Tirzepatide interacts in the following cases:
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.
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.
Experience with the use of tirzepatide in patients with severe hepatic impairment is limited. Caution should be exercised when treating these patients with tirzepatide.
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.
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.
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.
Tirzepatide has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and should be used with caution in these patients.
Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy or diabetic macular oedema, and should be used with caution in these patients with appropriate monitoring.
Tirzepatide has not been studied in patients with a history of pancreatitis, and should be used with caution in these patients.
There are no or a limited amount of data from the use of tirzepatide in pregnant women. Studies in animals have shown reproductive toxicity. Tirzepatide is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is unknown whether tirzepatide is excreted in human milk. A risk to the newborn/infant cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from tirzepatide therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
The effect of tirzepatide on fertility in humans is unknown.
Animal studies with tirzepatide did not indicate direct harmful effects with respect to fertility.
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.
In 7 completed phase 3 studies, 5119 patients were exposed to tirzepatide alone or in combination with other glucose lowering medicinal products. The most frequently reported adverse reactions were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common). In general, these reactions were mostly mild or moderate in severity and occurred more often during dose escalation and decreased over time.
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.
Adverse reactions:
| System organ class | Very common | Common | Uncommon |
|---|---|---|---|
| Immune system disorders | Hypersensitivity reactions | ||
| Metabolism and nutrition disorders | Hypoglycaemia* when used with sulphonylurea or insulin | Hypoglycaemia* when used with metformin and SGLT2i, decreased appetite | Hypoglycaemia* when used with metformin, weight decreased |
| Gastrointestinal disorders | Nausea, diarrhoea | Abdominal pain, vomiting, dyspepsia, constipation, abdominal distention, eructation, flatulence, gastroesophageal reflux disease | Cholelithiasis, acute pancreatitis |
| General disorders and administration site conditions | Fatigue†, injection site reactions | ||
| Investigations | Heart rate increased, lipase increased, amylase increased | Blood calcitonin increased |
* Hypoglycaemia defined below.
† Fatigue includes the terms fatigue, asthenia, malaise, and lethargy.
Hypersensitivity reactions have been reported with tirzepatide in the pool of placebo-controlled trials, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2% of tirzepatide-treated patients compared to 1.7% of placebo-treated patients.
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).
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.
In the placebo-controlled 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 subjects 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.
5 025 tirzepatide-treated patients in the phase 3 clinical studies were assessed for anti-drug antibodies (ADAs). Of these, 51.1% developed treatment-emergent (TE) ADAs during the on-treatment period. In 38.3% of the assessed patients, TE ADAs were persistent (ADAs present for a period of 16-weeks or greater). 1.9% and 2.1% had neutralizing antibodies against tirzepatide activity on the glucosedependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, respectively and 0.9% and 0.4% had neutralising antibodies against native GIP and GLP-1, respectively. There was no evidence of an altered pharmacokinetic profile or an impact on efficacy and safety of tirzepatide associated with the development of ADAs.
In the placebo-controlled phase 3 studies, treatment with tirzepatide resulted in a maximum mean increase in heart rate of 3 to 5 beats per minute. The maximum mean increase in heart rate in placebotreated patients was 1 beat per minute.
The incidence of patients who had a change of baseline heart rate of >20 bpm for 2 or more consecutive visits was 2.1%, 3.8% and 2.9%, for tirzepatide 5 mg, 10 mg and 15 mg, respectively, compared with 2.1% for placebo.
Small mean increases in PR interval were observed with tirzepatide when compared to placebo (mean increase of 1.4 to 3.2 msec and mean decrease of 1.4 msec respectively). No difference in arrythmia and cardiac conduction disorder treatment emergent events were observed between tirzepatide 5 mg, 10 mg, 15 mg and placebo (3.8%, 2.1%, 3.7% and 3% respectively).
In the placebo-controlled phase 3 studies, injection site reactions were increased for tirzepatide (3.2%) compared with placebo (0.4%).
Overall, in the phase 3 studies, the most common signs and symptoms of injection site reactions were erythema and pruritus. The maximum severity of injection site reactions for patients was mild (90%) or moderate (10%). No injection site reactions were serious.
In the placebo-controlled phase 3 studies, treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33% to 38% and lipase of 31% to 42%. Placebo treated patients had an increase from baseline in amylase of 4% and no changes were observed in lipase.
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