semaglutide: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Kayshild

4.1 Therapeutic indications

Kayshild is indicated in conjunction with diet and exercise for the treatment of adults with non- cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (fibrosis stages F2 to F3).

4.2 Posology and method of administration

Posology

The maintenance dose of semaglutide 2.4 mg once weekly is reached by starting with a dose of 0.25 mg. To reduce the likelihood of gastrointestinal symptoms, the dose should be escalated over a 16-week period to a maintenance dose of 2.4 mg once weekly (see Table 1). In case of significant gastrointestinal symptoms, consider delaying dose escalation or lowering to the previous dose until symptoms have improved. When symptoms have improved, attempt to re-escalate the dose.

Table 1 Dose escalation schedule
Dose escalation
Weekly dose
Week 1–4
0.25 mg
Week 5–8
0.5 mg
Week 9–12
1 mg
Week 13–16
1.7 mg
Maintenance dose
2.4 mg

Weekly doses higher than 2.4 mg are not recommended.

Patients with type 2 diabetes
When initiating semaglutide in patients with type 2 diabetes, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce the risk of hypoglycaemia, see section 4.4.

Missed dose
If a dose is missed, it should be administered as soon as possible and within 5 days after the missed dose. If more than 5 days have passed, the missed dose should be skipped, and the next dose should be administered on the regularly scheduled day. In each case, patients can then resume their regular once- weekly dosing schedule. If more doses are missed, reducing the starting dose for re-initiation should be considered.

Special populations

Elderly
No dose adjustment is required based on age. Therapeutic experience in patients ≥75 years of age is limited.

Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment. Experience with the use of semaglutide in patients with severe renal impairment is limited. Semaglutide is not recommended for use in patients with severe renal impairment (eGFR< 30 mL/min/1.73m2) including patients with end-stage renal disease (see sections 4.4, 4.8 and 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Experience with the use of semaglutide in patients with severe (Child-Pugh C) hepatic impairment is limited. Semaglutide is not recommended to be initiated for use in patients with severe hepatic impairment and should be used cautiously in patients with moderate hepatic impairment

(see sections 4.4 and 5.2). In patients with MASH and preserved hepatic function the safety profile is well established (see section 4.8). There is limited experience in patients with MASH and F4c (Child- Pugh A), however with similar safety results as in studies in patients with preserved hepatic function.
There is no experience in patients with MASH and moderate or severe hepatic impairment.

Paediatric population
The safety and efficacy of Kayshild in children and adolescents below 18 years of age have not yet been established. No data are available.

Method of administration

Subcutaneous use.

Kayshild is administered once weekly at any time of the day, with or without meals.

It is to be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site can be changed. It should not be administered intravenously or intramuscularly.

The day of weekly administration can be changed if necessary, as long as the time between two doses is at least 3 days (> 72 hours). After selecting a new dosing day, once-weekly dosing should be continued.

Patients should be advised to read carefully the instructions for use included in the package leaflet before administering the medicinal product.

For further information before administration see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.8 Undesirable effects

Summary of the safety profile

The most frequently reported adverse reactions during treatment with semaglutide in the phase 3 clinical trial in MASH (ESSENCE, see section 5.1) were gastrointestinal disorders including nausea (36.1%), diarrhoea (26.8%), constipation (22.1%), and vomiting (18.5%), and fatigue (see section ‘Description of selected adverse reactions’).

Tabulated list of adverse reactions

Table 2 lists adverse reactions identified with semaglutide. The frequencies presented are the highest if difference is observed in reporting between the phase 3 clinical trial in MASH (ESSENCE, see section 5.1), weight management phase 3a trials (STEP 1-4) and post-marketing reports.

Adverse reactions are listed by MedDRA 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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Adverse reactions
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
Headachea,b
Dizzinessb
Dysaesthesiaa,c
Dysgeusiab,c
Eye disorders
Diabetic retinopathy in patients with type 2 diabetesa
Non- arteritic anterior ischemic optic neuropathy
(NAION)a, d
Cardiac disorders
Hypotension
Orthostatic hypotension
Increased heart ratea,c
Gastrointestinal disorders
Vomitinga,b
Diarrhoeaa,b
Constipationa,b
Nauseaa,b
Abdominal painb,c
Gastritisb,c
Gastroesophageal reflux diseaseb
Dyspepsiab
Eructationb
Flatulenceb
Abdominal distensionb
Delayed gastric emptying
Gastroenteritis
Increased lipasec
Acute pancreatitisa
Increased amylasec
Intestinal obstructionc,d
,e
Hepatobiliary disorders
Cholelithiasisa
Skin and subcutaneous disorders
Hair lossa
Angioedema
General disorders and administration site conditions
Fatigueb,c
Injection site reactionsc 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 with other marketed semaglutide products e) Grouped term covering PTs Intestinal obstruction, ileus, small intestinal obstruction

Description of selected adverse reactions

Gastrointestinal adverse reactions
The events were most frequently reported during dose escalation. In ESSENCE, nausea occurred in 36.1% of patients when treated with semaglutide (12.4% for placebo), diarrhoea in 26.8% (12.2% for placebo) and vomiting in 18.5% (5.6% for placebo). Most events were mild to moderate in severity and of short duration. Constipation occurred in 22.1% of patients treated with semaglutide (7.8% for placebo) and was mild to moderate in severity and of longer duration.
In ESSENCE, the gastrointestinal events led to permanent treatment discontinuation in 1.6% of patients treated with semaglutide.
In the weight management phase 3a trials with semaglutide 2.4 mg, 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.

According to data from the weight management phase 3a trials with semaglutide 2.4 mg, patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min/1.73m2) may experience more gastrointestinal effects when treated with semaglutide.

Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.

Acute pancreatitis
The frequency of acute pancreatitis reported in ESSENCE was 0.4% for semaglutide and 0.5% for placebo.
The frequency of adjudication-confirmed acute pancreatitis reported in the weight management phase 3a clinical trials with semaglutide 2.4 mg 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.

Acute gallstone disease/Cholelithiasis
In ESSENCE, cholelithiasis was reported in 1.4% of patients treated with semaglutide and in 0.8% of patients treated with placebo.
In the weight management phase 3a trials with semaglutide 2.4 mg, 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.

Headache
In ESSENCE, headache was reported in 8% of patients with semaglutide and in 6.3% of patients treated with placebo.
In the weight management phase 3a trials with semaglutide 2.4 mg, headache was reported in 12.8% of patients treated with semaglutide and in 8.7% of patients treated with placebo.

