MOUNJARO 5mg injectible solution medication leaflet

Mounjaro 2.5 mg solution for injection in pre-filled pen

Mounjaro 5 mg solution for injection in pre-filled pen

Mounjaro 7.5 mg solution for injection in pre-filled pen

Mounjaro 10 mg solution for injection in pre-filled pen

Mounjaro 12.5 mg solution for injection in pre-filled pen

Mounjaro 15 mg solution for injection in pre-filled pen

Mounjaro 2.5 mg solution for injection in vial

Mounjaro 5 mg solution for injection in vial

Mounjaro 7.5 mg solution for injection in vial

Mounjaro 10 mg solution for injection in vial

Mounjaro 12.5 mg solution for injection in vial

Mounjaro 15 mg solution for injection in vial

Mounjaro 2.5 mg/dose KwikPen solution for injection in pre-filled pen

Mounjaro 5 mg/dose KwikPen solution for injection in pre-filled pen

Mounjaro 7.5 mg/dose KwikPen solution for injection in pre-filled pen

Mounjaro 10 mg/dose KwikPen solution for injection in pre-filled pen

Mounjaro 12.5 mg/dose KwikPen solution for injection in pre-filled pen

Mounjaro 15 mg/dose KwikPen solution for injection in pre-filled pen

Mounjaro 2.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 2.5 mg of tirzepatide in 0.5 ml solution (5 mg/ml).

Mounjaro 5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 5 mg of tirzepatide in 0.5 ml solution (10 mg/ml).

Mounjaro 7.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 7.5 mg of tirzepatide in 0.5 ml solution (15 mg/ml).

Mounjaro 10 mg solution for injection in pre-filled pen

Each pre-filled pen contains 10 mg of tirzepatide in 0.5 ml solution (20 mg/ml).

Mounjaro 12.5 mg solution for injection in pre-filled pen

Each pre-filled pen contains 12.5 mg of tirzepatide in 0.5 ml solution (25 mg/ml).

Mounjaro 15 mg solution for injection in pre-filled pen

Each pre-filled pen contains 15 mg of tirzepatide in 0.5 ml solution (30 mg/ml).

Vial, single-dose

Mounjaro 2.5 mg solution for injection in vial

Each vial contains 2.5 mg of tirzepatide in 0.5 ml solution (5 mg/ml).

Mounjaro 5 mg solution for injection in vial

Each vial contains 5 mg of tirzepatide in 0.5 ml solution (10 mg/ml).

Mounjaro 7.5 mg solution for injection in vial

Each vial contains 7.5 mg of tirzepatide in 0.5 ml solution (15 mg/ml).

Mounjaro 10 mg solution for injection in vial

Each vial contains 10 mg of tirzepatide in 0.5 ml solution (20 mg/ml).

Mounjaro 12.5 mg solution for injection in vial

Each vial contains 12.5 mg of tirzepatide in 0.5 ml solution (25 mg/ml).

Mounjaro 15 mg solution for injection in vial

Each vial contains 15 mg of tirzepatide in 0.5 ml solution (30 mg/ml).

Pre-filled pen (KwikPen), multi-dose

Mounjaro 2.5 mg/dose KwikPen solution for injection in pre-filled pen

Each dose contains 2.5 mg of tirzepatide in 0.6 ml solution. Each multi-dose pre-filled pen contains10 mg of tirzepatide in 2.4 ml (4.17 mg/ml). Each pen delivers 4 doses of 2.5 mg.

Mounjaro 5 mg/dose KwikPen solution for injection in pre-filled pen

Each dose contains 5 mg of tirzepatide in 0.6 ml solution. Each multi-dose pre-filled pen contains20 mg of tirzepatide in 2.4 ml (8.33 mg/ml). Each pen delivers 4 doses of 5 mg.

Mounjaro 7.5 mg/dose KwikPen solution for injection in pre-filled pen

Each dose contains 7.5 mg of tirzepatide in 0.6 ml solution. Each multi-dose pre-filled pen contains30 mg of tirzepatide in 2.4 ml (12.5 mg/ml). Each pen delivers 4 doses of 7.5 mg.

Mounjaro 10 mg/dose KwikPen solution for injection in pre-filled pen

Each dose contains 10 mg of tirzepatide in 0.6 ml solution. Each multi-dose pre-filled pen contains40 mg of tirzepatide in 2.4 ml (16.7 mg/ml). Each pen delivers 4 doses of 10 mg.

Mounjaro 12.5 mg/dose KwikPen solution for injection in pre-filled pen

Each dose contains 12.5 mg of tirzepatide in 0.6 ml solution. Each multi-dose pre-filled pen contains50 mg of tirzepatide in 2.4 ml (20.8 mg/ml). Each pen delivers 4 doses of 12.5 mg.

Mounjaro 15 mg/dose KwikPen solution for injection in pre-filled pen

Each dose contains 15 mg of tirzepatide in 0.6 ml solution. Each multi-dose pre-filled pen contains60 mg of tirzepatide in 2.4 ml (25 mg/ml). Each pen delivers 4 doses of 15 mg.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless to slightly yellow solution.

Mounjaro is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitusas an adjunct to diet and exercise

* as monotherapy when metformin is considered inappropriate due to intolerance orcontraindications

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

For study results with respect to combinations, effects on glycaemic control and the populationsstudied, 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 weightmanagement, including weight loss and weight maintenance, 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 comorbidcondition (e.g., hypertension, dyslipidaemia, obstructive sleep apnoea, cardiovascular disease,prediabetes, or type 2 diabetes mellitus).

For trial results with respect to obstructive sleep apnoea (OSA), see section 5.1.

The starting dose of tirzepatide is 2.5 mg once weekly. After 4 weeks, the dose should be increased to5 mg once weekly. If needed, dose increases can be made in 2.5 mg increments after a minimum of4 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 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 doseof sulphonylurea or insulin may be considered to reduce the risk of hypoglycaemia. Blood glucoseself-monitoring is necessary to adjust the dose of sulphonylurea and insulin. A stepwise approach toinsulin reduction is recommended (see sections 4.4 and 4.8).

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 regularlyscheduled 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 dosesis at least 3 days.

Elderly, gender, race, ethnicity or body weight

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

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 islimited. Caution should be exercised when treating these patients with tirzepatide (see section 5.2).

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

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

No data are available.

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 carefully read the instructions for use included with the package leafletbefore administering the medicinal product.

Vial

Patients and their caregivers should be trained in subcutaneous injection technique beforeadministering Mounjaro.

For further information before administration see section 6.6.

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

Tirzepatide has not been studied in patients with a history of pancreatitis, and should be used withcaution 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 notbe restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreaticenzymes alone are not predictive of acute pancreatitis (see section 4.8).

Patients receiving tirzepatide in combination with an insulin secretagogue (for example, asulphonylurea) or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemiamay be lowered by a reduction in the dose of the insulin secretagogue or insulin (see sections 4.2 and4.8).

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, whichcould lead to a deterioration in renal function including acute renal failure. Patients treated withtirzepatide should be advised of the potential risk of dehydration, due to the gastrointestinal adversereactions and take precautions to avoid fluid depletion and electrolyte disturbances. This shouldparticularly 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 severegastroparesis, and should be used with caution in these patients.

Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acutetherapy, proliferative diabetic retinopathy or diabetic macular oedema, and should be used withcaution 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 agonistsundergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastriccontent due to delayed gastric emptying (see section 4.8) should be considered prior to performingprocedures with general anaesthesia or deep sedation.

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 ofconcomitantly administered oral medicinal products. This effect, resulting in decreased Cmax and adelayed 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 toevaluate the effect of tirzepatide on gastric emptying, no dose adjustments are expected to be requiredfor most concomitantly administered oral medicinal products. However, it is recommended to monitorpatients 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 effectshould also be considered for oral medicinal products for which a rapid onset of effect is ofimportance.

