Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of safety profile
In 8 phase 3a trials 4,792 patients were exposed to semaglutide up to 1 mg. The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common). In general, these reactions were mild or moderate in severity and of short duration.

Tabulated list of adverse reactions

Table 1 lists adverse reactions identified in all phase 3 trials (including the long-term cardiovascular outcomes trial) and post-marketing reports in patients with type 2 diabetes mellitus (further described in section 5.1). The frequencies of the adverse reactions (except diabetic retinopathy complications, 

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see footnote in Table 1) are based on a pool of the phase 3a trials excluding the cardiovascular outcomes trial (see text below the table for additional details).

The reactions are listed below by system organ class and absolute frequency. Frequencies are defined as: 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) and not known: (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Frequency of adverse reactions of semaglutide
MedDRA            Very common           Common                  Uncommon             Rare           Not known system organ class
Immune system                                                   Hypersensitivityc    Anaphylactic disorders                                                                            reaction Metabolism and Hypoglycaemiaa           Hypoglycaemiaa nutrition         when used with        when used with disorders         insulin or            other oral sulfonylurea          antidiabetics
(OAD)

Decreased appetite

Nervous system                               Dizziness          Dysgeusia disorders
Eye disorders                                Diabetic retinopathy complicationsb
Cardiac                                                         Increased heart disorders                                                       rate
Gastrointestinal        Nausea               Vomiting           Acute pancreatitis                  Intestinal disorders               Diarrhoea            Abdominal pain     Delayed gastric                     Obstructiond Abdominal          emptying distension
Constipation
Dyspepsia
Gastritis
Gastro- oesophageal reflux disease
Eructation
Flatulence
Hepatobiliary                                Cholelithiasis disorders
Skin and                                                                                            Angioedemad subcutaneous tissue disorders
General                                      Fatigue            Injection site disorders and                                                   reactions administration site conditions
Investigations                               Increased lipase


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Increased amylase
Weight decreased a)
Hypoglycaemia defined as severe (requiring the assistance of another person) or symptomatic in combination with a blood glucose <3.1 mmol/L.
b)
Diabetic retinopathy complications is a composite of: retinal photocoagulation, treatment with intravitreal agents, vitreous haemorrhage, diabetes-related blindness (uncommon). Frequency based on cardiovascular outcomes trial.
c)
Grouped term covering also adverse events related to hypersensitivity such as rash and urticaria.
d)
From post-marketing reports.

2-year cardiovascular outcomes and safety trial
In cardiovascular high risk population the adverse reaction profile was similar to that seen in the other phase 3a trials (described in section 5.1).

Description of selected adverse reactions

Hypoglycaemia
No episodes of severe hypoglycaemia were observed when semaglutide was used as monotherapy.
Severe hypoglycaemia was primarily observed when semaglutide was used with a sulfonylurea (1.2% of subjects, 0.03 events/patient year) or insulin (1.5% of subjects, 0.02 events/patient year). Few episodes (0.1% of subjects, 0.001 events/patient year) were observed with semaglutide in combination with oral antidiabetics other than sulfonylureas.

Gastrointestinal adverse reactions
Nausea occurred in 17% and 19.9% of patients when treated with semaglutide 0.5 mg and 1 mg, respectively, diarrhoea in 12.2% and 13.3% and vomiting in 6.4% and 8.4%. Most events were mild to moderate in severity and of short duration. The events led to treatment discontinuation in 3.9% and 5% of patients. The events were most frequently reported during the first months on treatment.
Patients with low body weight may experience more gastrointestinal side effects when treated with semaglutide.

Acute pancreatitis
The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was 0.3% for semaglutide and 0.2% for the comparator, respectively. In the 2-year cardiovascular outcomes trial the frequency of acute pancreatitis confirmed by adjudication was 0.5% for semaglutide and 0.6% for placebo (see section 4.4).

Diabetic retinopathy complications
A 2-year clinical trial investigated 3,297 patients with type 2 diabetes, with high cardiovascular risk, long duration of diabetes and poorly controlled blood glucose. In this trial, adjudicated events of diabetic retinopathy complications occurred in more patients treated with semaglutide (3%) compared to placebo (1.8%). This was observed in insulin-treated patients with known diabetic retinopathy. The treatment difference appeared early and persisted throughout the trial. Systematic evaluation of diabetic retinopathy complication was only performed in the cardiovascular outcomes trial. In clinical trials up to 1 year involving 4,807 patients with type 2 diabetes, adverse events related to diabetic retinopathy were reported in similar proportions of subjects treated with semaglutide (1.7%) and comparators (2.0%).

Discontinuation due to an adverse event
The incidence of discontinuation of treatment due to adverse events was 6.1% and 8.7% for patients treated with semaglutide 0.5 mg and 1 mg, respectively, versus 1.5% for placebo. The most frequent adverse events leading to discontinuation were gastrointestinal.


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Injection site reactions
Injection site reactions (e.g. injection site rash, erythema) have been reported by 0.6% and 0.5% of patients receiving semaglutide 0.5 mg and 1 mg, respectively. These reactions have usually been mild.

Immunogenicity
Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies following treatment with semaglutide. The proportion of patients tested positive for anti-semaglutide antibodies at any time point post-baseline was low (1−3%) and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect at end-of-trial.

Heart rate increase
Increased heart rate has been observed with GLP-1 receptor agonists. In the phase 3a trials, mean increases of 1 to 6 beats per minute (bpm) from a baseline of 72 to 76 bpm were observed in subjects treated with Ozempic. In a long-term trial in subjects with cardiovascular risk factors, 16% of Ozempic-treated subjects had an increase in heart rate of >10 bpm compared to 11% of subjects on placebo after 2 years of treatment.

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. 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