4.1. Therapeutic indications

Mounjaro is indicated:

1. For the treatment of adults, adolescents and children aged 10 years and above 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 medicinal products for the treatment of diabetes.

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

• ≥ 30 kg/ m2 (obesity) or

• ≥ 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).

For study results with respect to combinations, effects on glycaemic control, weight reduction and the populations studied, see sections 4.4, 4.5 and 5.1.

For trial results with respect to obstructive sleep apnoea (OSA) and to heart failure with preserved ejection fraction (HFpEF), see section 5.1.

4.2. Posology and method of administration

Posology

The starting dose of tirzepatide 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.

Adults

The recommended maintenance doses are 5, 10 and 15 mg.

The maximum dose is 15 mg once weekly.

Children and adolescents aged 10 to less than 18 years for the treatment of type 2 diabetes mellitus

The recommended maintenance doses are 5 mg and 10 mg.

The maximum dose is 10 mg once weekly.

Combination therapy

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).

For weight management, if patients have been unable to lose at least 5% of their initial body weight 6 months after titrating to the highest tolerated dose, a decision is required on whether to continue treatment, taking into account the benefit/risk profile in the individual patient (see section 5.1).

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 4.4, 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 maximum dose is 10 mg once weekly for children and adolescents. No dose adjustment is needed based on age, gender, race, ethnicity or body weight in children and adolescents aged 10 to less than 18 years treated for type 2 diabetes mellitus.

No data are available for children and adolescents with type 2 diabetes mellitus with a body weight < 50 kg and BMI below the 85th percentile at treatment initiation. In children weighing < 60 kg, caution is advised when escalating to the 10 mg dose, since safety data are limited.

The safety and efficacy of tirzepatide have not been established in children aged less than 10 years for treatment of type 2 diabetes mellitus and in children and adolescents aged less than 18 years for weight management.

Method of administration

Mounjaro is to be injected subcutaneously in the abdomen, thigh or another person should inject in the back of the 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 and caregivers should be advised to carefully read the instructions for use and the package leaflet for the pre-filled KwikPen before administering the medicinal product. In paediatric patients, a caregiver may give injections or a patient may self-inject if a healthcare provider determines that it is appropriate.

For further information before administration see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

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. This includes post-marketing reports of necrotising pancreatitis and reports with a fatal outcome.

Patients should be informed of the symptoms of acute pancreatitis, including persistent, severe abdominal pain. Patients should be advised to seek immediate medical attention if they occur. 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 in patients with type 2 diabetes mellitus

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.

Elderly

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

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

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

Benzyl Alcohol [E1519]

This medicine contains 5.4 mg Benzyl Alcohol [E1519] in each 0.6 ml dose.

Benzyl alcohol may cause allergic reactions.

Patients with hepatic or renal impairment should be informed of the potential risk of metabolic acidosis due to accumulation of benzyl alcohol over time.

4.5. Interaction with other medicinal products and other forms of interaction

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 Cmax and a delayed tmax, 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

No dose adjustment of paracetamol is necessary when administered with tirzepatide. Following a 5 mg single dose of tirzepatide, the maximum plasma concentration (Cmax) of paracetamol was reduced by 50 %, and the median (tmax) 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.

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 Cmax and area under the curve (AUC). Ethinyl estradiol Cmax was reduced by 59 % and AUC by 20 % with a delay in tmax of 4 hours. Norelgestromin Cmax was reduced by 55 % and AUC by 23 % with a delay in tmax of 4.5 hours. Norgestimate Cmax was reduced by 66 %, and AUC by 20 % with a delay in tmax 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 in women with normal BMI.

There is limited information about the effect of tirzepatide on the pharmacokinetics and efficacy of oral contraceptives in women with obesity or overweight. Since reduced efficacy of oral contraceptives cannot be excluded, it is advised switching to a non-oral contraceptive method, or add a barrier method of contraception upon initiating tirzepatide therapy (for 4 weeks), or after each dose escalation (for 4 weeks).

4.6. Fertility, pregnancy and lactation

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 should not be used during pregnancy and is not recommended in women of childbearing potential not using contraception. If a patient wishes to become pregnant, tirzepatide should be discontinued at least 1 month before a planned pregnancy due to the long half-life of tirzepatide.