Following a 5 mg single dose of tirzepatide, the maximum plasma concentration (Cmax) of paracetamolwas reduced by 50 %, and the median (tmax) was delayed by 1 hour. The effect of tirzepatide on theoral absorption of paracetamol is dose and time dependent. At low doses (0.5 and 1.5 mg), there wasonly 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 withtirzepatide.

Administration of a combination oral contraceptive (0.035 mg ethinyl estradiol plus 0.25 mgnorgestimate, 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 wasreduced by 55 % and AUC by 23 % with a delay in tmax of 4.5 hours. Norgestimate Cmax was reducedby 66 %, and AUC by 20 % with a delay in tmax of 2.5 hours. This reduction in exposure after a singledose of tirzepatide is not considered clinically relevant. No dose adjustment of oral contraceptives isrequired.

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

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

It is unknown whether tirzepatide is excreted in human milk. A risk to the newborn/infant cannot beexcluded.

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

The effect of tirzepatide on fertility in humans is unknown.

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

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

In 12 completed phase 3 studies, 8 158 patients were exposed to tirzepatide alone or in combinationwith other glucose lowering medicinal products. The most frequently reported adverse reactions weregastrointestinal 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 (seesections 4.2, and 4.4).

The following related adverse reactions from clinical studies are listed below by system organ classand 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 incidencegrouping, adverse reactions are presented in order of decreasing frequency.

Table 1. Adverse reactions

System organ Very common Common Uncommon Rareclass

Immune Hypersensitivity Anaphylacticsystem reactions reaction#,disorders Angioedema#

Metabolism Hypoglycaemia1* Hypoglycaemia1* when Hypoglycaemia1*and nutrition when used with used with metformin when used withdisorders sulphonylurea or and SGLT2i, metformin,insulin Decreased appetite1 Weight decreased1

Nervous system Dizziness2 Dysgeusia,disorders Dysaesthesia

Vascular Hypotension2disorders

Gastrointestina Nausea, Diarrhoea, Dyspepsia, Cholelithiasis,l disorders Vomiting3, Abdominal distention, Cholecystitis,

Abdominal pain3, Eructation, Flatulence, Acute pancreatitis,

Constipation3 Gastroesophageal Delayed gastricreflux disease emptying

Skin and Hair loss2subcutaneoustissue disorders

General Fatigue†, Injection site Injection site paindisorders and reactionsadministrationsite conditions

Investigations Heart rate increased,

Lipase increased,

Amylase increased,

Blood calcitoninincreased4#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.3 Frequency was very common in weight management and OSA trials, and common in T2DM trials.4 Frequency was common in weight management trials, and uncommon in T2DM and OSA trials.

Hypersensitivity reactions have been reported with tirzepatide in the pool of T2DM placebo-controlledtrials, 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 anaphylacticreaction 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 weightmanagement trials and in a pool of 2 placebo-controlled OSA trials, sometimes severe (e.g., rash anddermatitis); hypersensitivity reactions were reported in 3.0 - 5.0 % of tirzepatide-treated patientscompared to 2.1 - 3.8 % of placebo-treated patients.

Type 2 diabetes studies

Clinically significant hypoglycaemia (blood glucose < 3.0 mmol/L (< 54 mg/dL)) or severehypoglycaemia (requiring the assistance of another person) occurred in 10 to 14 % (0.14 to0.16 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 whenadded to other oral antidiabetic medicinal products was up to 0.04 events/patient year (see table 1 andsections 4.2, pct. 4.4 and 5.1).

In phase 3 clinical studies, 10 (0.2 %) patients reported 12 episodes of severe hypoglycaemia. Of these10 patients, 5 (0.1 %) were on a background of insulin glargine or sulphonylurea who reported1 episode each.

Weight management study

In a placebo-controlled weight management phase 3 trial in patients with T2DM, hypoglycaemia(blood glucose < 3.0 mmol/L (< 54 mg/dL)) was reported in 4.2 % of tirzepatide-treated patientsversus 1.3 % of placebo-treated patients. In this trial, patients taking tirzepatide in combination with aninsulin secretagogue (e.g., sulfonylurea) had a higher incidence of hypoglycaemia (10.3 %) comparedto tirzepatide-treated patients not taking a sulfonylurea (2.1 %). No severe hypoglycaemia episodeswere reported.

In the placebo-controlled T2DM phase 3 studies, gastrointestinal disorders were dose-dependentlyincreased 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. Theincidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period anddecreased over time.

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

In a placebo-controlled weight management phase 3 study in patients without T2DM, gastrointestinaldisorders were increased for tirzepatide 5 mg (55.6 %), 10 mg (60.8 %) and 15 mg (59.2 %) comparedwith placebo (30.3 %). Nausea occurred in 24.6 %, 33.3 % and 31.0 % versus 9.5 % and diarrhoea in18.7 %, 21.2 % and 23.0 % versus 7.3 % for tirzepatide 5 mg, 10 mg and 15 mg respectively versusplacebo. Gastrointestinal adverse reactions were mostly mild (60.8 %) or moderate (34.6 %) inseverity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalationperiod and decreased over time.

More patients in the tirzepatide 5 mg (1.9 %), 10 mg (4.4 %) and 15 mg (4.1 %) groups compared tothe placebo group (0.5 %) discontinued study treatment permanently due to the gastrointestinal event.

Gallbladder-related events

In a pool of 3 placebo-controlled weight management phase 3 studies, the overall incidence ofcholecystitis and cholecystitis acute was 0.6 % and 0.2 % for tirzepatide- and placebo-treated patients,respectively.

In a pool of 3 placebo-controlled weight management phase 3 studies and in a pool of 2 placebo-controlled OSA phase 3 studies, acute gallbladder disease was reported in up to 2.0 % of tirzepatide-treated patients and in up to 1.6 % of placebo-treated patients.

In the weight management phase 3 studies, acute gallbladder events were positively associated withweight reduction.

There was no evidence of an altered pharmacokinetic profile or an impact on efficacy of tirzepatideassociated with the development of anti-drug antibodies (ADA) or neutralising antibodies.

5 025 tirzepatide-treated patients in the T2DM phase 3 clinical studies were assessed for ADA. Ofthese, 51.1 % developed treatment-emergent (TE) ADA during the on-treatment period. In 38.3 % ofthe assessed patients, TE ADA were persistent (that is TE ADA present for a period of 16 weeks orgreater). 1.9 % and 2.1 % had neutralising 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 native GLP-1,respectively.

3 710 tirzepatide-treated patients in the 4 phase 3 weight management and 2 phase 3 OSA studies wereassessed for ADA. Of these, 60.6 - 65.1 % developed TE ADA during the on-treatment period. In 46.5

- 51.3 % of the assessed patients, TE ADA were persistent. Up to 2.3 % and 2.3 % had neutralisingantibodies against tirzepatide activity on the GIP and GLP-1 receptors, respectively and up to 0.7 %and 0.1 % had neutralising antibodies against native GIP and native GLP-1, respectively.

In the placebo-controlled T2DM phase 3 studies, treatment with tirzepatide resulted in a maximummean increase in heart rate of 3 to 5 beats per minute. The maximum mean increase in heart rate inplacebo-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 moreconsecutive 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 (meanincrease of 1.4 to 3.2 msec and mean decrease of 1.4 msec respectively). No difference in arrhythmiaand 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 3 placebo-controlled weight management phase 3 studies, treatment with tirzepatide resulted in amean increase in heart rate of 3 beats per minute. There was no mean increase in heart rate in theplacebo treated patients.

In a placebo-controlled weight management study in patients without T2DM, the percentage ofpatients who had a change in baseline heart rate of > 20 bpm for 2 or more consecutive visits was2.4 %, 4.9 % and 6.3 %, for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 1.2 % forplacebo. Small mean increases in PR interval were observed with tirzepatide and placebo (meanincrease of 0.3 to 1.4 msec and of 0.5 msec respectively). No difference in arrhythmia and cardiacconduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mgand placebo (3.7 %, 3.3 %, 3.3 % and 3.6 % respectively).

