Adverse reactions : תופעות לוואי

   4.8    Undesirable effects

Summary of safety profile
In four phase 3a trials, 2,650 adult patients were exposed to Wegovy. The duration of the trials were 68 weeks. The most frequently reported adverse reactions were gastrointestinal disorders including nausea, diarrhoea, constipation and vomiting.

Tabulated list of adverse reactions

Table 3 lists adverse reactions identified in phase 3a clinical trials in adults and post-marketing reports. The frequencies are based on a pool of the phase 3a trials.

Adverse reactions associated with Wegovy are listed by system organ class and frequency. Frequency categories 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 the available data).


Table 3 Frequency of adverse reactions of semaglutide
MedDRA              Very
Common            Uncommon                  Rare              Not known system organ class common
Immune system                                                                    Anaphylactic disorders                                                                        reaction Metabolism and                       Hypoglycaemia nutrition disorders                  in patients with type 2 diabetesa b
Nervous system      Headache         Dizzinessb disorders                            Dysgeusiab,c

Eye disorders                            Diabetic retinopathy in patients with type 2 diabetesa
Cardiac disorders                                             Hypotension Orthostatic hypotension
Increased heart ratea,c
Gastrointestinal      Vomitinga,b        Gastritisb,c         Acute                                Intestinal disorders             Diarrhoeaa,b       Gastrooesophag       pancreatitisa                        obstructiond Constipationa,b    eal reflux           Delayed gastric
Nauseaa,b          diseaseb             emptying
Abdominal          Dyspepsiab painb,c            Eructationb
Flatulenceb
Abdominal distensionb
Hepatobiliary                            Cholelithiasisa disorders
Skin and                                 Hair lossa                              Angioedema subcutaneous tissue disorders
General disorders     Fatigueb,c         Injection site and administration                       reactionsc site conditions

MedDRA                       Very
Common       Uncommon            Rare      Not known system organ class           common
Investigations                                                     Increased amylasec
Increased lipasec a) see description of selected adverse reactions below b) mainly seen in the dose-escalation period c)
Grouped preferred terms d)
From post-marketing reports


Description of selected adverse reactions

Gastrointestinal adverse reactions
Over the 68 weeks trial period, nausea occurred in 43.9% of patients when treated with semaglutide (16.1% for placebo), diarrhoea in 29.7% (15.9% for placebo) and vomiting in 24.5% (6.3% for placebo). Most events were mild to moderate in severity and of short duration. Constipation occurred in 24.2% of patients treated with semaglutide (11.1% for placebo) and was mild to moderate in severity and of longer duration. In patients treated with semaglutide, median duration of nausea was 8 days, vomiting 2 days, diarrhoea 3 days, and constipation 47 days.

Patients with moderate renal impairment (eGFR ≥30 mL/min/1.73m2) may experience more gastrointestinal effects when treated with semaglutide.

The gastrointestinal events led to permanent treatment discontinuation in 4.3% of patients.

Acute pancreatitis
The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was 0.2% for semaglutide and <0.1% for placebo, respectively.

Acute gallstone disease/Cholelithiasis
Cholelithiasis was reported in 1.6% and led to cholecystitis in 0.6% of patients treated with semaglutide. Cholelithiasis and cholecystitis was reported in 1.1% and 0.3%, respectively, of patients treated with placebo.

Hair loss
Hair loss was reported in 2.5% of patients treated with semaglutide and in 1.0% of patients treated with placebo. The events were mainly of mild severity and most patients recovered while on continued treatment. Hair loss was reported more frequently in patients with a greater weight loss (≥20%).

Increased heart rate
In the phase 3a trials, a mean increase of 3 beats per minute (bpm) from a baseline mean of 72 bpm was observed in patients treated with semaglutide. The proportions of subjects with an increase in pulse from baseline ≥10 bpm at any timepoint during the on-treatment period were 67.0% in the semaglutide group vs. 50.1% in the placebo group.

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 testing positive for anti-semaglutide antibodies at any time post-baseline was low (2.9%) and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect at end-of-trial. During treatment, high semaglutide concentrations might have lowered the sensitivity of the assays, hence the risk of false negatives cannot be excluded. However, in subjects testing positive for antibodies during and after treatment, the presence of antibodies was transient and with no apparent impact on efficacy and safety.



Hypoglycaemia in patients with type 2 diabetes
In STEP 2, clinically significant hypoglycaemia was observed in 6.2% (0.1 events/patient year) of subjects treated with semaglutide compared with 2.5% (0.03 events/patient year) of subjects treated with placebo. Hypoglycaemia with semaglutide was seen both with and without concomitant use of sulfonylurea. One episode (0.2% of subjects, 0.002 events/patient year) was reported as severe in a subject not concomitantly treated with a sulfonylurea. The risk of hypoglycaemia was increased when semaglutide was used with a sulfonylurea.

Diabetic retinopathy in patients with type 2 diabetes
A 2-year clinical trial investigated semaglutide 0.5 mg and 1 mg vs. placebo in 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 (3.0%) 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. In STEP 2, retinal disorders were reported by 6.9% of patients treated with Wegovy, 6.2% of patients treated with semaglutide 1 mg, and 4.2% of patients treated with placebo. The majority of events were reported as diabetic retinopathy (4.0%, 2.7%, and 2.7%, respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively).

Paediatric population

In a clinical trial conducted in adolescents of 12 years to below 18 years with obesity or overweight with at least one weight-related comorbidity, 133 patients were exposed to Wegovy. The trial duration was 68 weeks.
Overall, the frequency, type and severity of adverse reactions in the adolescents were comparable to that observed in the adult population. Cholelithiasis was reported in 3.8% of patients treated with Wegovy and 0% of patients treated with placebo.

No effects on growth or pubertal development were found after 68 weeks of treatment.

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 http://sideeffects.health.gov.il