Hair loss
In ESSENCE, hair loss was reported in 1.6% of patients treated with semaglutide and in 0.5% of patients treated with placebo.
In the weight management phase 3a trials with semaglutide 2.4 mg, hair loss was reported in 2.5% of patients treated with semaglutide and in 1% 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 ESSENCE, a mean increase of 2 beats per minute (bpm) at week 72 from a baseline mean of 75 bpm was observed in patients treated with semaglutide. The proportions of patients with a maximum increase from baseline ≥ 10 bpm at any timepoint during the on-treatment period were 43.3% in the semaglutide 2.4 mg group vs 50.4% in the placebo group.
In the weight management phase 3a trials with semaglutide 2.4 mg, a mean increase of 3 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% 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. In ESSENCE, the proportion of patients testing positive for anti-semaglutide antibodies at any time post-baseline was low (0.4%).
In the weight management phase 3a trials with semaglutide 2.4 mg, 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.

Dysaesthesia
In ESSENCE, events related to a clinical picture of altered skin sensation such as paraesthesia, hyperaesthesia, pain of skin, sensitive skin, dysaesthesia and burning skin sensation were reported in 2.9% of patients treated with semaglutide and 1.5% of patients treated with placebo.
In the weight management phase 3a trials with semaglutide 2.4 mg, events related to a clinical picture of altered skin sensation were reported in 2.1% of patients treated with semaglutide 2.4 mg and 1.2% of patients treated with placebo.
In both clinical development programmes, the events were mild to moderate in severity and most patients recovered while on continued treatment.

Hypoglycaemia in patients with type 2 diabetes
In ESSENCE, clinically significant hypoglycaemia (< 3.0 mmol/L) was observed in 6.1% (0.068 events/patient year) of patients treated with semaglutide compared with 5% (0.12 events/patient year) of patients treated with placebo. Severe hypoglycaemia (requiring external assistance for recovery) was reported with semaglutide in 2.2% of patients (0.015 events/patient year) and with placebo in 0.5% of patients (0.003 events/patient year).
In a phase 3a trial in adults with overweight or obesity and type 2 diabetes (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%) 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 ESSENCE, retinal disorders were reported by 3.1% of patients treated with semaglutide and 4.1% of patients treated with placebo. Few patients reported diabetic retinopathy (1.1%, and 1.4%, respectively).

In a phase 3a trial in adults with overweight or obesity and type 2 diabetes (STEP 2), retinal disorders were reported by 6.9% of patients treated with semaglutide 2.4 mg, 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%, 2.7%, and 2.7%, respectively) and non-proliferative retinopathy (0.7%, 0%, and 0%, respectively).

Non-arteritic anterior ischaemic optic neuropathy (NAION)
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.

Paediatric population

Semaglutide has not been studied in children and adolescents below 18 years with MASH.

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 semaglutide. 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.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Aspiration in association with general anaesthesia or deep sedation

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 (see section 4.8) should be considered prior to performing procedures with general anaesthesia or deep sedation.

Gastrointestinal effects and Dehydration

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 in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

Acute pancreatitis

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.

Patients with type 2 diabetes

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, as it has not been evaluated and an increased risk of adverse reactions related to overdose is considered likely.

Hypoglycaemia in patients with type 2 diabetes

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 Kayshild in patients treated with insulin has not been evaluated.

Diabetic retinopathy in patients with type 2 diabetes

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 Kayshild in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy. In these patients, treatment with Kayshild is not recommended.

Non-arteritic anterior ischemic optic neuropathy (NAION)

Data from epidemiological studies indicates an increased risk for non-arteritic anterior ischaemic optic neuropathy (NAION) during treatment with semaglutide. There is no identified time interval for when NAION may develop following treatment start. A sudden loss of vision should lead to ophthalmological examination and treatment with semaglutide should be discontinued if NAION is confirmed (see section 4.8).

Patients with gastroparesis

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 (see section 4.8).

Populations not studied

The safety and efficacy of Kayshild have not been investigated in patients:
- with type 1 diabetes,
- with severe renal impairment (see section 4.2),
- with moderate or severe hepatic impairment and MASH (see section 4.2),
- with congestive heart failure New York Heart Association (NYHA) class IV.
Use in these patients is not recommended.

There is limited experience with Kayshild in patients:
- aged 75 years or more (see section 4.2),
- with moderate or severe hepatic impairment (see section 4.2),
- with inflammatory bowel disease,
- MASH and BMI< 25 kg/m2 (or BMI< 23 kg/m2 for Asian population).
Use with caution in these patients.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Semaglutide delays gastric emptying and could potentially influence the absorption of concomitantly administered oral medicinal products. However, 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.

Warfarin and other coumarin derivatives

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 (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.

Paracetamol

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.

Oral contraceptives

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.

Atorvastatin

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.

Digoxin

Semaglutide did not change the overall exposure or Cmax of digoxin following a single dose of digoxin (0.5 mg).

Metformin

Semaglutide did not change the overall exposure or Cmax of metformin following dosing of 500 mg twice daily over 3.5 days.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential are recommended to use contraception when treated with semaglutide (see section 4.5).

Pregnancy

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).

Breast-feeding

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.

Fertility

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).

4.7 Effects on ability to drive and use machines

Semaglutide has no or negligible influence on the ability to drive and use machines. However, dizziness can be experienced mainly during the dose escalation period (see section 4.8). Driving or use of machines should be done cautiously if dizziness occurs.

Patients with type 2 diabetes

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).

4.9 Overdose

Overdose with semaglutide may be associated with gastrointestinal disorders which could lead to dehydration. In the event of overdose, the patient should be observed for clinical signs and appropriate supportive treatment initiated.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ06

Mechanism of action

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1. GLP-1 receptors are widely distributed throughout the body (e.g. pancreas, kidney, brain, heart, vasculature, immune system and lung); however, they have not been detected on liver cells.

The liver-specific mechanism of action is multifactorial and thought to be mediated through improvement in metabolic factors, including weight loss, improved glucose and lipid metabolism, and reduced inflammation. Semaglutide affects gene pathways of both inflammation and fibrosis, consequently positively changing the proteomic pattern of an individual with MASH. Moreover, semaglutide lowers liver fat deposition.

Semaglutide lowers body weight through reduced appetite and thereby reduced energy intake. In addition, semaglutide reduces the preference for high-fat foods.

Furthermore, semaglutide reduces blood glucose levels in a glucose-dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose levels are high. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

Semaglutide has a beneficial effect on blood lipid levels and results in lower systolic blood pressure and reduced inflammation. Furthermore, animal studies have shown that semaglutide attenuates the development of atherosclerosis and has an anti-inflammatory action in the cardiovascular system.

Pharmacodynamic effects

MASH disease activity
Semaglutide improves components of the MASH disease activity by reducing steatosis, inflammation and ballooning assessed by histology. Additionally, semaglutide reduces liver steatosis assessed by transient elastography (TE) using Controlled Attenuation Parameter (CAP) and Magnetic Resonance Imaging Proton Density Fat Fraction (MRI-PDFF).
Improvements in the levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) have also been observed.