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

In 3 placebo-controlled weight management phase 3 studies and in 2 placebo-controlled OSA phase 3studies, injection site reactions were increased for tirzepatide (8.0 - 8.6 %) compared with placebo(1.8 - 2.6 %).

Overall, in phase 3 studies, the most common signs and symptoms of injection site reactions wereerythema 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 increasesfrom baseline in pancreatic amylase of 33 % to 38 % and lipase of 31 % to 42 %. Placebo treatedpatients had an increase from baseline in amylase of 4 % and no changes were observed in lipase.

In 3 placebo-controlled weight management phase 3 studies and 2 placebo-controlled OSA phase 3studies, treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of23 - 24.6 % and lipase of 34 - 39 %. Placebo treated patients had an increase from baseline in amylaseof 0.7 - 1.8 % and in lipase of 3.5 - 5.7 %.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

ATC code: A10BX16

Tirzepatide is a long acting GIP and GLP-1 receptor agonist, highly selective to human GIP and

GLP-1 receptors. Tirzepatide has high affinity to both the GIP and GLP-1 receptors. The activity oftirzepatide 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. Both receptors are present on thepancreatic α and β endocrine cells, heart, vasculature, immune cells (leukocytes), gut and kidney. GIPreceptors are also present on adipocytes.

In addition, both GIP and GLP-1 receptors are expressed in the areas of the brain important to appetiteregulation. Animal studies show that tirzepatide distributes to and activates neurons in brain regionsinvolved in regulation of appetite and food intake. Animal studies show that tirzepatide can modulatefat utilization through the GIP receptor. In human adipocytes cultured in vitro, tirzepatide acts on GIPreceptors to regulate glucose uptake and modulate lipid uptake and lipolysis.

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

Appetite regulation and energy metabolism

Tirzepatide lowers body weight and body fat mass. The body weight reduction is mostly due toreduced fat mass. The mechanisms associated with body weight and body fat mass reduction involvedecreased food intake through the regulation of appetite. Clinical studies show that tirzepatide reducesenergy intake and appetite by increasing feelings of satiety and fullness, and decreasing feelings ofhunger. Tirzepatide also reduces the intensity of food cravings and preferences for high sugar and highfat foods. Tirzepatide modulates fat utilisation.

Insulin secretion

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

In a hyperglycaemic clamp study in patients with type 2 diabetes, tirzepatide was compared to placeboand the selective GLP-1 receptor agonist semaglutide 1 mg for insulin secretion. Tirzepatide 15 mgenhanced 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 forplacebo.

Insulin sensitivity

Tirzepatide improves insulin sensitivity.

Tirzepatide 15 mg improved whole body insulin sensitivity by 63 %, as measured by M-value, ameasure of glucose tissue uptake using hyperinsulinemic euglycaemic clamp. The M-value wasunchanged for placebo.

Tirzepatide lowers body weight in patients with obesity and overweight, and in patients with type 2diabetes (irrespective of body weight), which may contribute to improvement in insulin sensitivity.

Glucagon concentration

Tirzepatide reduced the fasting and postprandial glucagon concentrations in a glucose dependentmanner. Tirzepatide 15 mg reduced fasting glucagon concentration by 28 % and glucagon AUC after amixed meal by 43 %, compared with no change for placebo.

Tirzepatide delays gastric emptying which may slow post meal glucose absorption and can lead to abeneficial effect on postprandial glycaemia. Tirzepatide induced delay in gastric emptying diminishesover time.

The safety and efficacy of tirzepatide were evaluated in five global randomised, controlled, phase 3studies (SURPASS 1-5) assessing glycaemic control as the primary objective. The studies involved6 263 treated patients with type 2 diabetes (4 199 treated with tirzepatide). The secondary objectivesincluded body weight, percentage of patients achieving weight reduction targets, fasting serum glucose(FSG) and percentage of patients reaching target HbA1c. All five phase 3 studies assessed tirzepatide5 mg, 10 mg and 15 mg. All patients treated with tirzepatide started with 2.5 mg for 4 weeks. Then thedose 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 andclinically meaningful reductions from baseline in HbA1c as the primary objective compared to eitherplacebo or active control treatment (semaglutide, insulin degludec and insulin glargine) for up to1 year. In 1 study these effects were sustained for up to 2 years. Statistically significant and clinicallymeaningful reductions from baseline in body weight were also demonstrated. Results from the phase 3studies are presented below based on the on-treatment data without rescue therapy in the modifiedintent-to-treat (mITT) population consisting of all randomly assigned patients who were exposed to atleast 1 dose of study treatment, excluding patients discontinuing study treatment due to inadvertentenrolment.

SURPASS-1 - Monotherapy

In a 40 week double-blind placebo-controlled study, 478 patients with inadequate glycaemic controlwith 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 durationof diabetes of 5 years and the mean BMI was 32 kg/m2.

Table 2. SURPASS-1: Results at week 40

Tirzepatide Tirzepatide Tirzepatide Placebo5 mg 10 mg 15 mgmITT population (n) 121 121 120 113

HbA1c (%) Baseline (mean) 7.97 7.88 7.88 8.08

Change from baseline -1.87## -1.89## -2.07## +0.04

Difference from -1.91** -1.93** -2.11** -placebo [95 % CI] [-2.18, -1.63] [-2.21, -1.65] [-2.39, -1.83]

HbA1c Baseline (mean) 63.6 62.6 62.6 64.8(mmol/mol) Change from baseline -20.4## -20.7## -22.7## +0.4

Difference from -20.8** -21.1** -23.1** -placebo [95 % CI] [-23.9, -17.8] [-24.1, -18.0] [-26.2, -20.0]

Patients (%) < 7 % 86.8** 91.5** 87.9** 19.6achieving HbA1c≤ 6.5 % 81.8†† 81.4†† 86.2†† 9.8< 5.7 % 33.9** 30.5** 51.7** 0.9

FSG (mmol/L) Baseline (mean) 8.5 8.5 8.6 8.6

Change from baseline -2.4## -2.6## -2.7## +0.7#

Difference from -3.13** -3.26** -3.45** -placebo [95 % CI] [-3.71, -2.56] [-3.84, -2.69] [-4.04, -2.86]

FSG (mg/dL) Baseline (mean) 153.7 152.6 154.6 155.2

Change from baseline -43.6## -45.9## -49.3## +12.9#

Difference from -56.5** -58.8** -62.1** -placebo [95 % CI] [-66.8, -46.1] [-69.2, -48.4] [-72.7, -51.5]

Body weight (kg) Baseline (mean) 87.0 85.7 85.9 84.4

Change from baseline -7.0## -7.8## -9.5## -0.7

Difference from -6.3** -7.1** -8.8** -placebo [95 % CI] [-7.8, -4.7] [-8.6, -5.5] [-10.3, -7.2]

Patients (%) ≥ 5 % 66.9†† 78.0†† 76.7†† 14.3achieving weight ≥ 10 % 30.6†† 39.8†† 47.4†† 0.9loss ≥ 15 % 13.2† 17.0† 26.7† 0.0

*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.

Time (Weeks) Time (Weeks)

MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Placebo MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Placebo

Figure 1. Mean HbA1c (%) 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 doseassignment) 1 879 patients were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or

Mean HbA1c (%)

Mean Body Weight (Kg)semaglutide 1 mg once weekly, all in combination with metformin. Patients had a mean age of57 years and 47 % were men. At baseline the patients had a mean duration of diabetes of 9 years andthe mean BMI was 34 kg/m2.

