Source: European Medicines Agency (EU) Revision Year: 2019 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.
Semaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Semaglutide is not a substitute for insulin.
There is no experience in patients with congestive heart failure NYHA class IV and semaglutide is therefore not recommended in these patients.
Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients, with impaired renal function as nausea, vomiting, and diarrhoea may cause dehydration which could cause a deterioration of renal function (see section 4.8).
Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. 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.
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 semaglutide (see section 4.8).
In patients with diabetic retinopathy treated with insulin and semaglutide, an increased risk of developing diabetic retinopathy complications has been observed (see section 4.8). Caution should be exercised when using semaglutide in patients with diabetic retinopathy treated with insulin. These patients should be monitored closely and treated according to clinical guidelines. Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy, but other mechanisms cannot be excluded.
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.
Semaglutide delays gastric emptying and has the potential to impact the rate of absorption of concomitantly administered oral medicinal products. 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 dose adjustment of paracetamol is necessary when administered with semaglutide.
Semaglutide is not anticipated to decrease the effect of oral contraceptives as semaglutide 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 the 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 (INR) 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 INR is recommended.
Women of childbearing potential are recommended to use contraception when treated with semaglutide.
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 half-life (see section 5.2).
In lactating rats, semaglutide was excreted in milk. As 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 (see section 5.3).
Semaglutide has no or negligible influence on the ability to drive or use machines. When it 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 8 phase 3a trials 4,792 patients were exposed to semaglutide. 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.
Table 1 lists adverse reactions identified in all phase 3a trials in patients with type 2 diabetes mellitus (further described in section 5.1). The frequencies of the adverse reactions 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) and very rare: (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions from long-term controlled phase 3a trials including the cardiovascular outcomes trial:
Rare: Anaphylactic reaction
Very common: Hypoglycaemiaa when used with insulin or sulfonylurea
Common: Hypoglycaemiaa when used with other OADs, Decreased appetite
Common: Dizziness
Uncommon: Dysgeusia
Common: Diabetic retinopathy complicationsb
Uncommon: Increased heart rate
Very common: Nausea, Diarrhoea
Common: Vomiting, Abdominal pain, Abdominal, distension, Constipation, Dyspepsia, Gastritis, Gastro-oesophageal reflux disease, Eructation, Flatulence
Common: Cholelithiasis
Common: Fatigue
Uncommon: Injection site reactions
Common: Increased lipase, Increased amylase, Weight decreased
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).
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.
Nausea occurred in 17.0% 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.
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 (3.0%) 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. 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%).
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.
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.
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 (1−2%) and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect at end-of-trial.
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 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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