at week 52 was 44 units/day.   

Table 6. SURPASS 4: Results at week 52

^* p < 0.05, ** p < 0.001 for superiority, adjusted for multiplicity.

^†p < 0.05, ^††p < 0.001 compared to insulin glargine, not adjusted for multiplicity.

^#p < 0.05, ^## p < 0.001 compared to baseline, not adjusted for multiplicity.

Figure 4. Mean HbA_1c (%) and mean body weight (kg) from baseline to week 52

SURPASS 5 - Combination therapy with titrated basal insulin, with or without metformin

In a 40 week double-blind placebo-controlled study, 475 patients with inadequate glycaemic control using insulin glargine with or without metformin were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or placebo. Insulin glargine doses were adjusted utilizing an algorithm with a fasting blood glucose target of < 5.6 mmol/L. At baseline the patients had a mean duration of diabetes of 13 years, a mean BMI of 33 kg/m2, a mean age of 61 years and 56 % were men. The overall estimated median dose of insulin glargine at baseline was 34 units/day. The median dose of insulin glargine at week 40 was 38, 36, 29 and 59 units/day for tirzepatide 5 mg, 10 mg, 15 mg and placebo respectively.

Table 7. SURPASS 5: Results at week 40

^*p < 0.05, ** p < 0.001 for superiority, adjusted for multiplicity.

^† p < 0.05, ^††p < 0.001 compared to placebo, not adjusted for multiplicity.

^# p < 0.05, ^## p < 0.001 compared to baseline, not adjusted for multiplicity.

Figure 5. Mean HbA_1c (%) and mean body weight (kg) from baseline to week 40

Chronic weight management

Weight Management Studies in Adults with Overweight or Obesity

Overview of Clinical Studies

The safety and efficacy of Mounjaro for chronic weight management (weight reduction and maintenance) in conjunction with a reduced-calorie diet and increased physical activity were studied in one 176-week (72-week primary endpoint), randomized, double-blind, placebo-controlled trial (SURMOUNT-1) and one 72-week, randomized, double-blind, placebo-controlled trial (SURMOUNT-2). In SURMOUNT-1, the dose of Mounjaro or matching placebo was escalated to 5 mg, 10 mg, or 15 mg subcutaneously once weekly during a 20-week period followed by the maintenance period. In SURMOUNT-2, the dose of Mounjaro or matching placebo was escalated to 10 mg or 15 mg subcutaneously once weekly during a 20-week period followed by the maintenance period.

In SURMOUNT-1 and SURMOUNT-2, all patients received instruction for a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended to a minimum of 150 min/week) that began with the first dose of study medication or placebo and continued throughout the trial.

SURMOUNT-1 (NCT04184622) was a 176-week (72-week primary endpoint) trial that enrolled 2539 adult patients with obesity (BMI ≥30 kg/m²), or with overweight (BMI 27-<30 kg/m²) and at least one weight-related comorbid condition, such as treated or untreated dyslipidemia, hypertension, obstructive sleep apnea, or cardiovascular disease; patients with type 2 diabetes mellitus were excluded. Patients were randomized in a 1:1:1:1 ratio to Mounjaro 5 mg, Mounjaro 10 mg, Mounjaro 15 mg or placebo once weekly. At baseline, mean age was 45 years (range 18-84) and 67.5% were women. At baseline 40.6% of patients had prediabetes. Mean baseline body weight was 104.8 kg and mean BMI was 38 kg/m².

SURMOUNT-2 (NCT04657003) was a 72-week trial that enrolled 938 adult patients with BMI ≥27 kg/m² and type 2 diabetes mellitus. Patients included in the trial had HbA1c 7-10% and were treated with either diet and exercise alone, or any oral glycemic-lowering agent except DPP-4 inhibitors or GLP‑1R agonists. Patients who were taking injectable therapies for type 2 diabetes mellitus were excluded from this study. Patients were randomized in a 1:1:1 ratio to Mounjaro 10 mg, Mounjaro 15 mg or placebo once weekly. At baseline, mean age was 54 years (range 18-85) and 50.7% were women. Mean baseline body weight was 100.7 kg and mean BMI was 36.1 kg/m².

The proportions of patients who discontinued study drug in SURMOUNT-1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg Mounjaro -treated group and 26.4% for the placebo-treated group. The proportions of patients who discontinued study drug in SURMOUNT-2 were 9.3% and 13.8% for the 10 mg and 15 mg Mounjaro -treated group and 14.9% for the placebo-treated group.

In adult patients with obesity and overweight, treatment with Mounjaro produced a statistically significant reduction from baseline in body weight compared to placebo. A reduction in body weight was observed with Mounjaro irrespective of age, sex, race, ethnicity, baseline BMI, and glycemic status.