Table 3. SURPASS-2: Results at week 40

Tirzepatide Tirzepatide Tirzepatide Semaglutide5 mg 10 mg 15 mg 1 mgmITT population (n) 470 469 469 468

HbA1c (%) Baseline (mean) 8.33 8.31 8.25 8.24

Change from baseline -2.09## -2.37## -2.46## -1.86##

Difference from -0.23** -0.51** -0.60** -semaglutide [-0.36, -0.10] [-0.64, -0.38] [-0.73, -0.47][95 % CI]

HbA1c Baseline (mean) 67.5 67.3 66.7 66.6(mmol/mol) Change from baseline -22.8## -25.9## -26.9## -20.3##

Difference from -2.5** -5.6** -6.6** N/Asemaglutide [-3.9, -1.1] [-7.0, -4.1] [-8.0, -5.1][95 % CI]

Patients (%) < 7 % 85.5* 88.9** 92.2** 81.1achieving ≤ 6.5 % 74.0† 82.1†† 87.1†† 66.2

HbA1c < 5.7 % 29.3†† 44.7** 50.9** 19.7

FSG (mmol/L) Baseline (mean) 9.67 9.69 9.56 9.49

Change from baseline -3.11## -3.42## -3.52## -2.70##

Difference from -0.41† -0.72†† -0.82†† -semaglutide [-0.65, -0.16] [-0.97, -0.48] [-1.06, -0.57][95 % CI]

FSG (mg/dL) Baseline (mean) 174.2 174.6 172.3 170.9

Change from baseline -56.0## -61.6## -63.4## -48.6##

Difference from † †† †† -semaglutide -7.3 -13.0 -14.7[95 % CI] [-11.7, -3.0] [-17.4, -8.6] [-19.1, -10.3]

Body weight Baseline (mean) 92.6 94.9 93.9 93.8(kg) Change from baseline -7.8## -10.3## -12.4## -6.2##

Difference from -1.7** -4.1** -6.2** -semaglutide [-2.6, -0.7] [-5.0, -3.2] [-7.1, -5.3][95 % CI]

Patients (%) ≥ 5 % 68.6† 82.4†† 86.2†† 58.4achieving ≥ 10 % 35.8†† 52.9†† 64.9†† 25.3weight loss ≥ 15 % 15.2† 27.7†† 39.9†† 8.7

*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.

Time (Weeks) Time (Weeks)

MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Semaglutide 1 mg MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Semaglutide 1 mg

Figure 2. Mean HbA1c (%) and 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 durationof 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 analgorithm for a target fasting blood glucose of < 5 mmol/L. The mean dose of insulin degludec atweek 52 was 49 units/day.

Mean HbA1c (%)

Mean Body Weight (Kg)

Table 4. SURPASS-3: Results at week 52

Tirzepatide Tirzepatide Tirzepatide Titrated5 mg 10 mg 15 mg insulindegludecmITT population (n) 358 360 358 359

HbA1c (%) Baseline (mean) 8.17 8.19 8.21 8.13

Change from baseline -1.93## -2.20## -2.37## -1.34##

Difference from insulin -0.59** -0.86** -1.04** -degludec [95 % CI] [-0.73, -0.45] [-1.00, -0.72] [-1.17, -0.90]

HbA1c Baseline (mean) 65.8 66.0 66.3 65.4(mmol/mol) Change from baseline -21.1## -24.0## -26.0## -14.6##

Difference from insulin -6.4** -9.4** -11.3** -degludec [95 % CI] [-7.9, -4.9] [-10.9, -7.9] [-12.8, -9.8]

Patients (%) < 7 % 82.4** 89.7** 92.6** 61.3achieving ≤ 6.5 % 71.4†† 80.3†† 85.3†† 44.4

HbA1c< 5.7 % 25.8†† 38.6†† 48.4†† 5.4

FSG (mmol/L) Baseline (mean) 9.54 9.48 9.35 9.24

Change from baseline -2.68## -3.04## -3.29## -3.09##

Difference from insulin 0.41† 0.05 -0.20 -degludec [95 % CI] [0.14, 0.69] [-0.24, 0.33] [-0.48, 0.08]

FSG (mg/dL) Baseline (mean) 171.8 170.7 168.4 166.4

Change from baseline -48.2## -54.8## -59.2## -55.7##

Difference from insulin 7.5† 0.8 -3.6 -degludec [95 % CI] [2.4, 12.5] [-4.3, 5.9] [-8.7, 1.5]

Body weight Baseline (mean) 94.5 94.3 94.9 94.2(kg) Change from baseline -7.5## -10.7## -12.9## +2.3##

Difference from insulin -9.8** -13.0** -15.2** -degludec [95 % CI] [-10.8, -8.8] [-14.0, -11.9] [-16.2, -14.2]

Patients (%) ≥ 5 % 66.0†† 83.7†† 87.8†† 6.3achieving ≥ 10 % 37.4†† 55.7†† 69.4†† 2.9weight loss ≥ 15 % 12.5†† 28.3†† 42.5†† 0.0

*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.

Time (Weeks) Time (Weeks)

MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Insulin Degludec MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Insulin Degludec

Figure 3. Mean HbA1c (%) and mean body weight (kg) from baseline to week 52

Continuous glucose monitoring (CGM)

A subset of patients (N = 243) participated in an evaluation of the 24 hour glucose profiles capturedwith blinded CGM. At 52 weeks, patients treated with tirzepatide (10 mg and 15 mg pooled) spentsignificantly more time with glucose values in the euglycaemic range defined as 71 to 140 mg/dL (3.9

Mean HbA1c (%)

Mean Body Weight (Kg)to 7.8 mmol/L) compared to patients treated with insulin degludec, with 73 % and 48 % of the 24 hourperiod in range, respectively.

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 tirzepatide5 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 meanduration of diabetes of 12 years, a mean BMI of 33 kg/m2, a mean age of 64 years and 63 % were men.

Patients treated with insulin glargine started at a dose of 10 U/day which was adjusted using analgorithm with a fasting blood glucose target of < 5.6 mmol/L. The mean dose of insulin glargine atweek 52 was 44 units/day.

Table 5. SURPASS-4: Results at week 52

Tirzepatide Tirzepatide Tirzepatide Titrated5 mg 10 mg 15 mg insulinglarginemITT population (n) 328 326 337 99852 weeks

HbA1c (%) Baseline (mean) 8.52 8.60 8.52 8.51

Change from baseline -2.24## -2.43## -2.58## -1.44##

Difference from insulin -0.80** -0.99** -1.14** -glargine [95 % CI] [-0.92, -0.68] [-1.11, -0.87] [-1.26, -1.02]

HbA1c Baseline (mean) 69.6 70.5 69.6 69.5(mmol/mol) Change from baseline -24.5## -26.6## -28.2## -15.7##

Difference from insulin -8.8** -10.9** -12.5** -glargine [95 % CI] [-10.1, -7.4] [-12.3, -9.6] [-13.8, -11.2]

Patients (%) < 7 % 81.0** 88.2** 90.7** 50.7achieving ≤ 6.5 % 66.0†† 76.0†† 81.1†† 31.7

HbA1c < 5.7 % 23.0†† 32.7†† 43.1†† 3.4

FSG (mmol/L) Baseline (mean) 9.57 9.75 9.67 9.37

Change from baseline -2.80## -3.06## -3.29## -2.84##

Difference from insulin 0.04 -0.21 -0.44†† -glargine [95 % CI] [-0.22, 0.30] [-0.48, 0.05] [-0.71, -0.18]

FSG (mg/dL) Baseline (mean) 172.3 175.7 174.2 168.7

Change from baseline -50.4## -54.9## -59.3## -51.4##

Difference from insulin 1.0 -3.6 -8.0†† -glargine [95 % CI] [-3.7, 5.7] [-8.2, 1.1] [-12.6, -3.4]

Body weight Baseline (mean) 90.3 90.7 90.0 90.3(kg) Change from baseline -7.1## -9.5## -11.7## +1.9##

Difference from insulin -9.0** -11.4** -13.5** -glargine [95 % CI] [-9.8, -8.3] [-12.1, -10.6] [-14.3, -12.8]

Patients (%) ≥ 5 % 62.9†† 77.6†† 85.3†† 8.0achieving ≥ 10 % 35.9†† 53.0†† 65.6†† 1.5weight loss ≥ 15 % 13.8†† 24.0†† 36.5†† 0.5

* 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.