Liver fibrosis
Semaglutide decreases liver stiffness assessed by TE and reduces the Enhanced Liver Fibrosis (ELF) score and the levels of the pro-peptide of type III collagen biomarker (Pro-C3).

Fasting lipids
Semaglutide compared to placebo lowered fasting triglyceride concentration by 17% and improved HDL concentration by 4.7%.

Glucose and insulin sensitivity
In patients with MASH and type 2 diabetes, semaglutide reduced HbA1c by 1.1% compared with placebo (0%).
In patients with MASH without type 2 diabetes, the estimated reduction in homeostasis model assessment of insulin resistance (HOMA-IR) was greater with semaglutide (-32.5%) than with placebo (-0.5%).

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Compared to native GLP-1, semaglutide has a prolonged half-life of around 1 week making it suitable for once-weekly subcutaneous administration. The principal mechanism of protraction is albumin binding, which results in decreased renal clearance and protection from metabolic degradation.
Furthermore, semaglutide is stabilised against degradation by the DPP-4 enzyme.

Absorption

The average semaglutide steady state concentration following subcutaneous administration of the semaglutide maintenance dose was approximately 80 nmol/L in patients with MASH and F2 or F3 based on data from a phase 3a trial, where 90% of patients had average concentrations between 52 nmol/L and 122 nmol/L. The steady state exposure of semaglutide increased proportionally with doses from 0.25 mg up to 2.4 mg once weekly. Steady state exposure was stable with time as assessed up to week 72. Similar exposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of semaglutide was 89%.

Distribution

The mean volume of distribution of semaglutide following subcutaneous administration in patients with MASH and F2 or F3 was approximately 13.7 L. Semaglutide was extensively bound to plasma albumin (> 99%).

Biotransformation

Prior to excretion, semaglutide is extensively metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid side chain. The enzyme neutral endopeptidase (NEP) was identified as one of the active metabolic enzymes.

Elimination

The primary excretion routes of semaglutide-related material are via the urine and faeces.
Approximately 3% of the absorbed dose was excreted in the urine as intact semaglutide.
The clearance of semaglutide in patients with MASH and F2 or F3 was approximately 0.05 L/h. With an elimination half-life of approximately 1 week, semaglutide will be present in the circulation for approximately 7 weeks after the last dose of 2.4 mg.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Ozempic

4.1 Therapeutic indications

Ozempic is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise

as monotherapy when metformin is considered inappropriate due to intolerance or contraindications

in addition to other medicinal products for the treatment of diabetes.

For trial results with respect to combinations, effects on glycaemic control, cardiovascular disease and kidney events and the populations studied, see sections 4.4, 4.5 and 5.1.

4.2 Posology and method of administration

Posology

The starting dose is 0.25 mg semaglutide once weekly. After 4 weeks the dose should be increased to 0.5 mg once weekly. After at least 4 weeks with a dose of 0.5 mg once weekly, the dose can be increased to 1 mg once weekly to further improve glycaemic control. After at least 4 weeks with a dose of 1 mg once weekly, the dose can be increased to 2 mg once weekly to further improve glycaemic control.

Semaglutide 0.25 mg is not a maintenance dose. Weekly doses higher than 2 mg are not recommended.

When Ozempic is added to existing metformin and/or thiazolidinedione therapy or to a sodium- glucose cotransporter 2 (SGLT2) inhibitor, the current dose of metformin and/or thiazolidinedione or SGLT2 inhibitor can be continued unchanged.

When Ozempic is added to existing therapy of sulfonylurea or insulin, a reduction in the dose of sulfonylurea or insulin should be considered to reduce the risk of hypoglycaemia (see sections 4.4 and 4.8).

Self-monitoring of blood glucose is not needed in order to adjust the dose of Ozempic. Blood glucose self-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when Ozempic is started and insulin is reduced. A stepwise approach to insulin reduction is recommended.

Changing the dosing day
The day of weekly administration can be changed if necessary, as long as the time between two doses is at least 3 days (>72 hours). After selecting a new dosing day, once-weekly dosing should be continued.

Special populations

Elderly
No dose adjustment is required based on age.

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 (see section 5.2).

Paediatric population
The safety and efficacy of semaglutide in children and adolescents below 18 years have not yet been established. No data are available.

Method of administration

Subcutaneous use.

Ozempic is to be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site can be changed without dose adjustment. Ozempic should not be administered intravenously or intramuscularly.

Ozempic is to be administered once weekly at any time of the day, with or without meals.

For further information on administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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,

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

Hypersensiti vityc
Anaph ylactic reactio n

Metabolism and nutrition disorders
Hypoglycaemiaa when used with insulin or sulfonylurea
Hypoglyca emiaa when used with other oral antidiabeti cs (OAD)

Decreased appetite

Nervous system disorders

Dizziness
Headache
Dysgeusia

Dysaesthes iad
Eye disorders

Diabetic retinopathy complicati onsb

Non- arteritic anterior ischaemic optic neuropathy
(NAION)

Cardiac disorders

Increased heart rate

Gastrointesti- nal disorders
Nausea
Diarrhoea
Vomiting
Abdominal pain
Abdominal distension
Constipatio n
Dyspepsia
Gastritis
Gastro- oesophage al reflux disease
Eructation
Flatulence
Acute pancreatitis
Delayed gastric emptying

Intestinal obstruction d

MedDRA system organ class
Very common
Common
Uncommon
Rare
Very Rare
Not known
Hepatobiliary disorders

Cholelithia sis

Skin and subcutaneous tissue disorders

Angioedem ad
General disorders and administra- tion 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.

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.

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.

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.

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.

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.

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.

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

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General

Semaglutide should not be used for the treatment of diabetic ketoacidosis. Semaglutide is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients whom had rapid discontinuation or dose reduction of insulin when treatment with a GLP-1 receptor agonist is started (see section 4.2).

There is no experience in patients with congestive heart failure NYHA class IV and semaglutide is therefore not recommended in these patients.

Aspiration in association with general anaesthesia or deep sedation

Gastrointestinal effects and dehydration

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 in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Acute pancreatitis

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.

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 semaglutide (see section 4.8).

Diabetic retinopathy

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.
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.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

NAION may develop following treatment start. A sudden loss of vision should lead to ophthalmological examination and treatment with semaglutide should be discontinued if NAION is confirmed (see section 4.8).

Patients with gastroparesis

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

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.

Paracetamol

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.

Oral contraceptives

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.

Atorvastatin

Digoxin

Semaglutide did not change the overall exposure or Cmax of digoxin following a single dose of digoxin (0.5 mg).

Metformin

Semaglutide did not change the overall exposure or Cmax of metformin following dosing of 500 mg twice daily over 3.5 days.

Warfarin and other coumarin derivatives

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.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential are recommended to use contraception when treated with semaglutide.

Pregnancy

Breast-feeding

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.

Fertility

4.7 Effects on ability to drive and use machines

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).

