Tirzepatide: prescribing information – dosing, contraindications, interactions, side effects

Type 2 diabetes mellitus

Mounjaro is indicated 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.

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

Weight management

Mounjaro is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of
- ≥ 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 trial results with respect to obstructive sleep apnoea (OSA) and heart failure with preserved ejection fraction (HFpEF), see section 5.1.

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 mg, 10 mg and 15 mg.

The maximum dose is 15 mg once weekly.

Paediatric population aged 10 years and above (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).

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 5.1 and 5.2). Only very limited data are available from patients aged ≥ 85 years.

Renal impairment
No dose adjustment is required for patients with renal impairment including end stage renal disease (ESRD). Experience with the use of 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
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 or 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 included with the package leaflet 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.

Before using Mounjaro KwikPen, the instructions for use must be read carefully.

Vial

Patients and their caregivers should be trained in subcutaneous injection technique before administering 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.

Summary of safety profile

In 14 completed phase 3 studies, 15 169 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 and these were mostly mild or moderate in severity. The incidence of nausea, diarrhoea and vomiting was higher during the dose escalation period and decreased over time (see sections 4.2, and 4.4).

Tabulated list of adverse reactions

The following related adverse reactions from clinical studies are listed below by system organ class and in order of decreasing incidence (very common: ≥ 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,
Decreased appetite1,7
Hypoglycaemia1* when used with metformin and SGLT2i-
Hypoglycaemia1* when used with metformin6,
Weight decreased1

#From post-marketing reports.
##From post-marketing reports and SURPASS-CVOT.
*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 SURPASS-CVOT, weight management, OSA, HFpEF and paediatric T2DM trials, and common in adult T2DM trials.
4 Frequency was very common in SURPASS-CVOT, weight management, OSA and HFpEF trials, and common in adult and paediatric T2DM trials.
5 Frequency was common in SURPASS-CVOT, weight management and HFpEF trials, uncommon in adult T2DM and OSA trials, and very rare in the paediatric T2DM trial.
6 Frequency was common in the paediatric T2DM trial.
7 Frequency was very common in SURPASS-CVOT, and common in adult and paediatric T2DM trials.
8 Frequency was very common in SURPASS-CVOT, and common in weight management, OSA, HFpEF, and adult and paediatric T2DM trials.

Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with tirzepatide in pooled adult T2DM placebo-controlled trials, pooled placebo-controlled weight management trials, pooled placebo- controlled OSA trials, and the placebo-controlled HFpEF trial, sometimes severe (e.g., urticaria, eczema, rash, dermatitis). 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 marketed use of tirzepatide.

Nervous system disorders

Dizziness2
Dysgeusia,
Dysaesthesia##

Vascular disorders

Hypotension2

Gastrointestina l disorders
Nausea, Diarrhoea,
Vomiting3,
Abdominal pain3,
Constipation4
Dyspepsia,
Abdominal distention,
Eructation, Flatulence,
Gastroesophageal reflux disease
Cholelithiasis,
Cholecystitis,
Acute pancreatitis,
Delayed gastric emptying

Skin and subcutaneous tissue disorders

Hair loss2

General disorders and administration site conditions
Fatigue
†8
Injection site reactions
Injection site pain

Investigations

Heart rate increased,
Lipase increased,
Amylase increased,
Blood calcitonin increased5

Hypoglycaemia in patients with type 2 diabetes mellitus

Type 2 diabetes studies in adults
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.

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 patients versus 1.3 % of placebo-treated patients. In this trial, patients taking tirzepatide in combination with an insulin secretagogue (e.g., sulfonylurea) had a higher incidence of hypoglycaemia (10.3 %) compared to tirzepatide-treated patients not taking a sulfonylurea (2.1 %). No severe hypoglycaemia episodes were reported.

Gastrointestinal adverse reactions

In pooled adult placebo-controlled T2DM phase 3 studies, gastrointestinal disorders were dose- dependently increased for tirzepatide 5 mg (37.1 %), 10 mg (39.6 %) and 15 mg (43.6 %) compared with placebo (20.4 %). Nausea occurred in 12.2 %, 15.4 % and 18.3 % versus 4.3 % and diarrhoea in 11.8 %, 13.3 % and 16.2 % versus 8.9 % for tirzepatide 5 mg, 10 mg and 15 mg versus placebo.
Gastrointestinal adverse reactions were mostly mild (74 %) or moderate (23.3 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time.

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

In a placebo-controlled weight management phase 3 study in patients without T2DM, gastrointestinal disorders were increased for tirzepatide 5 mg (55.6 %), 10 mg (60.8 %) and 15 mg (59.2 %) compared with placebo (30.3 %). Nausea occurred in 24.6 %, 33.3 % and 31.0 % versus 9.5 % and diarrhoea in 18.7 %, 21.2 % and 23.0 % versus 7.3 % for tirzepatide 5 mg, 10 mg and 15 mg respectively versus placebo. Gastrointestinal adverse reactions were mostly mild (60.8 %) or moderate (34.6 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time.

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

Gallbladder-related events

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

In pooled placebo-controlled weight management phase 3 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 the weight management phase 3 studies, acute gallbladder events were positively associated with weight reduction.

Immunogenicity

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.

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

Heart rate

In pooled placebo-controlled T2DM 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 percentage of patients who had a change of baseline heart rate of > 20 bpm for 2 or more consecutive visits was 2.1 %, 3.8 % and 2.9 %, for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 2.1 % for placebo.

Small mean increases in PR interval were observed with tirzepatide when compared to placebo (mean increase of 1.4 to 3.2 msec and mean decrease of 1.4 msec respectively). No difference in arrhythmia and cardiac conduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mg and placebo (3.8 %, 2.1 %, 3.7 % and 3 % respectively).