Time (Weeks) Time (Weeks)

MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Insulin Glargine MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Insulin Glargine

Figure 4. Mean HbA1c (%) 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 controlusing insulin glargine with or without metformin were randomised to tirzepatide 5 mg, 10 mg or

Mean HbA1c (%)

Mean Body Weight (Kg)15 mg once weekly or placebo. Insulin glargine doses were adjusted utilizing an algorithm with afasting blood glucose target of < 5.6 mmol/L. At baseline the patients had a mean duration of diabetesof 13 years, a mean BMI of 33 kg/m2, a mean age of 61 years and 56 % were men. The overallestimated median dose of insulin glargine at baseline was 34 units/day. The median dose of insulinglargine at week 40 was 38, 36, 29 and 59 units/day for tirzepatide 5 mg, 10 mg, 15 mg and placeborespectively.

Table 6. SURPASS-5: Results at week 40

Tirzepatide Tirzepatide Tirzepatide Placebo5 mg 10 mg 15 mgmITT population (n) 116 118 118 119

HbA1c (%) Baseline (mean) 8.29 8.34 8.22 8.39

Change from baseline -2.23## -2.59## -2.59## -0.93##

Difference from -1.30** -1.66** -1.65** -placebo [95 % CI] [-1.52, -1.07] [-1.88, -1.43] [-1.88, -1.43]

HbA1c Baseline (mean) 67.1 67.7 66.4 68.2(mmol/mol) Change from baseline -24.4## -28.3## -28.3## -10.2##

Difference from -14.2** -18.1** -18.1** -placebo [95 % CI] [-16.6, -11.7] [-20.6, -15.7] [-20.5, -15.6]

Patients (%) < 7 % 93.0** 97.4** 94.0** 33.9achieving≤ 6.5 % 80.0†† 94.7†† 92.3††

HbA 17.01c< 5.7 % 26.1†† 47.8†† 62.4†† 2.5

FSG (mmol/L) Baseline (mean) 9.00 9.04 8.91 9.13

Change from baseline -3.41## -3.77## -3.76## -2.16##

Difference from -1.25** -1.61** -1.60** -placebo [95 % CI] [-1.64, -0.86] [-2.00, -1.22] [-1.99, -1.20]

FSG (mg/dL) Baseline (mean) 162.2 162.9 160.4 164.4

Change from baseline -61.4## -67.9## -67.7## -38.9##

Difference from -22.5** -29.0** -28.8** -placebo [95 % CI] [-29.5, -15.4] [-36.0, -22.0] [-35.9, -21.6]

Body weight Baseline (mean) 95.5 95.4 96.2 94.1(kg) Change from baseline -6.2## -8.2## -10.9## +1.7#

Difference from -7.8** -9.9** -12.6** -placebo [95 % CI] [-9.4, -6.3] [-11.5, -8.3] [-14.2, -11.0]

Patients (%) ≥ 5 % 53.9†† 64.6†† 84.6†† 5.9achieving ≥ 10 % 22.6†† 46.9†† 51.3†† 0.9weight loss ≥ 15 % 7.0† 26.6† 31.6†† 0.0

*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.

Time (Weeks) Time (Weeks)

MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Placebo MOUNJARO 5 mg MOUNJARO 10 mg MOUNJARO 15 mg Placebo

Figure 5. Mean HbA1c (%) and mean body weight (kg) from baseline to week 40

Weight management

The efficacy and safety of tirzepatide for weight management, in combination with a reduced calorieintake and increased physical activity, in patients with obesity (BMI ≥ 30 kg/m2), or overweight(BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-related comorbidity (such as treated oruntreated dyslipidaemia, hypertension, obstructive sleep apnoea, or cardiovascular disease), and withprediabetes or normoglycemia, but without type 2 diabetes mellitus, were evaluated in threerandomised double-blinded, placebo-controlled phase 3 studies (SURMOUNT-1, SURMOUNT-3,

SURMOUNT-4). A total of 3 900 adult patients (2 518 randomised to tirzepatide) were included inthese studies.

Treatment with tirzepatide demonstrated clinically meaningful and sustained weight reductioncompared with placebo. Furthermore, a higher percentage of patients achieved ≥ 5 %, ≥ 10 %, ≥ 15 %and ≥ 20 % weight loss with tirzepatide compared with placebo.

The efficacy and safety of tirzepatide for weight management in patients with type 2 diabetes wereevaluated in a randomised double-blinded, placebo-controlled phase 3 study (SURMOUNT-2), and ina subpopulation of patients with BMI ≥ 27 kg/m2 in five randomised phase 3 studies (SURPASS-1to -5). A total of 6 330 patients with BMI ≥ 27 kg/m2 (4 249 randomised to treatment with tirzepatide)were included in these studies. In SURMOUNT-2 treatment with tirzepatide demonstrated clinicallymeaningful and sustained weight reduction compared with placebo. Furthermore, a higher percentageof patients achieved ≥ 5 %, ≥ 10 %, ≥ 15 % and ≥ 20 % weight loss with tirzepatide compared withplacebo. Subgroup analyses of patients with obesity or overweight in the SURPASS studies(amounting to 86 % of the overall SURPASS-1 to -5 population) showed sustained weight reduction,and a higher percentage of patients achieving weight reduction targets compared to activecomparator/placebo.

In all SURMOUNT studies, the same tirzepatide dose escalation scheme was used as in the SURPASSprogramme (starting with 2.5 mg for 4 weeks, followed by increases in 2.5 mg increments every4 weeks until the assigned dose was reached).

SURMOUNT-1

In a 72 week double-blind placebo-controlled study, 2 539 adult patients with obesity (BMI ≥30 kg/m2) or with overweight (BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight-relatedcomorbid condition, were randomised to tirzepatide 5 mg, 10 mg or 15 mg once weekly or placebo.

All patients were counselled on a reduced-calorie diet and increased physical activity throughout thetrial. At baseline, patients had a mean age of 45 years, 67.5 % were women and 40.6 % of patients hadprediabetes. Mean BMI at baseline was 38 kg/m2.

Mean HbA1c (%)

Mean Body Weight (Kg)

Table 7. SURMOUNT-1: Results at week 72

Tirzepatide Tirzepatide Tirzepatide Placebo5 mg 10 mg 15 mgmITT population (n) 630 636 630 643

Baseline (kg) 102.9 105.9 105.5 104.8

Change (%) from baseline -16.0†† -21.4†† -22.5†† -2.4

Difference (%) from placebo -13.5** -18.9** -20.1** -[95 % CI] [-14.6, -12.5] [-20.0, -17.8] [-21.2, -19.0]

Change (kg) from baseline -16.1†† -22.2†† -23.6†† -2.4††

Difference (kg) from placebo -13.8## -19.8## -21.2## -[95 % CI] [-15.0, -12.6] [-21.0, -18.6] [-22.4, -20.0]

Patients (%) achieving body weight reduction≥ 5 % 89.4** 96.2** 96.3** 27.9≥ 10 % 73.4## 85.9** 90.1** 13.5≥ 15 % 50.2## 73.6** 78.2** 6.0≥ 20 % 31.6## 55.5** 62.9** 1.3

Waist circumference (cm)

Baseline 113.2 114.9 114.4 114.0

Change from baseline -14.6†† -19.4†† -19.9†† -3.4††

Difference from placebo -11.2## -16.0** -16.5** -[95 % CI] [-12.3, -10.0] [-17.2, -14.9] [-17.7, -15.4]††p < 0.001 versus baseline.