Breast‑feeding

In a study of 11 women, the concentration of tirzepatide in breastmilk was found to be undetectable to very low (<10 ng/ml) compared to plasma concentrations following a single 5 mg dose. As tirzepatide is an amino acid sequence, any low amount present in breastmilk is expected to be degraded and not orally absorbed as intact drug by the breastfed infant. It is not known whether the reduced maternal food intake caused by tirzepatide affects composition or nutrient content of the breast milk. Overall, tirzepatide could be considered for use during breast-feeding.

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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

Summary of safety profile

In 13 completed phase 3 studies, 8 522 adult patients were exposed to tirzepatide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions were gastrointestinal disorders. In general, these reactions were mostly mild or moderate in severity. The incidence of nausea, diarrhoea and vomiting occurred primarily 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

System organ class

Very common

Common

Uncommon

Rare

Immune system disorders

Hypersensitivity reactions

Anaphylactic reaction#, Angioedema#

Metabolism and nutrition disorders

Hypoglycaemia1* when used with sulphonylurea or insulin

Hypoglycaemia1* when used with metformin and SGLT2ia, Decreased appetite1

Hypoglycaemia1* when used with metformin3, Weight decreased1

Nervous system disorders

Dizziness2

Dysgeusia, Dysaesthesia

Vascular disorders

Hypotension related events2**

Gastrointestinal disorders

Nausea, Diarrhoea, Vomiting4, Constipation2, Abdominal pain4

Dyspepsia, Vomiting1, Constipation1, Abdominal pain1, Abdominal distention, Eructation, Flatulence, Gastroesophageal reflux disease, Cholelithiasis2

Cholelithiasis1, Cholecystitis2, Acute pancreatitis, Delayed gastric emptying

Skin and subcutaneous tissue disorders

Hair loss2

General disorders and administration site conditions

Fatigue†, Injection site reactions

Injection site pain

Investigations

Heart rate increased1, Blood calcitonin increased2, Lipase increased, Amylase increased1

Blood calcitonin increased1, Heart rate increased2, Amylase increased2

#From post-marketing reports.

*Hypoglycaemia defined below.

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

** “hypotension-related” events include “blood pressure decreased,” “hypotension,” and “orthostatic hypotension”. In Weight Management placebo-controlled trials, hypotension-related events were observed, 94% of the events observed were mild to moderate.

1 Frequency reported in clinical trials supporting the type 2 diabetes indication.

2 Frequency reported in clinical trials supporting the weight management indication.

3 Frequency was common in the paediatric type 2 diabetes mellitus trial

4 Frequency was very common in the weight management and in the paediatric type 2 diabetes mellitus trials.

a sodium-glucose co-transporter 2 inhibitor.

Tirzepatide was evaluated in a placebo-controlled phase 3 study (SUMMIT) in adults with HFpEF and obesity and in 2 placebo-controlled phase 3 studies (SURMOUNT-OSA) in adults with OSA and obesity (see section 5.1). The adverse drug reactions were consistent with those reported in the pooled, placebo-controlled clinical trials for weight management.

The frequencies of adverse drug reactions in Table 1 reflect those observed in clinical trials in adults. Adverse drug reactions in the placebo-controlled period of the clinical trial with paediatric patients aged 10 to less than 18 years with type 2 diabetes mellitus were similar with the exception of the frequencies of hypoglycaemia with metformin alone (common), vomiting (very common), abdominal pain (very common) and blood calcitonin (very rare).

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with tirzepatide in pooled adult type 2 diabetes mellitus placebo-controlled studies, pooled placebo-controlled weight management studies (SURMOUNT-1, -2, and -3), pooled placebo-controlled OSA studies and a placebo-controlled HFpEF phase 3 study, sometimes severe (e.g., urticaria, eczema, dermatitis and rash). Hypersensitivity reactions were reported in 3.2 %, 5.0 %, 3.0 %, and 4.7 % of tirzepatide-treated patients, respectively, compared to 1.7 %, 3.8 %, 2.1 %, and 3.5 % of placebo-treated patients, respectively.

Cases of anaphylactic reaction and angioedema have been rarely reported with tirzepatide during post-marketing surveillance.

Hypoglycaemia in patients with type 2 diabetes mellitus in adults

SURPASS 1-to-5

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.

