Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions that can cause dehydration, which in rare cases can lead to a deterioration of renal function. Patients should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.
Acute pancreatitis has been observed with the use of GLP-1 receptor agonists (see section 4.8). Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted. Caution should be exercised in patients with a history of pancreatitis. In the absence of other signs and symptoms of acute pancreatitis, elevations in pancreatic enzymes alone are not predictive of acute pancreatitis.
Semaglutide should not be used as a substitute for insulin in patients with type 2 diabetes.
Semaglutide should not be used in combination with other GLP-1 receptor agonist products. It has not been evaluated and an increased risk of adverse reactions related to overdose is considered likely.
Insulin and sulfonylurea are known to cause hypoglycaemia. Patients treated with semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia. The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with a GLP-1 receptor agonist. The addition of Wegovy in patients treated with insulin has not been evaluated.
In patients with diabetic retinopathy treated with semaglutide, an increased risk of developing diabetic retinopathy complications has been observed (see section 4.8). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannot be excluded. Patients with diabetic retinopathy using semaglutide should be monitored closely and treated according to clinical guidelines. There is no experience with Wegovy in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy. In these patients, treatment with Wegovy is not recommended.
The safety and efficacy of Wegovy have not been investigated in patients:
Use in these patients is not recommended.
There is limited experience with Wegovy in patients:
Use with caution in these patients.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
Semaglutide delays gastric emptying and could potentially influence the absorption of concomitantly administered oral medicinal products. No clinically relevant effect on the rate of gastric emptying was observed with semaglutide 2.4 mg, probably due to a tolerance effect. Semaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption.
Semaglutide delays the rate of gastric emptying as assessed by paracetamol pharmacokinetics during a standardised meal test. Paracetamol AUC0-60min and Cmax were decreased by 27% and 23%, respectively, following concomitant use of semaglutide 1 mg. The total paracetamol exposure (AUC0-5h) was not affected. No clinically relevant effect on paracetamol was observed with semaglutide. No dose adjustment of paracetamol is necessary when administered with semaglutide.
Semaglutide is not anticipated to decrease the effectiveness of oral contraceptives. It did not change the overall exposure of ethinylestradiol and levonorgestrel to a clinically relevant degree, when an oral contraceptive combination medicinal product (0.03 mg ethinylestradiol/0.15 mg levonorgestrel) was co-administered with semaglutide. Exposure of ethinylestradiol was not affected; an increase of 20% was observed for levonorgestrel exposure at steady state. Cmax was not affected for any of the compounds.
Semaglutide did not change the overall exposure of atorvastatin following a single dose administration of atorvastatin (40 mg). Atorvastatin Cmax was decreased by 38%. This was assessed not to be clinically relevant.
Semaglutide did not change the overall exposure or Cmax of digoxin following a single dose of digoxin (0.5 mg).
Semaglutide did not change the overall exposure or Cmax of metformin following dosing of 500 mg twice daily over 3.5 days.
Semaglutide did not change overall exposure or Cmax of R- and S-warfarin following a single dose of warfarin (25 mg), and the pharmacodynamic effects of warfarin as measured by the international normalised ratio were not affected in a clinically relevant manner. However, upon initiation of semaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of international normalised ratio (INR) is recommended.
Women of childbearing potential are recommended to use contraception when treated with semaglutide (see section 4.5).
Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data from the use of semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, semaglutide should be discontinued. Semaglutide should be discontinued at least 2 months before a planned pregnancy due to the long halflife (see section 5.2).
In lactating rats, semaglutide was excreted in milk. A risk to a breast-fed child cannot be excluded. Semaglutide should not be used during breast-feeding.
The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male fertility in rats. In female rats, an increase in oestrous length and a small reduction in number of ovulations were observed at doses associated with maternal body weight loss.
Semaglutide has no or negligible influence on the ability to drive or use machines. However, dizziness can be experienced mainly during the dose escalation period. Driving or use of machines should be done cautiously if dizziness occurs.
If semaglutide is used in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines (see section 4.4).
In four phase 3a trials, 2,650 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.
Table 2 lists adverse reactions identified in phase 3a clinical trials. 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).
Table 2. Adverse reactions from controlled phase 3 trials:
| MedDRA system organ class | Very common | Common | Uncommon | Rare |
|---|---|---|---|---|
| Immune system disorders | Anaphylactic reaction | |||
| Metabolism and nutrition disorders | Hypoglycaemia in patients with type 2 diabetesa | |||
| Nervous system disorders | Headacheb | Dizzinessb | ||
| Eye disorders | Diabetic retinopathy in patients with type 2 diabetesa | |||
| Cardiac disorders | Hypotension Orthostatic hypotension Increased heart ratea,c | |||
| Gastrointestinal | ||||
| Vomitinga,b Diarrhoeaa,b Constipationa,b Nauseaa,b Abdominal painb,c | Gastritisb,c Gastrooesophageal reflux diseaseb Dyspepsiab Eructationb Flatulenceb Abdominal distensionb | Acute pancreatitisa | ||
| Hepatobiliary disorders | Cholelithiasisa | |||
| Skin and subcutaneous tissue disorders | Hair lossa | Angioedema | ||
| General disorders and administration site conditions | Fatigueb,c | Injection site reactionsc | ||
| 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
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.
The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was 0.2% for semaglutide and <0.1% for placebo, respectively.
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 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%).
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.
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.
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.
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 insulintreated 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).
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.
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.
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