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, weight and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1

Posology

Start MOUNJARO as a 2.5 mg subcutaneous injection once weekly. After 4 weeks, increase the dose to 5 mg 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. The maximum dose of MOUNJARO is 15 mg once weekly.

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).

If a dose is missed, it should be administered 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.

Method of administration

Important Administration Instructions

·     Administer MOUNJARO once weekly, any time of day, with or without meals.

·     Inject MOUNJARO subcutaneously in the abdomen, thigh, or upper arm.

·     Rotate injection sites with each dose.

·     Inspect MOUNJARO visually before use. It should appear clear and colorless to slightly yellow. Do not use MOUNJARO if particulate matter 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.

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.

Pancreatitis

Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP‑1 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. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on MOUNJARO.

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). If pancreatitis is suspected, discontinue MOUNJARO and initiate appropriate management.

Hypoglycaemia

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 events 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, particularly in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

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 Complications in Patients with a History of Diabetic Retinopathy

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy.

Acute Gallbladder Disease

Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP‑1 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.

Sodium content

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

Tirzepatide delays gastric emptying, as assessed by paracetamol pharmacokinetics and thereby has the potential to impact the rate of absorption of concomitantly administered oral medicinal products.

Based on physiologically-based pharmacokinetic models, it is not anticipated that tirzepatide treatment will result in a clinically meaningful impact on orally administered medicinal products (i.e., warfarin, metformin, lisinopril, metoprolol, digoxin, paracetamol, norelgestromin, ethinylestradiol, sitagliptin, and atorvastatin). No dosage adjustments of concomitantly administered oral medicinal products are required.

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.

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

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

Oral contraceptives

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. Hormonal contraceptives that are not administered orally should not be affected [see sections 5.1 and 5.2].

Administration of a combination oral contraceptive (0.035 mg ethinyl estradiol plus 0.25 mg norgestimate) in the presence of a single dose of tirzepatide (5 mg) resulted in a reduction of oral contraceptive C_max by 55 to 66 %, with a 16 to 23 % reduction in area under the curve (AUC) and a delay in t_max of 2.5 to 4.5 hours. The reduction in C_max is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.

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).

No studies on the effects on the ability to drive and use machines have been performed. 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

In 7 completed phase 3 studies, 5 119 patients were exposed to tirzepatide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions in clinical studies were gastrointestinal disorders, including nausea (very common), diarrhoea (very 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. Adverse reactions

*Clinically significant hypoglycaemia defined as blood glucose <3.0 mmol/L (<54 mg/dL) or severe hypoglycaemia (requiring the assistance of another person).

Description of selected adverse reactions

Hypoglycaemia

The risk of severe hypoglycaemia with tirzepatide is low. In clinical studies, 10 (0.20 %) patients reported 12 episodes of severe hypoglycaemia. Of these 10 patients, 5 (0.10 %) were on a background of insulin glargine or sulphonylurea who reported 1 episode each.

Clinically significant hypoglycaemia 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 0.03 events/patient year (see table 1 and sections 4.2, 4.4 and 5.1).

Gastrointestinal adverse reactions

Gastrointestinal events were mostly mild or moderate in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time.

Immunogenicity

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.

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. A 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: not yet assigned

Mechanism of action

Tirzepatide is a long acting dual GIP and GLP-1 receptor agonist. It is a 39‑amino acid peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs half life.

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

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 is a biased agonist at the GLP‑1 receptor with preferential signaling towards the activation of adenylyl cyclase as opposed to the recruitment of β‑arrestin.

Tirzepatide increases β‑cell glucose sensitivity. It enhances first- and second-phase insulin secretion, and reduces plasma glucagon levels, both in a glucose dependent manner.

Tirzepatide improves insulin sensitivity.

In preclinical models the improvement in insulin sensitivity was mediated through weight-dependent and weight-independent actions.

Tirzepatide delays gastric emptying and this effect diminishes over time.

Tirzepatide decreases food intake.

Pharmacodynamic effects

Glycaemic Control

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

Insulin Secretion

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 and the rates increased for semaglutide 1 mg by 298 % and 223 %, respectively. 

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 and increased in semaglutide 1 mg by 35 %.

Tirzepatide lowers body weight in patients with type 2 diabetes, 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. Tirzepatide 15 mg reduced fasting glucagon concentration by 28 % and glucagon AUC after a mixed meal by 43 %, compared with no change for placebo and decreases for semaglutide 1 mg in fasting glucagon by 22 % and in glucagon AUC by 29 %.

Gastric Emptying

Tirzepatide delays gastric emptying which may slow post meal glucose absorption and can lead to a beneficial effect on postprandial glycaemia.

Clinical efficacy and safety

Glycaemic control and body weight

The safety and efficacy of tirzepatide were evaluated in five global randomised, controlled, phase 3 studies (SURPASS 1‑5) assessing glycaemic efficacy as the primary objective involving 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 and body weight 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. Results from the phase 3 studies are presented below based on 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. The analysis aligned to the efficacy estimand for a longitudinal continuous variable employed a mixed model for repeated measurements.

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. At baseline the patients had a mean duration of diabetes of 5 years.

Table 2. 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.

Figure 1. Mean HbA_1c (%) from baseline and mean change in body weight (kg) from baseline over time

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. At baseline the patients had a mean duration of diabetes of 9 years.

Table 3. 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.

Figure 2. Mean HbA_1c (%) from baseline and mean change in body weight (kg) from baseline over time

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. Patient 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. At baseline the patients had a mean duration of diabetes of 8 years.

Table 4. SURPASS 3: Results at week 52

^a      The mean dose of insulin degludec at week 52 was 49 units/day.

^* 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.