4.9 Overdose

Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have been reported in clinical trials. The most commonly reported adverse reaction was nausea. All patients recovered without complications.

There is no specific antidote for overdose with semaglutide. In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the long half-life of semaglutide of approximately 1 week (see section 5.2).

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ06

Mechanism of action

GLP-1 is a physiological hormone that has multiple actions in glucose and appetite regulation, in the cardiovascular system and in the kidneys. The glucose and appetite effects are specifically mediated via GLP-1 receptors in the pancreas and the brain.

Semaglutide reduces blood glucose in a glucose dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

Semaglutide reduces body weight and body fat mass through lowered energy intake, involving an overall reduced appetite. In addition, semaglutide reduces the preference for high fat foods.

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys. The mechanism of action of semaglutide is likely multifactorial. Indirect effects are indicated by the beneficial effect of semaglutide on plasma lipids, lowered systolic blood pressure and reduced inflammation in clinical studies but direct effects are likely also involved. In animal studies, semaglutide attenuates the development of atherosclerosis by preventing aortic plaque progression and reducing inflammation in the plaque.

Clinical data showed that semaglutide lowered albuminuria in patients with kidney disease.

Pharmacodynamic effects

All pharmacodynamic evaluations were performed after 12 weeks of treatment (including dose escalation) at steady state with semaglutide 1 mg once weekly.

Fasting and postprandial glucose
Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes, treatment with semaglutide 1 mg resulted in reductions in glucose in terms of absolute change from baseline (mmol/L) and relative reduction compared to placebo (%) for fasting glucose (1.6 mmol/L;
22% reduction), 2 hour postprandial glucose (4.1 mmol/L; 37% reduction), mean 24 hour glucose concentration (1.7 mmol/L; 22% reduction) and postprandial glucose excursions over 3 meals (0.6-1.1 mmol/L) compared with placebo. Semaglutide lowered fasting glucose after the first dose.

Beta-cell function and insulin secretion
Semaglutide improves beta-cell function. Compared to placebo, semaglutide improved first- and second-phase insulin response with a 3– and 2–fold increase, respectively, and increased maximal beta-cell secretory capacity in patients with type 2 diabetes. In addition, semaglutide treatment increased fasting insulin concentrations compared to placebo.

Glucagon secretion

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Compared to native GLP-1, semaglutide has a prolonged half-life of around 1 week making it suitable for once weekly subcutaneous administration. The principal mechanism of protraction is albumin binding, which results in decreased renal clearance and protection from metabolic degradation.
Furthermore, semaglutide is stabilised against degradation by the DPP-4 enzyme.

Absorption

Maximum concentration was reached 1 to 3 days post dose. Steady state exposure was achieved following 4–5 weeks of once weekly administration. In patients with type 2 diabetes, the mean steady state concentrations following subcutaneous administration of 0.5 mg and 1 mg semaglutide were approximately 16 nmol/L and 30 nmol/L, respectively. In the trial comparing semaglutide 1 mg and 2 mg, the mean steady state concentrations were 27 nmol/L and 54 nmol/L, respectively. Semaglutide exposure increased in a dose proportional manner for doses of 0.5 mg, 1 mg and 2 mg. Similar exposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm. Absolute bioavailability of subcutaneous semaglutide was 89%.

Distribution

The mean volume of distribution of semaglutide following subcutaneous administration in patients with type 2 diabetes was approximately 12.5 L. Semaglutide was extensively bound to plasma albumin (>99%).

Biotransformation

Prior to excretion, semaglutide is extensively metabolised through proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain. The enzyme neutral endopeptidase (NEP) is expected to be involved in the metabolism of semaglutide.

Elimination

In a trial with a single subcutaneous dose of radiolabelled semaglutide, it was found that the primary excretion routes of semaglutide-related material were via urine and faeces; approximately 2/3 of

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Rybelsus

4.1 Therapeutic indications

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets · Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Rybelsus is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus to improve glycaemic control as an adjunct to diet and exercise

as monotherapy when metformin is considered inappropriate
in combination with other medicinal products for the treatment of diabetes.

For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studied, see sections 4.4, 4.5 and 5.1.

4.2 Posology and method of administration

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets

Posology

The starting dose of semaglutide is 1.5 mg once daily for one month. After one month, the dose should be increased to a maintenance dose of 4 mg once daily. If needed, the dose can be escalated to the next higher dose after a minimum of one month on the current dose. The recommended single daily maintenance doses are 4 mg, 9 mg, 25 mg and 50 mg.

The maximum recommended single daily dose of semaglutide is 50 mg. Rybelsus should always be used as one tablet per day. Taking more than one tablet a day should not be done to achieve the effect of a higher dose.

Switching from subcutaneous to oral semaglutide
The effect of switching between oral and subcutaneous semaglutide cannot easily be predicted because oral semaglutide displays higher pharmacokinetic variability in absorption compared to subcutaneous semaglutide.

Patients treated with subcutaneous semaglutide 0.5 mg once weekly can be transitioned to oral semaglutide 4 mg or 9 mg once daily.
Patients treated with subcutaneous semaglutide 1 mg once weekly can be transitioned to oral semaglutide 9 mg or 25 mg once daily.
Patients treated with subcutaneous semaglutide 2 mg once weekly can be transitioned to oral semaglutide 25 mg or 50 mg once daily.
Patients can start oral semaglutide (Rybelsus) one week after their last dose of subcutaneous semaglutide.

When semaglutide is used in combination with metformin and/or a sodium-glucose co-transporter-2 inhibitor (SGLT2i) or thiazolidinedione, the current dose of metformin and/or SGLT2i or thiazolidinedione can be continued.

When semaglutide is used in combination with a sulfonylurea or with insulin, a reduction in the dose of sulfonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.4 and 4.8).

Self-monitoring of blood glucose is not needed in order to adjust the dose of semaglutide. Blood glucose self-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when semaglutide is started and insulin is reduced. A stepwise approach to insulin reduction is recommended.

Missed dose
If a dose is missed, the missed dose should be skipped and the next dose should be taken the following day.

Elderly
No dose adjustment is required based on age.

Renal impairment
No dose adjustment is required for patients with mild, moderate or severe renal impairment.
Experience with the use of semaglutide in patients with end-stage kidney disease is limited. Caution should be exercised when treating these patients with oral semaglutide (see section 5.2).

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 (see section 5.2).

Paediatric population

The safety and efficacy of Rybelsus in children and adolescents below 18 years have not been established. No data are available.

Method of administration

Rybelsus is a tablet for once-daily oral use.

This medicinal product should be taken on an empty stomach after a recommended fasting period of at least 8 hours (see section 5.2).
It should be swallowed whole with a sip of water (up to half a glass of water equivalent to 120 mL). Tablets should not be split, crushed or chewed, as it is not known whether this impacts absorption of semaglutide.
Patients should wait at least 30 minutes before eating, drinking or taking other oral medicinal products. Waiting less than 30 minutes decreases the absorption of semaglutide (see sections 4.5 and 5.2).

