Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
In 10 completed phase 3 studies, 7,925 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                                      Hypersensitivity reactions                                  Anaphylactic disorders                                                                                                      reaction#, Angioedema#
Metabolism and        Hypoglycaemia1* when       Hypoglycaemia1* when           Hypoglycaemia1* nutrition disorders   used with                  used with metformin and        when used with sulphonylurea or insulin   SGLT2i, Decreased              metformin, Weight appetite1                      decreased1
Nervous system                                   Dizziness2                     Dysgeusia disorders
Vascular disorders                               Hypotension2

Gastrointestinal      Nausea, Diarrhoea,         Dyspepsia,                     Cholelithiasis, disorders             Vomiting3, Abdominal       Abdominal distention,          Cholecystitis, Acute pain3, Constipation3       Eructation, Flatulence,        pancreatitis Gastroesophageal reflux disease
Skin and                                         Hair loss2 subcutaneous tissue disorders
General disorders                                        †
Fatigue , Injection site       Injection site pain and administration                               reactions site conditions

Investigations                                   Heart rate increased, Lipase increased, Amylase increased, Blood calcitonin increased4


#
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 trials, and common in T2DM trials.
4
Frequency was common in weight management trials, and uncommon in T2DM trials.
Description of selected adverse reactions

Hypersensitivity reactions

Hypersensitivity reactions have been reported with tirzepatide in the pool of T2DM placebo-controlled trials, sometimes severe (e.g., urticaria and eczema); hypersensitivity reactions were reported in 3.2 % of tirzepatide-treated patients compared to 1.7 % of placebo-treated patients. Cases of anaphylactic reaction and angioedema have been rarely reported with marketed use of tirzepatide.




Hypersensitivity reactions have been reported with tirzepatide in a pool of 3 placebo-controlled weight management trials, sometimes severe (e.g., rash and dermatitis); hypersensitivity reactions were reported in 5.0 % of tirzepatide-treated patients compared to 3.8 % of placebo-treated patients.

Hypoglycaemia in patients with type 2 diabetes mellitus

Type 2 diabetes studies
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 the placebo-controlled T2DM phase 3 studies, gastrointestinal disorders were dose-dependently increased for tirzepatide 5 mg (37.1 %), 10 mg (39.6 %) and 15 mg (43.6 %) compared with placebo (20.4 %). Nausea occurred in 12.2 %, 15.4 % and 18.3 % versus 4.3 % and diarrhoea in 11.8 %, 13.3 % and 16.2 % versus 8.9 % for tirzepatide 5 mg, 10 mg and 15 mg versus placebo. Gastrointestinal adverse reactions were mostly mild (74 %) or moderate (23.3 %) in severity. The incidence of nausea, vomiting, and diarrhoea was higher during the dose escalation period and decreased over time.

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

In 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 a pool of 3 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 a pool of 3 placebo-controlled weight management phase 3 studies, acute gallbladder disease was reported by 2.0 % of tirzepatide-treated patients and 1.6 % of placebo-treated patients. These acute gallbladder events were positively associated with weight reduction.

Immunogenicity

5,025 tirzepatide-treated patients in the T2DM phase 3 clinical studies were assessed for anti-drug antibodies (ADAs). Of these, 51.1 % developed treatment-emergent (TE) ADAs during the on-treatment period. In 38.3 % of the assessed patients, TE ADAs were persistent (ADAs present for a period of 16-weeks or greater). 1.9 % and 2.1 % had neutralizing antibodies against tirzepatide activity on the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, respectively and 0.9 % and 0.4 % had neutralising antibodies against native GIP and GLP-1, respectively. There was no evidence of an altered pharmacokinetic profile or an impact on efficacy of tirzepatide associated with the development of ADAs.

3,484 tirzepatide-treated patients in the 4 phase 3 weight management studies were assessed for anti-drug antibodies (ADAs). Of these, 65.1 % developed treatment-emergent (TE) ADAs during the on-treatment period. In 51.3 % of the assessed patients, TE ADAs were persistent (ADAs present for a period of 16 weeks or greater). 2.3 % 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 0.7 % and 0.1 % had neutralising antibodies against native GIP and GLP-1, respectively.

Heart rate

In the placebo-controlled T2DM phase 3 studies, treatment with tirzepatide resulted in a maximum mean increase in heart rate of 3 to 5 beats per minute. The maximum mean increase in heart rate in placebo-treated patients was 1 beat per minute.

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

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

In 3 placebo-controlled weight management phase 3 studies, treatment with tirzepatide resulted in a mean increase in heart rate of 3 beats per minute. There was no mean increase in heart rate in the 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 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, injection site reactions were increased for tirzepatide (8.0 %) compared with placebo (1.8 %).

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 the placebo-controlled T2DM phase 3 studies, treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 33 % to 38 % and lipase of 31 % to 42 %. Placebo treated patients had an increase from baseline in amylase of 4 % and no changes were observed in lipase.

In 3 placebo-controlled weight management phase 3 studies, treatment with tirzepatide resulted in mean increases from baseline in pancreatic amylase of 23 % and lipase of 34 %. Placebo treated patients had an increase from baseline in amylase of 1.8 % and in lipase of 5.7 %.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il