Table 8. SURMOUNT-1: Results at week 72

^##p‑Value < 0.01, ^###p‑value < 0.001 versus placebo, not adjusted for multiplicity.

***p‑Value < 0.001 versus placebo, adjusted for multiplicity.

^††p‑value < 0.01, ^†††p‑value < 0.001 versus baseline.

Figure 6. Mean change in body weight (%) from baseline to week 72

Among the participants in SURMOUNT‑1 with prediabetes at baseline (N = 1032), 95.3 % participants treated with tirzepatide reverted to normoglycemia at week 72, as compared with 61.9 % of participants in the placebo group.

In a 72-week trial, adult patients with BMI ≥27 kg/m² and type 2 diabetes mellitus were enrolled. Patients included in the trial had HbA1c 7-10% and were treated with either diet and exercise alone, or any oral glycemic-lowering agent except DPP-4 inhibitors or GLP‑1R agonists. Patients who were taking injectable therapies for type 2 diabetes mellitus were excluded from this study. 938 patients were randomized in a 1:1:1 ratio to Mounjaro 10 mg, Mounjaro 15 mg or placebo once weekly. At baseline, mean age was 54 years (range 18-85) and 50.7% were women. Mean baseline body weight was 100.7 kg and mean BMI was 36.1 kg/m².

Table 9. SURMOUNT-2: Results at week 72

***p-Value <0.001 versus placebo for objectives controlled for type 1 error.

##p-Value <0.01, ###p-value <0.001 versus placebo for objectives not controlled for type 1 error.

†p-Value <0.05, †††p-value <0.001 versus baseline.

## p-value < 0.01

Figure 7. Mean change in body weight (%) from baseline to week 72

Cardiovascular evaluation

Cardiovascular (CV) risk was assessed via a meta-analysis of patients with at least one adjudication confirmed major adverse cardiac event (MACE). The composite endpoint of MACE‑4 included CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalisation for unstable angina.

In a primary meta-analysis of phase 2 and 3 registration studies in patients with type 2 diabetes, a total of 116 patients (tirzepatide: 60 [n = 4 410]; all comparators: 56 [n = 2 169]) experienced at least one adjudication confirmed MACE‑4: The results showed that tirzepatide was not associated with excess risk for CV events compared with pooled comparators (HR: 0.81; CI: 0.52 to 1.26).

An additional analysis was conducted specifically for the SURPASS‑4 study that enrolled patients with established CV disease. A total of 109 patients (tirzepatide: 47 [n = 995]; insulin glargine: 62 [n = 1 000]) experienced at least one adjudication confirmed MACE‑4: The results showed that tirzepatide was not associated with excess risk for CV events compared with insulin glargine (HR: 0.74; CI: 0.51 to 1.08).

In addition, analysis was conducted for the SURMOUNT‑1 study. A total of 14 patients (tirzepatide: 9 [n = 1 896]; placebo:5 [n = 643]) experienced at least one adjudication confirmed MACE: the event rate was similar across placebo and tirzepatide 5 and 10 mg groups. There was no event for tirzepatide 15 mg group.

Blood pressure

In the placebo-controlled phase 3 studies in patients with type 2 diabetes, treatment with tirzepatide 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.

In the placebo‑controlled phase 3 studies in patients with BMI ≥ 27kg/m², treatment with tirzepatide resulted in a mean decrease in systolic and diastolic blood pressure of 7 to 8 mmHg and 4 to 5 mmHg, respectively. There was a mean decrease in systolic and diastolic blood pressure of 1 mmHg each in placebo treated patients.

Other information

Fasting serum glucose

Across SURPASS‑1 to -5 trials, treatment with tirzepatide resulted in significant reductions from baseline in FSG (changes from baseline to primary end point were -2.4 mmol/L to -3.8 mmol/L). Significant reductions from baseline in FSG could be observed as early as 2 weeks. Further improvement in FSG was seen through to 42 weeks then was sustained through the longest study duration of 104 weeks.

Postprandial glucose

Across SURPASS‑1 to -5 trials, treatment with tirzepatide resulted in significant reductions in mean 2 hour post prandial glucose (mean of 3 main meals of the day) from baseline (changes from baseline to primary end point were ‑3.35 mmol/L to ‑4.85 mmol/L).

Triglycerides

Across SURPASS-1 to ‑5 trials, tirzepatide 5 mg, 10 mg and 15 mg resulted in reduction in serum triglyceride of 15‑19 %, 18‑27 % and 21‑25 % respectively.

In the 40 week trial versus semaglutide 1 mg, tirzepatide 5 mg, 10 mg and 15 mg resulted in 19 %, 24 % and 25 % reduction in serum triglycerides levels respectively compared to 12 % reduction with semaglutide 1 mg.

