Chemical formula: C₁₈₇H₂₉₁N₄₅O₅₉ Molecular mass: 4,113.641 g/mol
Semaglutide interacts in the following cases:
No dose adjustment is required for patients with mild or moderate hepatic impairment. Semaglutide should be used cautiously in patients with mild or moderate hepatic impairment.
No dose adjustment is required for patients with hepatic impairment. Experience with the use of Semaglutide in patients with severe hepatic impairment is limited. Caution should be exercised when treating these patients with semaglutide.
Experience with the use of semaglutide in patients with severe hepatic impairment is limited. Semaglutide is not recommended for use in patients with severe hepatic impairment.
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, cases of decreased INR have been reported during concomitant use of acenocoumarol and semaglutide. Upon initiation of semaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of INR is recommended.
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 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 the rate of gastric emptying was observed with semaglutide 2.4 mg, following 20 weeks of administration of semaglutide, probably due to a tolerance effect. No dose adjustment of paracetamol is necessary when administered with semaglutide.
Semaglutide treated patients with gastroparesis may experience more serious or severe gastrointestinal adverse events. Semaglutide should be used with caution in these patients, and semaglutide is not recommended if gastroparesis is severe.
In patients with diabetic retinopathy treated with insulin and semaglutide, an increased risk of developing diabetic retinopathy complications has been observed. 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.
There is no experience with semaglutide 2 mg in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy and semaglutide 2 mg is therefore not recommended in these patients.
In patients with diabetic retinopathy treated with semaglutide, an increased risk of developing diabetic retinopathy complications has been observed. 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 semaglutide in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy. In these patients, treatment with semaglutide is not recommended.
Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonists undergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastric content due to delayed gastric emptying should be considered prior to performing procedures with general anaesthesia or deep sedation.
Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Caution should be exercised in patients with a history of pancreatitis.
Studies in animals have shown reproductive toxicity. 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.
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.
Women of childbearing potential are recommended to use contraception when treated with semaglutide.
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.
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.
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. The frequencies of the adverse reactions (except diabetic retinopathy complications, 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 system organ class | Very common | Common | Uncommon | Rare | Very Rare | Not known |
|---|---|---|---|---|---|---|
| Immune system disorders | Hypersensitivityc | Anaphylactic reaction | ||||
| Metabolism and nutrition disorders | Hypoglycaemiaa when used with insulin or sulfonylurea | Hypoglycaemiaa when used with other oral antidiabetics (OAD) Decreased appetite | ||||
| Nervous system disorders | Dizziness Headache | Dysgeusia | Dysaesthesiad | |||
| Eye disorders | Diabetic retinopathy complicationsb | Non-arteritic anterior ischaemic optic neuropathy (NAION) | ||||
| Cardiac disorders | Increased heart rate | |||||
| Gastrointestinal disorders | Nausea Diarrhoea | Vomiting Abdominal pain Abdominal distension Constipation Dyspepsia Gastritis Gastrooesophageal reflux disease Eructation Flatulence | Acute pancreatitis Delayed gastric emptying | Intestinal obstructiond | ||
| Hepatobiliary disorders | Cholelithiasis | |||||
| Skin and subcutaneous tissue disorders | Angioedemad | |||||
| General disorders and administration site conditions | Fatigue | Injection site reactions | ||||
| Investigations | Increased lipase 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.
In cardiovascular high risk population the adverse reaction profile was similar to that seen in the other phase 3a trials.
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.
American Diabetes Association (ADA) classified hypoglycaemia occurred in 11.3% (0.3 events/patient year) of patients when semaglutide 1 mg was added to SGLT2 inhibitor in SUSTAIN 9 compared to 2.0% (0.04 events/patient year) of placebo-treated patients. Severe hypoglycaemia was reported in 0.7% (0.01 events/patient year) and 0% of patients, respectively.
In a 40-week phase 3b trial in patients receiving semaglutide 1 mg and 2 mg, the majority of the hypoglycaemic episodes (45 out of 49 episodes) occurred when semaglutide was used in combination with sulfonylurea or insulin. Overall, there was no increased risk of hypoglycaemia with semaglutide 2 mg.