SURMOUNT- 2

Clinically significant hypoglycaemia (blood glucose < 3.0 mmol/L (< 54 mg/dL) occurred in 4.2 % of tirzepatide-treated patients versus 1.3 % of placebo-treated patients.

The rate of clinically significant hypoglycaemic episodes was similar across tirzepatide 10 mg and 15 mg (4.3, and 6.1 events per 100 patient years of exposure, respectively) and the placebo-treated group (9.7 events per 100 patient years of exposure). The risk of hypoglycaemia was increased when tirzepatide was used with a sulfonylurea.

No cases of severe hypoglycaemia were reported.

Gastrointestinal adverse reactions

Type 2 diabetes mellitus

In pooled adult placebo-controlled type 2 diabetes mellitus 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 treated with tirzepatide 5 mg (3.0 %), 10 mg (5.4 %) and 15 mg (6.6 %) discontinued permanently due to the gastrointestinal event compared with placebo (0.4%).

Weight management

In pooled SURMOUNT-1 and SURMOUNT-2 phase 3 weight management studies, gastrointestinal disorders were 55.6 % for tirzepatide 5 mg, 55.8% for tirzepatide 10 mg and 55.6 % for tirzepatide 15 mg compared with placebo 29.7 %. Nausea occurred in 24.6 %, 29.0 % and 28.0 % versus 8.5 % and diarrhoea in 18.7 %, 20.8 % and 22.5 % versus 7.8 % for tirzepatide 5 mg, 10 mg and 15 mg versus placebo. Gastrointestinal adverse reactions were mostly mild (61.0 %) or moderate (34.4 %) 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 (3.3 %) and 15 mg (4.3 %) groups compared to the placebo group (0.5 %) discontinued permanently due to the gastrointestinal event.

In pooled OSA phase 3 studies, gastrointestinal disorders were more common with tirzepatide (54.9 %) compared with placebo (23.5 %). Nausea occurred in 23.6 % versus 7.7 % and diarrhoea in 24.0 % versus 10.7 % for tirzepatide versus placebo. Gastrointestinal adverse reactions were mostly mild (59.4 %) or moderate (35.2 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period.

More patients in the tirzepatide group (2.1 %) compared to the placebo group (0.4 %) discontinued permanently due to the gastrointestinal event.

In a placebo controlled HFpEF phase 3 study, gastrointestinal disorders were more common with tirzepatide maximum tolerated dose (MTD, 54.1 %) compared with placebo (26.2 %). Diarrhoea occurred in 18.4 % versus 6.3 %, and nausea in 17.0 % versus 6.5 % for tirzepatide MTD versus placebo. Gastrointestinal adverse reactions were mostly mild (48.7 %) or moderate (42.6 %) 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 MTD group (4.1 %) compared to the placebo group (0 %) discontinued study treatment permanently due to the gastrointestinal event.

Gallbladder related disorders

Type 2 diabetes mellitus

In pooled placebo-controlled type 2 diabetes mellitus phase 3 studies, cholelithiasis was reported in 0.3% of tirzepatide-treated patients and 0 placebo-treated patients.

Weight management

In pooled SURMOUNT-1, -2, and -3 phase 3 weight management studies, in pooled placebo-controlled OSA phase 3 studies, and in a placebo-controlled HFpEF phase 3 study, acute gallbladder disease was reported in 2.0 %, 0.9 %, and 4.4 % of tirzepatide-treated patients, respectively, and in 1.6 %, 0.9 % and 2.7 % of placebo-treated patients, respectively.

In pooled SURMOUNT-1, -2, and -3 phase 3 weight management studies, and in a phase 3 HFpEF study, cholecystitis (including cholecystitis and cholecystitis acute) was reported by 0.6% and 2.2% of tirzepatide-treated patients, respectively, and by 0.2% and 1.1% of placebo-treated patients, respectively.

In pooled SURMOUNT-1, -2, and -3 phase 3 weight management studies, in pooled placebo-controlled OSA phase 3 studies and in a placebo-controlled HFpEF phase 3 study, cholelithiasis was reported by 1.1%, 0.9 % and 2.5% of tirzepatide-treated patients respectively, and by 1.0%, 0.9 % and 1.1% of placebo treated patients respectively.

In the weight management studies, acute gallbladder events were positively correlated with weight reduction.