In SURPASS-CVOT, treatment with tirzepatide resulted in a maximum mean increase in heart rate of 6 bpm.

In pooled placebo-controlled weight management phase 3 studies, in pooled placebo-controlled OSA phase 3 studies, and in a placebo-controlled 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

In a placebo-controlled weight management study in patients without T2DM, the percentage of patients who had a change in baseline heart rate of > 20 bpm for 2 or more consecutive visits was 2.4 %, 4.9 % and 6.3 %, for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 1.2 % for placebo. Small mean increases in PR interval were observed with tirzepatide and placebo (mean increase of 0.3 to 1.4 msec and of 0.5 msec respectively). No difference in arrhythmia and cardiac conduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mg and placebo (3.7 %, 3.3 %, 3.3 % and 3.6 % respectively).

Injection site reactions

In pooled placebo-controlled T2DM phase 3 studies in adult patients, in pooled placebo-controlled weight management phase 3 studies, in pooled placebo-controlled OSA phase 3 studies, and in a placebo-controlled HFpEF phase 3 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

In pooled placebo-controlled T2DM 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.

In SURPASS-CVOT, at month 36, treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 29 % and lipase of 28 %.

In pooled placebo-controlled weight management phase 3 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 pancreatic amylase 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 T2DM treated with tirzepatide 5 mg and 10 mg once-weekly were consistent with those described above for adult patients with T2DM with the exception of a higher frequency of vomiting, abdominal pain, and hypoglycaemia when added to metformin alone.

No severe hypoglycaemic episodes occurred during the paediatric T2DM 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 national reporting system listed in Appendix V.

Acute pancreatitis

Tirzepatide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients.

Acute pancreatitis has been reported in patients treated with tirzepatide.

Patients should be informed of the symptoms of acute pancreatitis. If pancreatitis is suspected, tirzepatide should be discontinued. If the diagnosis of pancreatitis is confirmed, tirzepatide should not be restarted. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis (see section 4.8).

Hypoglycaemia

Patients receiving tirzepatide in combination with an insulin secretagogue (for example, a sulphonylurea) or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia may be lowered by a reduction in the dose of the insulin secretagogue or insulin (see sections 4.2 and 4.8).

Gastrointestinal effects

Tirzepatide has been associated with gastrointestinal adverse reactions, which include nausea, vomiting, and diarrhoea (see section 4.8). These adverse reactions may lead to dehydration, which could lead to a deterioration in renal function including acute renal failure. Patients treated with tirzepatide should be advised of the potential risk of dehydration, due to the gastrointestinal adverse reactions and take precautions to avoid fluid depletion and electrolyte disturbances. This should particularly be considered in the elderly, who may be more susceptible to such complications.

Severe gastrointestinal disease

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

Diabetic retinopathy

Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with diabetic retinopathy should be monitored closely and treated according to clinical guidelines.

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

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

Tirzepatide delays gastric emptying and thereby has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. This effect, resulting in decreased 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

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. No dose adjustment of paracetamol is necessary when administered with tirzepatide.

Oral contraceptives

Administration of a combination oral contraceptive (0.035 mg ethinyl estradiol plus 0.25 mg norgestimate, a prodrug of norelgestromin) in the presence of a single dose of tirzepatide (5 mg) resulted in a reduction of oral contraceptive 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.

Women of childbearing potential

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

Pregnancy

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

pregnancy and in women of childbearing potential not using contraception. If a patient wishes to become pregnant, or pregnancy occurs, tirzepatide should be discontinued. Tirzepatide should be discontinued at least 1 month before a planned pregnancy due to the long half-life (see section 5.2).

Breast-feeding

Following a single 5 mg dose, the concentration of tirzepatide in breast milk was found to be undetectable to very low compared to plasma concentrations. As tirzepatide is an amino acid sequence, any low amount present in breast milk 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).

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).

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).

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, blood glucose lowering drugs, excl. insulins, ATC code: A10BX16

Mechanism of action

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 of tirzepatide on the GIP receptor is similar to native GIP hormone. The activity of tirzepatide on the GLP-1 receptor is lower compared to native GLP-1 hormone. Both receptors are present on the pancreatic α and β endocrine cells, heart, vasculature, immune cells (leukocytes), gut and kidney. GIP receptors are also present on adipocytes.

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

Glycaemic control

Tirzepatide improves glycaemic control by lowering fasting and postprandial glucose concentrations in 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 to reduced fat mass. The mechanisms associated with body weight and body fat mass reduction involve decreased food intake through the regulation of appetite. Clinical studies show that tirzepatide reduces energy intake and appetite by increasing feelings of satiety and fullness, and decreasing feelings of hunger. Tirzepatide also reduces the intensity of food cravings and preferences for high sugar and high fat foods. Tirzepatide modulates fat utilisation.

Pharmacodynamic effects

Insulin secretion

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

In a hyperglycaemic clamp study in adult patients with type 2 diabetes, tirzepatide was compared to placebo and the selective GLP-1 receptor agonist semaglutide 1 mg for insulin secretion. Tirzepatide 15 mg enhanced the first and second-phase insulin secretion rate by 466 % and 302 % from baseline, respectively. There was no change in first- and second-phase insulin secretion rate for placebo.

Insulin sensitivity

Tirzepatide improves insulin sensitivity.

In adults, tirzepatide 15 mg improved whole body insulin sensitivity by 63 %, as measured by M-value, a measure of glucose tissue uptake using hyperinsulinemic euglycaemic clamp. The M-value was unchanged for placebo.

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

Absorption

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

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

Absolute bioavailability of subcutaneous tirzepatide was 80 %.

Distribution

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

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

Biotransformation

Tirzepatide is metabolised by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis.

Elimination

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

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

Special populations

Age, gender, race, ethnicity, body weight

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

Renal impairment