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.
In a 40-week phase 3b trial in patients receiving semaglutide 1 mg and 2 mg, nausea occurred in similar proportions of patients when treated with semaglutide 1 mg and 2 mg, respectively. Diarrhoea and vomiting occurred in higher proportions of patients when treated with semaglutide 2 mg compared to semaglutide 1 mg. The gastrointestinal adverse reactions led to treatment discontinuation in similar proportions in the semaglutide 1 mg and 2 mg treatment groups.
In concomitant use with an SGLT2 inhibitor in SUSTAIN 9, constipation and gastro-oesophageal reflux disease occurred in 6.7% and 4% respectively of patients treated with semaglutide 1 mg compared to no events for placebo-treated patients. The prevalence of these events did not decrease over time.
Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.
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.
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%).
Results from several large epidemiological studies suggest that exposure to semaglutide in adults with type 2 diabetes is associated with an approximately two-fold increase in the relative risk of developing NAION, corresponding to approximately one additional case per 10 000 person-years of treatment.
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 (1−3%) 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.
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.
Table 2 lists adverse reactions identified in clinical trials in adults and post-marketing reports. The frequencies are based on a pool of the phase 3a trials.
Adverse reactions associated with semaglutide 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 2. Frequency of adverse reactions of semaglutide:
| MedDRA system organ class | Very common | Common | Uncommon | Rare | Very Rare | Not known |
| Immune system disorders | Anaphylactic reaction | |||||
| Metabolism and nutrition disorders | Hypoglycaemia in patients with type 2 diabetesa | |||||
| Nervous system disorders | Headacheb | Dizzinessb Dysgeusiab,c Dysaesthesiaa | ||||
| Eye disorders | Diabetic retinopathy in patients with type 2 diabetesa | Non-arteritic anterior ischaemic optic neuropathy (NAION) | ||||
| Cardiac disorders | Hypotension Orthostatic hypotension Increased heart ratea,c | |||||
| Gastrointestinal disorders | Vomitinga,b Diarrhoeaa,b Constipationa,b Nauseaa,b Abdominal painb,c | Gastritisb,c Gastrooesophageal reflux diseaseb Dyspepsiab Eructationb Flatulenceb Abdominal distensionb | Acute pancreatitisa Delayed gastric emptying | Intestinal obstruction | ||
| 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
The below information on specific adverse reactions, unless otherwise specified, pertains to the phase 3a trials.
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.
Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.
The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was 0.2% for semaglutide and <0.1% for placebo, respectively. In SELECT, the cardiovascular outcomes trial, the frequency of acute pancreatitis confirmed by adjudication was 0.2% for semaglutide and 0.3% for placebo.
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.
In STEP-HFpEF-DM, clinically significant hypoglycaemia was observed in 4.2% of subjects in both the semaglutide and placebo groups when used in combination with sulfonylurea and/or insulin (0.065 events/patient year with semaglutide and 0.098 events/patient year with placebo).
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).
Events related to a clinical picture of altered skin sensation such as paraesthesia, pain of skin, sensitive skin, dysaesthesia and burning skin sensation were reported in 2.1% of patients treated with semaglutide 2.4 mg and 1.2% of patients treated with placebo. The events were mild to moderate in severity and most patients recovered while on continued treatment.
Results from several large epidemiological studies suggest that exposure to semaglutide in adults with type 2 diabetes is associated with an approximately two-fold increase in the relative risk of developing NAION, corresponding to approximately one additional case per 10 000 person-years of treatment.
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 semaglutide and 0% of patients treated with placebo.
No effects on growth or pubertal development were found after 68 weeks of treatment.
In the SELECT and SUSTAIN 6 trials, in adults with established cardiovascular disease, the adverse reaction profile was similar to that seen in the weight management phase 3a trials.
In the HFpEF trials, in adults with obesity related heart failure with preserved ejection fraction (HFpEF), the adverse reaction profile was similar to that seen in the weight management phase 3a trials.
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