**p < 0.001 versus placebo, adjusted for multiplicity.##p < 0.001 versus placebo, not adjusted for multiplicity.

- 2.4 %

- 16.0 %

- 21.4 %

- 22.5 %0 4 8 12 16 20 24 36 48 60 72

Time (Weeks)

MOUNJARO 5mg MOUNJARO 10mg MOUNJARO 15mg Placebo

Change in Body Weight (%)

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

In SURMOUNT-1, pooled doses of tirzepatide 5 mg, 10 mg, and 15 mg led to a significantimprovement compared to placebo in systolic blood pressure (-8.1 mmHg vs. -1.3 mmHg),triglycerides (-27.6 % vs. -6.3 %), non-HDL-C (-11.3 % vs. -1.8 %), HDL-C (7.9 % vs. 0.3 %), andfasting insulin (-46.9 % vs. -9.7 %).

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

SURMOUNT-2

In a 72 week double-blind placebo-controlled study, 938 adult patients with obesity (BMI ≥ 30 kg/m2)or with overweight (BMI ≥ 27 kg/m2 to < 30 kg/m2) and type 2 diabetes, were randomised totirzepatide 10 mg or 15 mg once weekly or placebo. Patients included in the trial had HbA1c 7-10 %and were treated with either diet and exercise alone, or with one or more oral anti-hyperglycemicagent . All patients were counselled on a reduced calorie diet and increased physical activitythroughout the trial. Patients had a mean age of 54 years and 51 % were women.Mean BMI at baselinewas 36.1 kg/m2.

Table 8. SURMOUNT-2: Results at week 72

Tirzepatide Tirzepatide Placebo10 mg 15 mgmITT population (n) 312 311 315

Baseline (kg) 101.1 99.5 101.7

Change (%) from baseline -13.4†† -15.7†† -3.3††

Difference (%) from placebo -10.1** -12.4** -[95 % CI] [-11.5, -8.8] [-13.7, -11.0]

Change (kg) from baseline -13.5†† -15.6†† -3.2

Difference (kg) from placebo -10.3## -12.4## -[95 % CI] [-11.7, -8.8] [-13.8,-11.0]

Patients (%) achieving body weight reduction≥ 5 % 81.6** 86.4** 30.5≥ 10 % 63.4** 69.6** 8.7≥ 15 % 41.4** 51.8** 2.6≥ 20 % 23.0** 34.0** 1.0

Waist circumference (cm)

Baseline 114.3 114.6 116.1

Change from baseline -11.2†† -13.8†† -3.4††

Difference from placebo -7.8** -10.4** -[95 % CI] [-9.2, -6.4] [-11.8, -8.9]

HbA1c (mmol/mol)

Baseline 64.1 64.7 63.4

Change from baseline -23.4†† -24.3†† -1.8†

Difference from placebo -21.6** -22.5** -[95 % CI] [-23.5, -19.6] [-24.4, -20.6]

HbA1c (%)

Baseline 8.0 8.1 8.0

Change from baseline -2.1†† -2.2†† -0.2†

Difference from placebo -2.0** -2.1** -[95 % CI] [-2.2, -1.8] [-2.2, -1.9]

Patients (%) achieving HbA1c< 7 % 90.0** 90.7** 29.3≤ 6.5 % 84.1** 86.7** 15.5< 5.7 % 50.2** 55.3** 2.8

FSG (mmol/L)

Baseline 8.8 9.0 8.7

Change from baseline -2.7†† -2.9†† -0.1

Difference from placebo -2.6** -2.7** -[95 % CI] [-2.9, -2.3] [-3.1, -2.4]

FSG (mg/dL)

Baseline 157.8 161.5 156.7

Change from baseline -49.2†† -51.7†† -2.4

Difference from placebo -46.8** -49.3** -[95 % CI] [-52.7, -40.9] [-55.2, -43.3]†p< 0.05 versus baseline††p < 0.001 versus baseline.

**p < 0.001 versus placebo, adjusted for multiplicity.##p < 0.001 versus placebo, not adjusted for multiplicity.

- 3.3 %

- 13.4 %

- 15 -15.7 %0 4 8 12 16 20 24 36 48 60 72

Time (Weeks)

MOUNJARO 10mg MOUNJARO 15mg Placebo

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

In SURMOUNT-2, pooled doses of tirzepatide 10 mg and 15 mg led to a significant improvementcompared to placebo in systolic blood pressure (-7.2 mmHg vs. -1.0 mmHg), triglycerides (-28.6 % vs.

- 5.8 %), non-HDL-C (-6.6 % vs. 2.3 %), and HDL-C (8.2 % vs. 1.1 %).

SURMOUNT-3

In an 84 week study, 806 adult patients with obesity (BMI ≥ 30 kg/m2) or with overweight(BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight related comorbid condition, entered a 12 weekintensive lifestyle intervention lead-in period consisting of a low calorie diet (1 200-1 500 kcal/day),increased physical activity and frequent behavioural counselling. At the end of the 12 week lead-inperiod, 579 patients who achieved ≥ 5.0 % weight reduction were randomised to tirzepatide maximumtolerated dose (MTD) of 10 mg or 15 mg once weekly or to placebo, for 72 weeks (double-blindphase). Patients were on a reduced-calorie diet and increased physical activity throughout the double-blind phase of the study. At randomisation patients had a mean age of 46 years and 63 % were women.

Mean BMI at randomisation was 35.9 kg/m2.

Change in Body Weight (%)

Table 9. SURMOUNT-3: Results at week 72

Tirzepatide Placebo

MTDmITT population (n) 287 292

Baseline1 (kg) 102.3 101.3

Change (%) from baseline1 -21.1†† 3.3††

Difference (%) from placebo -24.5** -[95 % CI] [-26.1, -22.8]

Change (kg) from baseline1 -21.5†† 3.5††

Difference (kg) from placebo -25.0## -[95 % CI] [-26.9, -23.2]

Patients (%) achieving body weight reduction≥ 5 % 94.4** 10.7≥ 10 % 88.0** 4.8≥ 15 % 73.9** 2.1≥ 20 % 54.9** 1.0

Patients (%) who maintain ≥80% of the body 98.6** 37.8weight lost during the 12-week lead-in period

Waist circumference (cm)

Baseline1 109.2 109.6

Change from baseline1 -16.8†† 1.1

Difference from placebo -17.9** -[95 % CI] [-19.5, -16.3]1Randomisation (Week 0)††p < 0.001 versus baseline1.

**p < 0.001 versus placebo, adjusted for multiplicity.##p < 0.001 versus placebo, not adjusted for multiplicity.

5.00.0

- 3.8

- 5.0

- 6.9

- 10.0

- 15.0

- 20.0

- 25.0

- 26.6

- 30.0

- 12 0 24 48 72

Week Relative to Randomization

Lead-in lifestyle MOUNJARO MTD Placebo

Figure 8. Mean change in body weight (%) from Week -12 to week 72

SURMOUNT-4

In an 88 week study, 783 adult patients with obesity (BMI ≥ 30 kg/m2) or with overweight(BMI ≥ 27 kg/m2 to < 30 kg/m2) and at least one weight related comorbid condition, were enrolled in a36 week open label tirzepatide lead-in phase. At the start of lead-in period, the enrolled patients had amean body weight of 107.0 kg and a mean BMI of 38.3 kg/m2. At the end of the lead-in period,670 patients who achieved tirzepatide MTD of 10 mg or 15 mg dose were randomised to continuetreatment with tirzepatide once weekly or to switch to placebo for 52 weeks (double-blind phase).

Patients were counselled on a reduced calorie diet and increased physical activity throughout the trial.

At randomisation (week 36), patients had a mean age of 49 years and 71 % were women. Mean bodyweight at randomisation was 85.2 kg and mean BMI was 30.5 kg/m2.

Patients who continued treatment with tirzepatide for an additional 52 weeks (up to 88 weeks in total)maintained and experienced further weigh loss after the initial weight reduction achieved during the36 week lead-in phase. The weight reduction was superior and clinically meaningful compared to theplacebo group, in which a substantial regain of body weight lost during the lead-in phase was observed(see Table 10 and Figure 9). Nevertheless, the observed mean body weight for placebo-treated patientswas lower at week 88 than at the start of the lead-in phase (see Figure 9).