Applies to: Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Posology

The starting dose of semaglutide is 3 mg once daily for one month. After one month, the dose should be increased to a maintenance dose of 7 mg once daily. If needed, the dose can be escalated to the next higher dose after a minimum of one month on the current dose. The recommended single daily maintenance doses are 7 mg, 14 mg, 25 mg and 50 mg.

Patients treated with subcutaneous semaglutide 0.5 mg once weekly can be transitioned to oral semaglutide 7 mg or 14 mg once daily.
Patients treated with subcutaneous semaglutide 1 mg once weekly can be transitioned to oral semaglutide 14 mg or 25 mg once daily.
Patients treated with subcutaneous semaglutide 2 mg once weekly can be transitioned to oral semaglutide 25 mg or 50 mg once daily.
Patients can start oral semaglutide (Rybelsus) one week after their last dose of subcutaneous semaglutide.

Missed dose
If a dose is missed, the missed dose should be skipped and the next dose should be taken the following day.

Elderly
No dose adjustment is required based on age.

Paediatric population

The safety and efficacy of Rybelsus in children and adolescents below 18 years have not been established. No data are available.

Method of administration

Rybelsus is a tablet for once-daily oral use.

This medicinal product should be taken on an empty stomach after a recommended fasting period of at least 8 hours (see section 5.2).
It should be swallowed whole with a sip of water (up to half a glass of water equivalent to 120 mL). Tablets should not be split, crushed or chewed, as it is not known whether this impacts absorption of semaglutide.
Patients should wait at least 30 minutes before eating, drinking or taking other oral medicinal products. Waiting less than 30 minutes decreases the absorption of semaglutide (see sections 4.5 and 5.2).

4.3 Contraindications

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets · Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.8 Undesirable effects

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets

Summary of the safety profile

In 10 phase 3a trials, 5 707 patients were exposed to semaglutide alone or in combination with other glucose-lowering medicinal products. The duration of the treatment ranged from 26 weeks to

78 weeks. The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common).

Tabulated list of adverse reactions

Table 1 lists adverse reactions identified in phase 3 trials (further described in section 5.1) and post- marketing reports in patients with type 2 diabetes mellitus. The frequencies of the adverse reactions (except diabetic retinopathy complications and dysaesthesia, see footnotes in Table 1) are based on a pool of the phase 3a trials excluding the cardiovascular outcomes trial.

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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Frequency of adverse reactions of oral semaglutide
MedDRA system organ class
Very common
Common
Uncommon
Rare
Very
Rare
Not known
Immune system disorders

Hypersensitiv ityc
Anaphylac tic reaction

Metabolism and nutrition disorders
Hypoglycae mia when used with insulin or sulfonylurea a
Hypoglycae mia when used with other oral antidiabetic productsa
Decreased appetite

Nervous system disorders

Dizziness
Dysaesthesia e
Headache
Dysgeusia

Eye disorders

Diabetic retinopathy complication sb

Non- arteritic anterior ischaemi c optic neuropat hy
(NAION
)

Cardiac disorders

Increased heart rate

Gastrointesti nal disorders
Nausea
Diarrhoea
Vomiting
Abdominal pain
Abdominal distension
Constipation
Dyspepsia
Gastritis
Gastro- oesophageal
Eructation
Delayed gastric emptying

Acute pancreatiti s

Intestinal obstructio nd,f

MedDRA system organ class
Very common
Common
Uncommon
Rare
Very
Rare
Not known reflux disease
Flatulence
Hepatobiliar y disorders

Cholelithiasis

General disorders and administrati on site conditions

Fatigue

Investigation s

Increased lipase
Increased amylase
Weight decreased

a) Hypoglycaemia defined as blood glucose < 3.0 mmol/L or < 54 mg/dL.
b) Diabetic retinopathy complications are a composite of retinal photocoagulation, treatment with intravitreal agents, vitreous haemorrhage and diabetes-related blindness (uncommon). Frequency is based on the cardiovascular outcomes trial with subcutaneous semaglutide, but it cannot be excluded that the risk of diabetic retinopathy complications identified also applies to Rybelsus.
c) Grouped term covering also adverse events related to hypersensitivity such as rash and urticaria.
d) From post-marketing reports.
e) The frequency is based on the PIONEER PLUS trial results for 25 mg and 50 mg. Please refer to dysaesthesia subheading below for more information. There were no imbalances of dysaesthesia events with Rybelsus® 3 mg, 7 mg and 14 mg (bioequivalent to 1.5 mg, 4 mg and 9 mg respectively) in phase 3a trials, however, events have been reported in the post- marketing experience.
f) Grouped term covering PTs ‘intestinal obstruction’, ‘ileus’, ‘small intestinal obstruction’.

Description of selected adverse reactions

Hypoglycaemia
Severe hypoglycaemia was primarily observed when semaglutide was used with a sulfonylurea (< 0.1% of subjects, < 0.001 events/patient year) or insulin (1.1% of subjects, 0.013 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 sulfonylurea.

Gastrointestinal adverse reactions
Nausea occurred in 15%, diarrhoea in 10%, and vomiting in 7% of patients when treated with semaglutide. Most events were mild to moderate in severity and of short duration. The events led to treatment discontinuation in 4% of subjects. The events were most frequently reported during the first months on treatment.

In PIONEER PLUS when treated with semaglutide 25 mg and 50 mg nausea occurred in 27% and 27%, diarrhoea in 13% and 14%, and vomiting in 17% and 18% of patients, respectively. These events led to treatment discontinuation in 6% and 8% of patients, respectively.

Most events were mild to moderate in severity and of short duration. The events were most frequently reported during dose escalation the first months on treatment.

Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.

section 4.4.). In phase 3b cardiovascular outcomes trial SOUL, the frequency of acute pancreatitis confirmed by adjudication was 0.4% for semaglutide and 0.4% for placebo.

Diabetic retinopathy complications
A 2-year clinical trial with subcutaneous semaglutide 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 subcutaneous 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 with subcutaneous semaglutide. In clinical trials with Rybelsus of up to 18 months duration involving 6 352 patients with type 2 diabetes, adverse events related to diabetic retinopathy were reported in similar proportions in subjects treated with semaglutide (4.2%) and comparators (3.8%).

Immunogenicity
Consistent with the potential immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies following treatment with semaglutide. The proportion of subjects tested positive for anti-semaglutide antibodies at any time point after baseline was low (0.5%) and no subjects had neutralising anti-semaglutide antibodies or anti-semaglutide antibodies with neutralising effect on endogenous GLP-1 at end-of-trial.

