MOUNJARO Solution for injection Ref.[50478] Active ingredients: Tirzepatide

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).

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 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

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

Sodium content

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

Benzyl alcohol

This medicinal product contains 5.4 mg benzyl alcohol in each 0.6 ml dose of Mounjaro KwikPen.

Tirzepatide delays gastric emptying and thereby has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. This effect, resulting in decreased C_max and a delayed t max, is most pronounced at the time of tirzepatide treatment initiation.

Based on the results from a study with paracetamol, which was used as a model medicinal product to evaluate the effect of tirzepatide on gastric emptying, no dose adjustments are expected to be required for most concomitantly administered oral medicinal products. However, it is recommended to monitor patients on oral medicinal products with a narrow therapeutic index (e.g., warfarin, digoxin), especially at initiation of tirzepatide treatment and following dose increase. The risk of delayed effect should also be considered for oral medicinal products for which a rapid onset of effect is of importance.

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 C_max and t max was observed. The overall exposure (AUC) was not influenced. No dose adjustment of paracetamol is necessary when administered with tirzepatide.

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 tirzepatide (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 tirzepatide is not considered clinically relevant. No dose adjustment of oral contraceptives is required.

Pregnancy

There are no or a limited amount of data from the use of tirzepatide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Tirzepatide is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether tirzepatide is excreted in human milk. A risk to the newborn/infant 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).

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

In 9 completed phase 3 studies, 7 702 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. Adverse reactions:

^# From post-marketing reports.
^* Hypoglycaemia defined below.
^† 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.

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with tirzepatide in the pool of T2DM 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. Cases of anaphylactic reaction and angioedema have been rarely reported with marketed use of tirzepatide.

Hypersensitivity reactions have been reported with tirzepatide in the pool of placebo-controlled trials in patients with BMI ≥27 kg/m² with or without T2DM, 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 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 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.

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 patients 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 with or without T2DM, 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%) 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 patients 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.

Gallbladder-related events

In the pool of placebo-controlled phase 3 studies in patients with BMI ≥27 kg/m² with or without T2DM, the overall incidence of cholecystitis and cholecystitis acute was 0.5% and 0% for tirzepatide- and placebo-treated patients, respectively.

In the pool of placebo-controlled phase 3 studies in patients with BMI ≥27 kg/m² with or without T2DM, acute gallbladder disease was reported by 1.6% of tirzepatide-treated patients and 1.0% of placebo-treated patients. These acute gallbladder events were positively associated with weight reduction.

Immunogenicity

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. There was no evidence of an altered pharmacokinetic profile or an impact on efficacy of tirzepatide associated with the development of ADAs.

6 206 tirzepatide-treated patients with BMI ≥27 kg/m² with or without T2DM 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 neutralising 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.

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 percentage 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 arrhythmia 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 with or without T2DM, 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 percentage of patients who had a change in 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 1.3 msec and of 0.6 msec respectively). No difference in arrhythmia 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 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 with or without T2DM, 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 were serious.

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 with or without T2DM, 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%.

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 in Appendix V.

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