Change in Body Weight (%)

Table 10. SURMOUNT-4: Results at week 88

Tirzepatide Placebo

MTDmITT population (n) only patients at Week 36 335 335

Weight (kg) at Week 0 (baseline) 106.7 107.8

Weight (kg) at Week 36 (randomisation) 84.5 85.9

Change (%) from Week 36 at Week 88 -6.7†† 14.8††

Difference (%) from placebo at Week 88 -21.4** -[95 % CI] [-22.9, -20.0]

Change (kg) from Week 36 at Week 88 -5.7†† 11.9††

Difference (kg) from placebo at Week 88 -17.6## -[95 % CI] [-18.8, -16.4]

Patients (%) achieving body weight reduction from Week 0 to Week 88≥ 5 % 98.5** 69.0≥ 10 % 94.0** 44.4≥ 15 % 87. 1** 24.0≥ 20 % 72.6** 11.6

Patients (%) who maintain ≥80% of the body weight 93.4** 13.5lost during the 36-week lead-in period at Week 88

Waist circumference (cm)

Baseline (Week 0) 114.9 115.6

Randomisation (Week 36) 96.7 98.2

Change from randomisation (Week 36) -4.6†† 8.3††

Difference from placebo -12.9** -[95 % CI] [-14.1, -11.7]††p < 0.001 versus baseline.

**p < 0.001 versus placebo, adjusted for multiplicity.##p < 0.001 versus placebo, not adjusted for multiplicity.

5.00.0

- 5.0

- 9.5

- 10.0

- 15.0

- 20.0 -20.9

- 25.0 -26.00 4 8 12 16 20 24 28 32 36 40 52 64 76 88

Time (Weeks)

MOUNJARO Lead-in MOUNJARO MTD Placebo

Figure 9. Mean change in body weight (%) from baseline (Week 0) to week 88

Risk of weight regain to > 95 % of study baseline (Week 0) weight at week 88

Time to event analysis showed that continued tirzepatide treatment during the double-blind periodreduced the risk of returning to greater than 95 % body weight observed at Week 0, for those who hadalready lost at least 5 % since week 0 by approximately 99 % compared with placebo (hazard ratio,0.013 [95 % CI, 0.004 to 0.046]; p < 0.001).

Changes in body composition were evaluated in a sub-study in SURMOUNT-1 using dual energy

X-ray absorptiometry (DEXA). The results of the DEXA assessment showed that treatment withtirzepatide was accompanied by greater reduction in fat mass than in lean body mass leading to animprovement in body composition compared to placebo after 72 weeks. Furthermore, this reduction intotal fat mass was accompanied by a reduction in visceral fat. These results suggest that most of thetotal weight loss was attributable to a reduction in fat tissue, including visceral fat.

Patients with obesity or overweight without diabetes who received tirzepatide showed smallimprovements in health-related quality of life, including physical functioning. The improvements weregreater in the tirzepatide-treated patients than in those who received placebo. Health-related quality oflife was assessed using the generic questionnaire Short Form-36v2 Health Survey Acute, Version(SF-36v2).

Obstructive sleep apnoea

The efficacy and safety of tirzepatide for the treatment of moderate to severe (AHI>15) obstructivesleep apnoea (OSA), in combination with diet and exercise, in patients with obesity were evaluated intwo randomized double-blinded, placebo-controlled phase 3 studies (SURMOUNT-OSA Study 1 and

Study 2). A total of 469 adult patients with moderate to severe OSA and obesity (234 randomised totreatment with tirzepatide) were included in these studies. Patients with T2DM were excluded. Study 1

Change in Body Weight (%)enrolled patients unable or unwilling to use Positive Airway Pressure (PAP) therapy. Study 2 enrolledpatients on PAP therapy. Study 2 does not allow any conclusion about a potentially added benefit oftirzepatide on top of PAP therapy, since PAP use was suspended 7 days prior to endpointmeasurement. All patients were treated with the maximum tolerated dose (MTD; 10 mg or 15 mg) oftirzepatide or placebo, once weekly for 52 weeks.

In both studies, treatment with tirzepatide demonstrated statistically significant and clinicallymeaningful reduction in the apnoea-hypopnoea index (AHI) compared with placebo (see Table 11).

Among tirzepatide treated patients, greater proportion of patients achieved at least 50 % AHIreduction compared to placebo.

SURMOUNT-OSA, Study 1 and Study 2

In two 52 week double-blind placebo-controlled studies, 469 adult patients with moderate to severe

OSA and obesity, were randomised to tirzepatide MTD of 10 mg or 15 mg once weekly, or to placebo,once weekly. In Study 1 patients had a mean age of 48 years, 33 % were female, 35 % had moderate

OSA, 63 % had severe OSA, 65 % had pre-diabetes, 76 % had hypertension, 10 % had cardiacdisorders, and 81 % had dyslipidemia. Patients had a mean Epworth Sleepiness Scale (ESS) of 10.5.

In Study 2 patients had a mean age of 52 years, 28 % were female, 31 % had moderate OSA, 68 % hadsevere OSA, 57 % had pre-diabetes, 77 % had hypertension, 11 % had cardiac disorders, and 84 % haddyslipidemia. Patients had a mean ESS of 10.0.

Table 11. SURMOUNT-OSA, Study 1 and Study 2: Results at week 52

OSA Study 1 OSA Study 2

Tirzepatide Placebo Tirzepatide Placebo

MTD MTDmITT population (n) 114 120 119 114

AHI (events/hr)

Baseline mean 54.3 50.9 45.8 53.1

Change from baseline -27.4†† -4.8† -30.4†† -6.0†

Difference from placebo -22.5** - -24.4** -[95 % CI] [-28.7, -16.4] [-30.3, -18.6]% Change in AHI% Change from baseline -55.0†† -5.0 -62.8†† -6.4% Difference from placebo -49.9** - -56.4** -[95% CI] [-62.8, -37.0] [-70.7, -42.2]

Patients (%) achieving reduction in AHI≥50% 62.3 19.2 74.3 22.9% Difference from placebo 43.6** - 50.8** -[95% CI] [31.1, 56.2] [38.6, 62.9]

Sleep apnoea-specific hypoxic burden (% min/h)a

Baseline geometric mean 156.6 148.2 129.9 139.1

Change from baseline -103.1†† -21.1 -103.0†† -40.7†

Difference from placebo -82.0** - -62.4** -[95% CI] [-107.0, -57.1] [-87.1, -37.6]

Body weight (kg)

Baseline mean 117.0 112.7 115.8 115.0% Change from baseline -18.1†† -1.3 -20.1†† -2.3†% Difference from placebo -16.8** - -17.8** -[95% CI] [-18.8, -14.7] [-19.9, -15.7]

Systolic Blood Pressure (mmHg) b

Baseline mean 128.2 130.3 130.7 130.5

Change from baseline -9.6†† -1.7 -7.6†† -3.3†

Difference from placebo -7.9** - -4.3* -[95% CI] [-11.0, -4.9] [-7.3, -1.2]hsCRP (mg/L) a

Baseline geometric mean 3.6 3.8 3.0 2.7

Change from baseline -1.6†† -0.8† -1.4†† -0.3

Difference from placebo -0.8* - -1.1** -[95% CI] [-1.4, -0.3] [-1.7, -0.5]† p < 0.05, ††p < 0.001 versus baseline.

* p < 0.05, **p < 0.001 versus placebo, adjusted for multiplicity.a Analysed using log transformed data.b Blood pressure was assessed at Week 48 because PAP withdrawal at Week 52 may confound bloodpressure assessment.