Heart rate increase
Increased heart rate has been observed with GLP-1 receptor agonists. In the phase 3a trials, mean changes of 0 to 4 beats per minute (bpm) from a baseline of 69 to 76 were observed in patients treated with Rybelsus.

Dysaesthesia
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% and 5.2% of patients treated with oral semaglutide 25 mg and 50 mg, respectively. The events were mild to moderate in severity and most patients recovered while on continued treatment.

Reporting of suspected adverse reactions

Applies to: Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Summary of the safety profile

In 10 phase 3a trials, 5 707 patients were exposed to semaglutide alone or in combination with other glucose-lowering medicinal products. The duration of the treatment ranged from 26 weeks to

78 weeks. The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common).

Tabulated list of adverse reactions

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); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Frequency of adverse reactions of oral semaglutide
MedDRA system organ class
Very common
Common
Uncommon
Rare
Very
Rare
Not known
Immune system disorders

Hypersensitiv ityc
Anaphylac tic reaction

Metabolism and nutrition disorders
Hypoglycae mia when used with insulin or sulfonylurea a
Hypoglycae mia when used with other oral antidiabetic productsa
Decreased appetite

Nervous system disorders

Dizziness
Dysaesthesia e
Headache
Dysgeusia

Eye disorders

Diabetic retinopathy complication sb

Non- arteritic anterior ischaemi c optic neuropat hy
(NAION
)

Cardiac disorders

Increased heart rate

Gastrointesti nal disorders
Nausea
Diarrhoea
Vomiting
Abdominal pain
Abdominal distension
Constipation
Dyspepsia
Gastritis
Gastro- oesophageal
Eructation
Delayed gastric emptying

Acute pancreatiti s

Intestinal obstructio nd,f

MedDRA system organ class
Very common
Common
Uncommon
Rare
Very
Rare
Not known reflux disease
Flatulence
Hepatobiliar y disorders

Cholelithiasis

General disorders and administrati on site conditions

Fatigue

Investigation s

Increased lipase
Increased amylase
Weight decreased

a) Hypoglycaemia defined as blood glucose < 3.0 mmol/L or < 54 mg/dL.
b) Diabetic retinopathy complications are a composite of retinal photocoagulation, treatment with intravitreal agents, vitreous haemorrhage and diabetes-related blindness (uncommon). Frequency is based on the cardiovascular outcomes trial with subcutaneous semaglutide, but it cannot be excluded that the risk of diabetic retinopathy complications identified also applies to Rybelsus.
c) Grouped term covering also adverse events related to hypersensitivity such as rash and urticaria.
d) From post-marketing reports.
e) The frequency is based on the PIONEER PLUS trial results for 25 mg and 50 mg. Please refer to dysaesthesia subheading below for more information. There were no imbalances of dysaesthesia events with Rybelsus® 3 mg, 7 mg and 14 mg in phase 3a trials, however, events have been reported in the post- marketing experience.
f) Grouped term covering PTs ‘intestinal obstruction’, ‘ileus’, ‘small intestinal obstruction’.

Description of selected adverse reactions

Most events were mild to moderate in severity and of short duration. The events were most frequently reported during dose escalation the first months on treatment.

Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.

Acute pancreatitis confirmed by adjudication has been reported in phase 3a trials, semaglutide (< 0.1%) and comparator (0.2%). In the cardiovascular outcomes trial PIONEER 6 the frequency of acute pancreatitis confirmed by adjudication was 0.1% for semaglutide and 0.2% for placebo (see section 4.4.). In phase 3b cardiovascular outcomes trial SOUL, the frequency of acute pancreatitis confirmed by adjudication was 0.4% for semaglutide and 0.4% for placebo.

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General

Semaglutide should not be used for the treatment of diabetic ketoacidosis. Diabetic ketoacidosis has been reported in insulin-dependent patients who had rapid discontinuation or dose reduction of insulin when treatment with a GLP-1 receptor agonist is started (see section 4.2).

There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and semaglutide is therefore not recommended in these patients.

There is no therapeutic experience with semaglutide in patients with bariatric surgery.

Aspiration in association with general anaesthesia or deep sedation

Gastrointestinal effects and dehydration

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 in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Acute pancreatitis

Hypoglycaemia

Patients treated with semaglutide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycaemia (see section 4.8). The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with semaglutide (see section 4.2).

Diabetic retinopathy

In patients with diabetic retinopathy treated with insulin and subcutaneous semaglutide, an increased risk of developing diabetic retinopathy complications has been observed, a risk that cannot be excluded for orally administered semaglutide (see section 4.8). Caution should be exercised when using semaglutide in patients with diabetic retinopathy. 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. Long- term glycaemic control decreases the risk of diabetic retinopathy.

There is no experience with oral semaglutide 25 mg and 50 mg in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

ophthalmological examination and treatment with semaglutide should be discontinued if NAION is confirmed (see section 4.8).

Patients with gastroparesis

Treatment response

Compliance with the dosing regimen is recommended for optimal effect of semaglutide. If the treatment response with semaglutide is lower than expected, the treating physician should be aware that the absorption of semaglutide is highly variable and may be minimal (2-4% of patients will not have any exposure), and that the absolute bioavailability of semaglutide is low.

Sodium content

1.5 mg, 4 mg and 9 mg tablets: This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

25 mg and 50 mg tablets: This medicinal product contains 23 mg sodium per tablet, equivalent to 1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Applies to: Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

General

There is no therapeutic experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and semaglutide is therefore not recommended in these patients.

There is no therapeutic experience with semaglutide in patients with bariatric surgery.

Aspiration in association with general anaesthesia or deep sedation

Gastrointestinal effects and dehydration

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 in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Acute pancreatitis

Hypoglycaemia

Diabetic retinopathy

There is no experience with oral semaglutide 25 mg and 50 mg in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Patients with gastroparesis

Treatment response

Sodium content

This medicinal product contains 23 mg sodium per tablet, equivalent to 1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets

Semaglutide delays gastric emptying which may influence the absorption of other oral medicinal products.

Effects of semaglutide on other medicinal products

Thyroxine
Total exposure (Area Under the Curve (AUC)) of thyroxine (adjusted for endogenous levels) was increased by 33% following administration of a single dose of levothyroxine. Maximum exposure (Cmax) was unchanged. Monitoring of thyroid parameters should be considered when treating patients with semaglutide at the same time as levothyroxine.

Warfarin and other coumarin derivatives
Semaglutide did not change the AUC or Cmax of R- and S-warfarin following a single dose of warfarin, 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.

Rosuvastatin
AUC of rosuvastatin was increased by 41% [90% CI: 24; 60] when co-administered with semaglutide.
Based on the wide therapeutic index of rosuvastatin the magnitude of changes in the exposure is not considered clinically relevant.

Digoxin, oral contraceptives, metformin, furosemide
No clinically relevant change in AUC or Cmax of digoxin, oral contraceptives (containing ethinylestradiol and levonorgestrel), metformin or furosemide was observed when concurrently administered with semaglutide.

Interactions with medicinal products with very low bioavailability (1%) have not been evaluated.

Effects of other medicinal products on semaglutide

Omeprazole
No clinically relevant change in AUC or Cmax of semaglutide was observed when taken with omeprazole.

In a trial investigating the pharmacokinetics of semaglutide co-administered with five other tablets, the AUC of semaglutide decreased by 34% and Cmax by 32%. This suggests that the presence of multiple tablets in the stomach influences the absorption of semaglutide if co-administered at the same time.
After administering semaglutide, the patients should wait 30 minutes before taking other oral medicinal products (see section 4.2).

Applies to: Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Semaglutide delays gastric emptying which may influence the absorption of other oral medicinal products.

Effects of semaglutide on other medicinal products

Rosuvastatin
AUC of rosuvastatin was increased by 41% [90% CI: 24;60] when co-administered with semaglutide.
Based on the wide therapeutic index of rosuvastatin the magnitude of changes in the exposure is not considered clinically relevant.

Interactions with medicinal products with very low bioavailability (1%) have not been evaluated.

Effects of other medicinal products on semaglutide

Omeprazole
No clinically relevant change in AUC or Cmax of semaglutide was observed when taken with omeprazole.

4.6 Fertility, pregnancy and lactation

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets · Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Women of childbearing potential

Women of childbearing potential have to use effective contraception during treatment with semaglutide.

Pregnancy

Breast-feeding

No measurable concentrations of semaglutide were found in breast milk of lactating women.
Salcaprozate sodium was present in breast milk and some of its metabolites were excreted in breast milk at low concentrations. As a risk to a breast-fed child cannot be excluded, Rybelsus should not be used during breast-feeding.

Fertility

4.7 Effects on ability to drive and use machines

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets · Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Semaglutide has no or negligible influence on the ability to drive and use machines. However, dizziness can be experienced mainly during dose escalation. Driving or use of machines should be done cautiously if dizziness occurs.

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).

4.9 Overdose

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets · Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Effects of overdose with semaglutide in clinical studies may be associated with gastrointestinal disorders. In the event of overdose, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. A prolonged period of observation and treatment of the symptoms may be necessary, taking into account the long half-life of semaglutide of approximately 1 week (see section 5.2). There is no specific antidote for overdose with semaglutide.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets · Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Pharmacotherapeutic group: Drugs used in diabetes, Glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ06

Mechanism of action

GLP-1 is a physiological hormone that has multiple actions in glucose and appetite regulation, and in the cardiovascular system. The glucose and appetite effects are specifically mediated via GLP-1 receptors in the pancreas and the brain.

Semaglutide reduces blood glucose in a glucose-dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high. The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion. The mechanism of semaglutide is independent of the route of administration.

Semaglutide reduces body weight and body fat mass through lowered energy intake, involving an overall reduced appetite. In addition, semaglutide reduces the preference for high fat foods.

GLP-1 receptors are expressed in the heart, vasculature, immune system and kidneys. Semaglutide has a beneficial effect on plasma lipids, lowers systolic blood pressure and reduces inflammation in clinical studies. In animal studies, semaglutide attenuates the development of atherosclerosis by preventing aortic plaque progression and reducing inflammation in the plaque.

The mechanism of action of semaglutide for cardiovascular risk reduction is likely multifactorial, in part driven by reduction in HbA1c and effects on known cardio-kidney-metabolic risk factors including reduction in blood pressure, and body weight, improvements in lipid profile, and kidney function, and anti-inflammatory effects as demonstrated by reductions in hsCRP. The exact mechanism of cardiovascular risk reduction has not been established.

Pharmacodynamic effects

The pharmacodynamic evaluations described below were performed with orally administered semaglutide after 12 weeks of treatment.

Fasting and postprandial glucose
Semaglutide reduces fasting and postprandial glucose concentrations. In patients with type 2 diabetes, treatment with semaglutide resulted in a relative reduction compared to placebo of 22% [13; 30] for fasting glucose and 29% [19; 37] for postprandial glucose.

Glucagon secretion
Semaglutide lowers the postprandial glucagon concentrations. In patients with type 2 diabetes, semaglutide resulted in the following relative reductions in glucagon compared to placebo:
postprandial glucagon response of 29% [15; 41].

Gastric emptying

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Rybelsus 1.5 mg tablets / Rybelsus 4 mg tablets / Rybelsus 9 mg tablets

Two formulations of the semaglutide tablets exist:
- 1.5 mg, 4 mg and 9 mg (round tablets)
- 3 mg, 7 mg and 14 mg (oval tablets)

Similar efficacy and safety can be expected for both formulations. Bioequivalent doses of the two formulations are outlined in the table below.

Table 10 Equal effect of the two oral formulations
Dose
One round tablet
One oval tablet
Starting dose
1.5 mg
Equal effect to
3 mg
Maintenance doses
4 mg
Equal effect to
7 mg
9 mg
Equal effect to
14 mg

Absorption

Orally administered semaglutide has a low absolute bioavailability and a variable absorption. Daily administration according to the recommended posology in combination with a long half-life reduces day-to-day fluctuation of the exposure.

The pharmacokinetics of semaglutide have been extensively characterised in healthy subjects and patients with type 2 diabetes. Following oral administration, maximum plasma concentration of semaglutide occurred approximately 1 hour post dose. Steady-state exposure was reached after 4-5 weeks of once-daily administration. In patients with type 2 diabetes, the average steady-state concentrations were approximately as listed below:
4 mg (bioequivalent to 7 mg): Average concentration was 7 nmol/L with 90% of subjects treated with semaglutide 7 mg having an average concentration between 2 and 22 nmol/L.
9 mg (bioequivalent to 14 mg): Average concentration was 15 nmol/L with 90% of subjects treated with semaglutide 14 mg having an average concentration between 4 and 45 nmol/L.
25 mg: Average concentration was 47 nmol/L with 90% of subjects treated with semaglutide 25 mg having an average concentration between 11 and 142 nmol/L.
50 mg: Average concentration was 92 nmol/L with 90% of subjects treated with semaglutide 50 mg having an average concentration between 23 and 279 nmol/L.

Systemic exposure of semaglutide increased in a dose-proportional manner.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Rybelsus 3 mg tablets / Rybelsus 7 mg tablets / Rybelsus 14 mg tablets

Two formulations of the semaglutide tablets exist:
- 1.5 mg, 4 mg and 9 mg (round tablets)
- 3 mg, 7 mg and 14 mg (oval tablets).

Similar efficacy and safety can be expected for both formulations. Bioequivalent doses of the two formulations are outlined in the table below.