Proportion of patients reaching HbA1c < 5.7 % without clinically significant hypoglycaemia

In the 4 studies where tirzepatide was not combined with basal insulin (SURPASS‑1 to -4), m93.6 % to 100 % of patients who achieved a normal glycaemia of HbA1c < 5.7 % (≤ 39 mmol/mol), at the primary endpoint visit with tirzepatide treatment did so without clinically significant hypoglycaemia. In Study SURPASS‑5, 85.9 % of patients treated with tirzepatide who reached HbA1c < 5.7 % (≤ 39 mmol/mol) did so without clinically significant hypoglycaemia.

Special populations

The efficacy of tirzepatide for the treatment of type 2 diabetes was not impacted by age, gender, race, ethnicity, region, or by baseline BMI, HbA1c, diabetes duration and level of renal function impairment.

The efficacy of tirzepatide for chronic weight management was not impacted by age, gender, race, ethnicity, region, baseline BMI, or presence or absence of prediabetes.

Pediatric Use

Safety and effectiveness of Mounjaro have not been established in pediatric patients (younger than 18 years of age)

Tirzepatide is a 39‑amino acid peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs half-life.

Absorption

Maximum concentration of tirzepatide is reached 8 to 72 hours post dose. Steady state exposure is achieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a dose proportional manner. Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh, or upper arm. Absolute bioavailability of subcutaneous tirzepatide was 80 %.

Distribution

The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration is approximately 10.3 L in patients with type 2 diabetes and 9.66 L in patients with obesity. Tirzepatide is highly bound to plasma albumin (99.06 %).

Metabolism

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

Elimination

The apparent population mean clearance of tirzepatide is approximately 0.06 L/h with an elimination half-life of approximately 5 days, enabling once weekly administration.

Excretion

Tirzepatide is eliminated by metabolism. The primary excretion routes of tirzepatide metabolites are via urine and faeces. Intact tirzepatide is not observed in urine or faeces.

Special populations

Age, gender, race, ethnicity, body weight

Age, gender, race, ethnicity or body weight, do not have a clinically relevant effect on the pharmacokinetics (PK) of tirzepatide.

Renal impairment

Renal impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of renal impairment (mild, moderate, severe, ESRD) compared with subjects with normal renal function and no clinically relevant differences were observed. This was also shown for patients with both type 2 diabetes mellitus and renal impairment based on data from clinical studies.

Hepatic impairment

Hepatic impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mg dose was evaluated in patients with different degrees of hepatic impairment (mild, moderate, severe) compared with subjects with normal hepatic function and no clinically relevant differences were observed. 

Paediatric population

Tirzepatide has not been studied in paediatric patients.

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology or repeat-dose toxicity or genotoxicity conducted with tirzepatide.

A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of 0.15, 0.50, and 1.5 mg/kg (0.12, 0.36, and 1.02-‑fold the maximum recommended human dose (MRHD) based on AUC administered by subcutaneous injection twice weekly. Tirzepatide caused an increase in thyroid C‑cell tumours (adenomas and carcinomas) at all doses compared to controls. The human relevance of these findings is unknown.

In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10 mg/kg administered by subcutaneous injection twice weekly did not produce increased incidences of thyroid C‑cell hyperplasia or neoplasia at any dose.

Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility. In reproductive toxicology studies, tirzepatide, at maternally toxic doses, caused malformations, developmental variations and reduced fetal growth [see Fertility, pregnancy and lactation (4.6)]).

In animal reproduction studies, tirzepatide caused foetal growth reductions and foetal abnormalities at exposures below the MRHD based on AUC. An increased incidence of external, visceral, and skeletal malformations and visceral and skeletal developmental variations were observed in rats. Foetal growth reductions were observed in rats and rabbits. All developmental effects occurred at maternally toxic doses.

Sodium phosphate dibasic heptahydrate

Sodium chloride

Hydrochloric acid, and sodium hydroxide (for pH adjustment)

Water for injections

Not applicable for subcutaneous single-dose product.

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2 ºC – 8 ºC).

Do not freeze.

Store in original package in order to protect from light.

Mounjaro may be stored unrefrigerated for up to 21 days at a temperature below 30 ºC.

Glass syringe encased in a disposable pre-filled pen.

The pre-filled pen has a hidden needle, which will automatically insert into the skin when the injection button is pressed.

Each pre‑filled pen contains 0.5 ml of solution.

Pack sizes of 2 pre-filled pens. 4 pre-filled pens and multipacks containing 12 (3 packs of 4) pre‑filled pens. Not all pack sizes may be marketed.

Instructions for use

The pre‑filled pen is for single‑use only.

The instructions for using the pen, included with the package leaflet, must be followed carefully.

Inspect Mounjaro visually before use and discard for particulate matter or discolouration.

Mounjaro that has been frozen must not be used.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.