Hair loss

Weight management

In pooled SURMOUNT-1, -2 and -3 phase 3 weight management studies, hair loss was reported in 4.9% of patients treated with tirzepatide and in 1.0 % of patients treated with placebo. The events were mainly of mild severity and most patients recovered while on continued treatment. No tirzepatide patients discontinued drug or study due to hair loss.

Immunogenicity

There was no identified clinically significant effect of anti-tirzepatide antibodies on pharmacokinetics or effectiveness of tirzepatide.

In phase 3 clinical studies, a total of 9 094 tirzepatide-treated patients were assessed for anti-drug antibodies (ADA). Across these studies, 45.1 - 65.1% developed treatment-emergent (TE) ADA during the on-treatment period. In 29.8 - 51.3% of the assessed patients, TE ADA were persistent (that is TE ADA present for a period of 16-weeks or greater). Up to 3 % and 2.3 % had neutralising antibodies against tirzepatide activity on the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, respectively and up to 1.2 % and 0.4 % had neutralising antibodies against native GIP and native GLP-1, respectively.

Heart rate

Type 2 diabetes mellitus

In pooled placebo-controlled type 2 diabetes mellitus, phase 3 studies in adult patients, treatment with tirzepatide resulted in a maximum mean increase in heart rate of 3 to 5 beats per minute across doses. 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).

Weight management

In pooled SURMOUNT-1, -2, and -3 phase 3 weight management studies, in pooled OSA phase 3 studies, and in a HFpEF phase 3 study, treatment with tirzepatide resulted in a mean increase in heart rate of 3, 2 and 3 beats per minute, respectively. There was a mean increase in heart rate of <1, <1 and 1 beat per minute, respectively, in placebo-treated patients.

Injection site reactions

In pooled placebo‑controlled type 2 diabetes mellitus phase 3 studies in adult patients, in pooled SURMOUNT-1, -2, and -3 phase 3 weight management studies , in pooled placebo-controlled OSA phase 3 studies, and in a placebo-controlled phase 3 HFpEF study, injection site reactions were increased for tirzepatide (3.2 %, 8.0 %, 8.2 %, and 6.0 %, respectively) compared with placebo (0.4 %, 1.8 %, 2.6 %, and 1.6 %, respectively).

Overall, in 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

The clinical significance of elevations in amylase or lipase with tirzepatide is unknown in the absence of other signs and symptoms of pancreatitis.

Type 2 diabetes mellitus

In pooled placebo-controlled type 2 diabetes mellitus phase 3 studies, treatment in adult patients with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33 % to 38 % and lipase of 31 % to 42 % across doses. Placebo treated patients had an increase from baseline in amylase of 4 % and no changes were observed in lipase.

Weight management

In pooled SURMOUNT-1, -2 and -3 phase 3 weight management studies, in pooled placebo-controlled OSA phase 3 studies, and in a placebo-controlled HFpEF phase 3 study, treatment with tirzepatide resulted in mean increases from baseline in serum pancreatic amylase concentrations of 23 %, 25 %, and 28 %, respectively, and lipase of 34 %, 39 %, and 32 %, respectively. Placebo treated patients had an increase from baseline in amylase of 2 %, 1 %, and 4 %, respectively, and in lipase of 6 %, 4 %, and 1 %, respectively.

Paediatric Population

The safety and immunogenicity profiles in children and adolescents aged 10 to less than 18 years with type 2 diabetes mellitus treated with tirzepatide 5 mg and 10 mg once-weekly were consistent with those described above for adult patients with type 2 diabetes mellitus with the exception of a higher frequency of vomiting, abdominal pain, and hypoglycemia when added to metformin alone.

No severe hypoglycaemic episodes occurred during the paediatric type 2 diabetes mellitus trial. During the placebo-controlled phase, clinically significant hypoglycaemia (blood glucose < 3.0 mmol/L (< 54 mg/dL)) occurred in 28.6 % (1.98 events/patient year) of patients treated with tirzepatide and in 10.0 % (0.35 events/patient year) of patients treated with placebo, when added to basal insulin with or without metformin. The rate was 9.1 % (0.28 events/patient year) and 4.2 % (0.07 events/patient year) for tirzepatide and placebo-treated patients, respectively, when added to metformin alone.

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 Yellow Card Scheme, website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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).