Cardiovascular (CV) risk was assessed via a meta-analysis of patients with at least one adjudicationconfirmed major adverse cardiovascular 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 totalof 116 patients (tirzepatide: 60 [n = 4 410]; all comparators: 56 [n = 2 169]) experienced at least oneadjudication confirmed MACE-4: The results showed that tirzepatide was not associated with excessrisk 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 patientswith 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 thattirzepatide was not associated with excess risk for CV events compared with insulin glargine(HR: 0.74; CI: 0.51 to 1.08).

In 3 placebo-controlled weight management phase 3 studies (SURMOUNT 1-3), a total of27 participants experienced at least one adjudication confirmed MACE (TZP: 17 (n = 2 806);placebo: 10 (n = 1 250)); the event rate was similar across placebo and tirzepatide.

In the placebo-controlled phase 3 studies in patients with T2DM, treatment with tirzepatide resulted ina 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 inplacebo treated patients.

In 3 placebo-controlled weight management phase 3 studies (SURMOUNT 1-3), treatment withtirzepatide resulted in a mean decrease in systolic and diastolic blood pressure of 7 mmHg and4 mmHg, respectively. There was a mean decrease in systolic and diastolic blood pressure of< 1 mmHg each in placebo treated patients.

In two placebo-controlled OSA phase 3 studies with pooled safety analysis, treatment with tirzepatideresulted in a mean decrease in systolic and diastolic blood pressure of 9.0 mmHg and 3.8 mmHg,respectively, at Week 52. There was a mean decrease in systolic and diastolic blood pressure of2.5 mmHg and 1.0 mmHg, respectively, in placebo treated patients at Week 52.

Fasting serum glucose

Across SURPASS-1 to -5 trials, treatment with tirzepatide resulted in significant reductions frombaseline 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. Furtherimprovement in FSG was seen through to 42 weeks then was sustained through the longest studyduration of 104 weeks.

Postprandial glucose

Across SURPASS-1 to -5 trials, treatment with tirzepatide resulted in significant reductions in mean2 hour post prandial glucose (mean of 3 main meals of the day) from baseline (changes from baselineto 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 serumtriglyceride 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 withsemaglutide 1 mg.

In the 72 week placebo-controlled phase 3 study in patients with obesity or overweight without T2DM(SURMOUNT-1), treatment with tirzepatide 5 mg, 10 mg, and 15 mg resulted in 24 %, 27 % and31 % reduction in serum triglyceride levels respectively compared to 6 % reduction with placebo.

In the 72 week placebo-controlled phase 3 study in patients with obesity or overweight with T2DM(SURMOUNT-2), treatment with tirzepatide 10 mg and 15 mg resulted in 27 % and 31 % reduction inserum triglyceride levels respectively compared to 6 % reduction with placebo.

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), 93.6 % to100 % of patients who achieved a normal glycaemia of HbA1c < 5.7 % (≤ 39 mmol/mol), at theprimary 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.

The efficacy of tirzepatide for the treatment of T2DM was not impacted by age, gender, race,ethnicity, region, or by baseline BMI, HbA1c, diabetes duration and level of renal functionimpairment.

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

The efficacy of tirzepatide for the treatment of moderate to severe OSA in patients with obesity wasnot impacted by age, sex, ethnicity, baseline BMI, or baseline OSA severity.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Mounjaro in one or more subsets of the paediatric population for the treatment of type 2 diabetesmellitus and for weight management (see section 4.2 for information on paediatric use).

Tirzepatide consists of 39-amino acids and has a C20 fatty diacid moiety attached, which enablesalbumin binding and prolongs half-life.

Maximum concentration of tirzepatide is reached 8 to 72 hours post dose. Steady state exposure isachieved following 4 weeks of once weekly administration. Tirzepatide exposure increases in a doseproportional manner.

Similar exposure was achieved with subcutaneous administration of tirzepatide in the abdomen, thigh,or upper arm.

Absolute bioavailability of subcutaneous tirzepatide was 80 %.

The mean apparent steady-state volume of distribution of tirzepatide following subcutaneousadministration in patients with type 2 diabetes is approximately 10.3 L, and 9.7 L in patients withobesity.

Tirzepatide is highly bound to plasma albumin (99 %).

Tirzepatide is metabolised by proteolytic cleavage of the peptide backbone, beta-oxidation of the

C20 fatty diacid moiety and amide hydrolysis.

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

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

Age, gender, race, ethnicity, body weight

Age, gender, race, ethnicity, or body weight do not have a clinically relevant effect on thepharmacokinetics (PK) of tirzepatide. Based on a population PK analysis, the exposure of tirzepatideincreases with decreasing body weight; however, the effect of body weight on the PK of tirzepatidedoes not appear to be clinically relevant.

Renal impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mgdose 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 wereobserved. This was also shown for patients with both type 2 diabetes mellitus and renal impairmentbased on data from clinical studies.

Hepatic impairment does not impact the PK of tirzepatide. The PK of tirzepatide after a single 5 mgdose 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 wereobserved.

Tirzepatide has not been studied in paediatric patients.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology or repeat-dose toxicity or genotoxicity.

A 2-year carcinogenicity study was conducted with tirzepatide in male and female rats at doses of0.15, 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 anincrease in thyroid C-cell tumours (adenomas and carcinomas) at all doses compared to controls. Thehuman 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/kgadministered 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 animal reproduction studies, tirzepatide caused foetal growth reductions and foetal abnormalities atexposures below the MRHD based on AUC. An increased incidence of external, visceral, and skeletalmalformations and visceral and skeletal developmental variations were observed in rats. Foetal growthreductions were observed in rats and rabbits. All developmental effects occurred at maternally toxicdoses.

Pre-filled pen, single-dose; vial, single-dose

Disodium hydrogen phosphate heptahydrate (E339)

Sodium chloride

Concentrated hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

Pre-filled pen (KwikPen), multi-dose

Disodium hydrogen phosphate heptahydrate (E339)

Benzyl alcohol (E1519)

Glycerol

Phenol

Sodium chloride

Concentrated hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

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

Pre-filled pen, single-dose; vial, single-dose

Before use2 years

Mounjaro may be stored unrefrigerated for up to 21 cumulative days at a temperature below 30 ºC andthen the pre-filled pen or vial must be discarded.

Pre-filled pen (KwikPen), multi-dose

Before use2 years

After first use30 days. Store unrefrigerated at room temperature below 30 ºC. The pre-filled KwikPen must bediscarded 30 days after first use.

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

Do not freeze.

Pre-filled pen, single-dose; vial, single-dose

Store in original package in order to protect from light.

Pre-filled pen (KwikPen), multi-dose

For storage conditions after first use of the medicinal product, see section 6.3.

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 injectionbutton is pressed.

Each pre-filled pen contains 0.5 ml of solution.

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

Vial, single-dose

Clear glass vial with a sealed stopper.

Each vial contains 0.5 ml of solution.

Pack sizes of 1 vial, 4 vials, 12 vials, multipack containing 4 (4 packs of 1) vials or multipackcontaining 12 (12 packs of 1) vials. Not all pack sizes may be marketed.

Pre-filled pen (KwikPen), multi-dose

Clear glass cartridge encased in a multi-dose pre-filled pen.

Each pre-filled KwikPen contains 2.4 ml of solution for injection (4 doses of 0.6 ml). Each pen hasexcess volume for priming. However, attempting to inject any leftover medicinal product will result inan incomplete dose even though the pen still has medicinal product left in it. Needles are not included.

Pack sizes of 1 and 3 pre-filled KwikPens. Not all pack sizes may be marketed.

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

Mounjaro that has been frozen must not be used.

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

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

Vial, single-dose

The vial is for single-use only.

The instructions in the package leaflet for how to inject Mounjaro from a vial must be followedcarefully.

Pre-filled pen (KwikPen), multi-dose

The pre-filled KwikPen is for multiple doses. Each KwikPen contains 4 doses. Dispose of the pen after4 weekly doses.

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

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

Eli Lilly Nederland B.V., Papendorpseweg 83, 3528 BJ Utrecht, The Netherlands.

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Date of first authorisation: 15 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu