Mounjaro 2,5; 5; 7,5; 10; 12,5 & 15 mg Solution for Injection

Type 2 diabetes mellitus

MOUNJARO is indicated for the treatment of adults with insufficiently controlled 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 medicines for the treatment of diabetes. For study results with respect to combinations, effects on glycaemic control and the populations studied, see sections 4.4, 4.5 and 5.1.

Weight management

MOUNJARO is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of

• u2265 30 kg/m2 (obesity) or
• u2265 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidaemia, obstructive sleep apnoea, cardiovascular disease, prediabetes, or type 2 diabetes mellitus).

Posology

The starting dose of MOUNJARO is 2,5 mg once weekly. After 4 weeks, the dose should be increased to 5 mg once weekly. If needed, dose increases can be made in 2,5 mg increments after a minimum of 4 weeks on the current dose. The recommended maintenance doses are 5 mg, 10 mg and 15 mg. The maximum dose is 15 mg once weekly.

When MOUNJARO 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 MOUNJARO 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, sex, race, ethnicity or body weight

No dose adjustment is needed based on age, sex, race, ethnicity or body weight (see sections 5.1 and 5.2). Only very limited data are available from patients aged u2265 85 years.

Renal impairment

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

Hepatic impairment

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

Paediatric population

The safety and efficacy of MOUNJARO in children aged less than 18 years have not yet been established.

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 MOUNJARO. Vial Patients and their caregivers should be trained in subcutaneous injection technique before administering MOUNJARO. For further information before administration see section 6.6.

MOUNJARO is contraindicated in patients who:

• are hypersensitive to tirzepatide or to any of the excipients of MOUNJARO listed in section 6.1
• has a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (see section 4.4).

Risk of Thyroid C-Cell Tumours

In both sexes of rats, tirzepatide caused a dose-dependent and treatment-duration-dependent increase in the incidence of thyroid C-cell tumours (adenomas and carcinomas) in a 2-year study at clinically relevant plasma exposures (see section 5.3). It is unknown whether MOUNJARO causes thyroid C-cell tumours, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumours 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 tumours (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

MOUNJARO 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 MOUNJARO. Patients should be informed of the symptoms of acute pancreatitis. If pancreatitis is suspected, MOUNJARO should be discontinued. If the diagnosis of pancreatitis is confirmed, MOUNJARO 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).

Hypoglycaemia

Patients receiving MOUNJARO 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

MOUNJARO 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 MOUNJARO 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

MOUNJARO has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and should be used with caution in these patients.

Diabetic retinopathy

MOUNJARO 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.

Aspiration in association with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying (see section 4.8) should be considered prior to performing procedures with general anaesthesia or deep sedation.

Sodium content

MOUNJARO contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially u2018sodium-freeu2019.

Benzyl alcohol

MOUNJARO KwikPen contains 5,4 mg benzyl alcohol in each 0,6 ml dose.

MOUNJARO delays gastric emptying and thereby has the potential to impact the rate of absorption of concomitantly administered oral medicine. This effect, resulting in decreased C max and a delayed t max, is most pronounced at the time of MOUNJARO treatment initiation. Based on the results from a study with paracetamol, which was used as a model medicine to evaluate the effect of MOUNJARO on gastric emptying, no dose adjustments are expected to be required for most concomitantly administered oral medicines. However, it is recommended to monitor patients on oral medicines with a narrow therapeutic index (e.g., warfarin, digoxin), especially at initiation of MOUNJARO treatment and following dose increase. The risk of delayed effect should also be considered for oral medicines for which a rapid onset of effect is of importance.

Paracetamol

Following a 5 mg single dose of MOUNJARO, 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 MOUNJARO 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 MOUNJARO (5/5/8/10 mg), no effect on the paracetamol C max and t max was observed. The overall exposure (AUC) was not influenced. No dose adjustment of paracetamol is necessary when administered with MOUNJARO.

Oral contraceptives

Administration of a combination oral contraceptive (0,035 mg ethinyl estradiol plus 0,25 mg norgestimate, a prodrug of norelgestromin) in the presence of a single dose of MOUNJARO (5 mg) resulted in a reduction of oral contraceptive C max and area under the curve (AUC). Ethinyl estradiol C max was reduced by 59 % and AUC by 20 % with a delay in t max of 4 hours. Norelgestromin C max was reduced by 55 % and AUC by 23 % with a delay in t max of 4,5 hours. Norgestimate C max was reduced by 66 %, and AUC by 20 % with a delay in t max of 2,5 hours. This reduction in exposure after a single dose of MOUNJARO is not considered clinically relevant. No dose adjustment of oral contraceptives is required.

Women of childbearing potential

Women of childbearing potential are recommended to use contraception when treated with MOUNJARO.

Pregnancy

There are no or a limited amount of data from the use of MOUNJARO in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). MOUNJARO is not recommended during pregnancy and in women of childbearing potential not using contraception. If a patient wishes to become pregnant, or pregnancy occurs, MOUNJARO should be discontinued. MOUNJARO should be discontinued at least 1 month before a planned pregnancy due to the long half-life (see section 5.2).

Breastfeeding

It is unknown whether MOUNJARO is excreted in human milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from MOUNJARO therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

The effect of MOUNJARO on fertility in humans is unknown. Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility (see section 5.3).

MOUNJARO has no or negligible influence on the ability to drive or use machines. When MOUNJARO 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

In 10 completed phase 3 studies, 7 925 patients were exposed to tirzepatide alone or in combination with other glucose lowering medicines. The most commonly reported adverse reactions were gastrointestinal disorders and these were mostly mild or moderate in severity. The incidence of nausea, diarrhoea and vomiting was higher during the dose escalation period 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: u2265 1/10; common: u2265 1/100 to < 1/10; uncommon: u2265 1/1 000 to < 1/100; rare: u2265 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. Adverse reactions

# From post-marketing reports

*Hypoglycaemia defined below.

u2020 Fatigue includes the terms fatigue, asthenia, malaise, and lethargy.

1 Adverse reaction that only applies to patients with type 2 diabetes mellitus (T2DM)

2 Adverse reaction that mainly applies to patients with overweight or obesity, with or without T2DM

3 Frequency was very common in weight management trials, and common in T2DM trials

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with MOUNJARO in the pool of T2DM placebo-controlled trials, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3,2 % of MOUNJARO-treated patients compared to 1,7 % of placebo-treated patients. Cases of anaphylactic reaction and angioedema have been rarely reported with marketed use of tirzepatide. Hypersensitivity reactions have been reported with tirzepatide in a pool of 3 placebo-controlled weight management trials, sometimes severe (e.g., rash and dermatitis); hypersensitivity reactions were reported in 5,0 % of tirzepatide-treated patients compared to 3,8 % of placebo-treated patients.

Hypoglycaemia in patients with type 2 diabetes mellitus

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 MOUNJARO was added to sulphonylurea and in 14 to 19 % (0,43 to 0,64 events/patient year) of patients when MOUNJARO was added to basal insulin. The rate of clinically significant hypoglycaemia when MOUNJARO was used as monotherapy or when added to other oral antidiabetic medicines 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.

Weight management study

In a placebo-controlled weight management phase 3 trial in patients with type 2 diabetes mellitus (T2DM), hypoglycaemia (blood glucose < 3,0 mmol/L (< 54 mg/dL)) was reported in 4,2 % of tirzepatide-treated patients versus 1,3 % of placebo-treated patients. In this trial, patients taking tirzepatide in combination with an insulin secretagogue (e.g., sulfonylurea) had a higher incidence of hypoglycaemia (10,3 %) compared to tirzepatide-treated patients not taking a sulfonylurea (2,1 %). No severe hypoglycaemia episodes were reported.

Gastrointestinal adverse reactions

In the placebo-controlled T2DM phase 3 studies, gastrointestinal disorders were dose-dependently increased for MOUNJARO 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 MOUNJARO 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 patients in the MOUNJARO 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 a placebo-controlled weight management phase 3 study in patients without T2DM, gastrointestinal disorders were increased for tirzepatide 5 mg (55,6 %), 10 mg (60,8 %) and 15 mg (59,2 %) compared with placebo (30,3 %). Nausea occurred in 24,6 %, 33,3 % and 31,0 % versus 9,5 % and diarrhoea in 18,7 %, 21,2 % and 23,0 % versus 7,3 % for tirzepatide 5 mg, 10 mg and 15 mg respectively versus placebo. Gastrointestinal adverse reactions were mostly mild (60,8 %) or moderate (34,6 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time. More patients in the tirzepatide 5 mg (1,9 %), 10 mg (4,4 %) and 15 mg (4.1 %) groups compared to the placebo group (0,5 %) discontinued study treatment permanently due to the gastrointestinal event.

In the event of overdose, appropriate supportive treatment should be initiated according to the patientu2019s 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).