Table 10 Equal effect of the two oral formulations
Dose
One round tablet

One oval tablet
Starting dose
1.5 mg
Equal effect to
3 mg
Maintenance doses
4 mg
Equal effect to
7 mg
9 mg
Equal effect to
14 mg

Absorption

The pharmacokinetics of semaglutide have been extensively characterised in healthy subjects and patients with type 2 diabetes. Following oral administration, maximum plasma concentration of semaglutide occurred approximately 1 hour post dose. Steady-state exposure was reached after 4-5 weeks of once-daily administration. In patients with type 2 diabetes, the average steady-state concentrations were approximately as listed below:
7 mg: Average concentration was 7 nmol/L with 90% of subjects treated with semaglutide 7 mg having an average concentration between 2 and 22 nmol/L.
14 mg: Average concentration was 15 nmol/L with 90% of subjects treated with semaglutide 14 mg having an average concentration between 4 and 45 nmol/L.
25 mg: Average concentration was 47 nmol/L with 90% of subjects treated with semaglutide 25 mg having an average concentration between 11 and 142 nmol/L.
50 mg: Average concentration was 92 nmol/L with 90% of subjects treated with semaglutide 50 mg having an average concentration between 23 and 279 nmol/L.

Systemic exposure of semaglutide increased in a dose-proportional manner within formulations (i.e.
between 7 mg and 14 mg, and between 25 mg and 50 mg), with higher bioavailability for the 25 and 50 mg strengths.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu

Wegovy

4.1 Therapeutic indications

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Adults

Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management, including weight loss and weight maintenance, in adults with an initial Body Mass Index (BMI) of
- ≥ 30 kg/m2 (obesity), or
- ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity e.g. dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease.

For trial results with respect to cardiovascular risk reduction, obesity-related heart failure, and populations studied, see section 5.1.

Adolescents (≥ 12 years of age)

Wegovy is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adolescents aged 12 years and above with
- obesity* and
- body weight above 60 kg.

Treatment with Wegovy should be discontinued and re-evaluated if adolescent patients have not reduced their BMI by at least 5% after 12 weeks on the 2.4 mg or maximum tolerated dose.

*Obesity (BMI ≥ 95th percentile) as defined on gender- and age-specific BMI growth charts (CDC.gov) (see Table 1).

Table 1 BMI cut-off points for obesity (≥ 95th percentile) by gender and age for paediatric patients aged 12 and older (CDC criteria)

Age (years)
BMI (kg/m2) at 95th Percentile
Males
Females

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

• ≥ 30 kg/m2 (obesity), or
• ≥ 27 kg/m2 to < 30 kg/m2 (overweight) in the presence of at least one weight-related comorbidity e.g.
dysglycaemia (prediabetes or type 2 diabetes mellitus), hypertension, dyslipidaemia, obstructive sleep apnoea or cardiovascular disease.

For trial results with respect to populations studied, see section 5.1.

4.2 Posology and method of administration

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Posology

Adults

The maintenance dose of semaglutide 2.4 mg once-weekly is reached by starting with a dose of 0.25 mg. To reduce the likelihood of gastrointestinal symptoms, the dose should be escalated over a 16-week period to a maintenance dose of 2.4 mg once weekly (see Table 2).

If needed, the dose can be increased to 7.2 mg once weekly after a minimum of 4 weeks on the 2.4 mg dose in adults with BMI ≥ 30 kg/m2 at treatment initiation.
If no additional clinical improvement in body weight is observed with the 7.2 mg, the dose should be reduced to 2.4 mg once weekly.
In case of significant gastrointestinal symptoms, delaying dose escalation or lowering to the previous dose until symptoms have improved could be considered.
Table 2 Dose escalation schedule
Dose escalation
Weekly dose
Week 1–4
0.25 mg
Week 5–8
0.5 mg
Week 9–12
1 mg
Week 13–16
1.7 mg
Maintenance dose
2.4 mg
Maintenance dose
7.2 mg

Switching from oral to subcutaneous semaglutide

The effect of switching between oral and subcutaneous semaglutide cannot easily be predicted because oral semaglutide displays higher pharmacokinetic variability in absorption compared to subcutaneous semaglutide.

Patients treated with oral semaglutide 25 mg once daily can be transitioned to subcutaneous semaglutide 2.4 mg once weekly. Patients can start subcutaneous semaglutide the day after their last dose of oral semaglutide (Wegovy tablet).

Adolescents

For adolescents aged 12 years and above, the same dose escalation schedule as for adults should be applied (see Table 2). The dose should be increased until 2.4 mg (maintenance dose) or maximum tolerated dose has been reached. Weekly doses higher than 2.4 mg are not recommended.

Patients with type 2 diabetes

The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with semaglutide (see sections 4.4 and 4.8).

Missed dose

If a dose is missed, it should be administered as soon as possible and within 5 days after the missed dose. If more than 5 days have passed, the missed dose should be skipped, and the next dose should be administered on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule. If more doses are missed, reducing the starting dose for re-initiation should be considered.
Special populations

Elderly (≥ 65 years of age)
No dose adjustment is required based on age. Therapeutic experience in patients ≥ 85 years of age is limited.

Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment. Experience with the use of semaglutide in patients with severe renal impairment is limited. Semaglutide is not recommended for use in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) including patients with end-stage renal disease (see sections 4.4, 4.8 and 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Experience with the use of semaglutide in patients with severe (Child-Pugh C) hepatic impairment is limited. Semaglutide should be used cautiously in patients with mild, moderate or severe hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
No dose adjustment is required for adolescents aged 12 years and above. Doses above 2.4 mg are not recommended.
The safety and efficacy of semaglutide in children below 12 years of age have not been established.

Method of administration

For subcutaneous use.

Wegovy solution for injection is administered once weekly at any time of the day, with or without meals.

It is to be injected subcutaneously in the abdomen, in the thigh or in the upper arm. The injection site can be changed. It should not be administered intravenously or intramuscularly.

The 7.2 mg dose can be administered either as one injection of 7.2 mg or as three injections of 2.4 mg depending on the device. The three injections of 2.4 mg can be administered in the same body area but should be at least 5 cm apart.

The day of weekly administration can be changed if necessary, as long as the time between doses is at least 3 days (> 72 hours). After selecting a new dosing day, once-weekly dosing should be continued.

When administering Wegovy pre-filled pen for single use, the pen should be pressed firmly against the skin until the yellow bar has stopped moving. The injection takes about 5–10 seconds.

Patients should be advised to read the instruction for use included in the package leaflet carefully before administering the medicinal product.

For further information before administration see section 6.6.

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Posology

The starting dose for orally administered semaglutide is 1.5 mg once daily. After four weeks at this dose, the dose escalation steps for orally administered semaglutide once daily are 4 mg, 9 mg and 25 mg with a minimum duration of four weeks at each dose level. The dose should be escalated until 25 mg (maintenance dose). If needed, the dose can be maintained at the previous dose level.

The maximum recommended single daily dose of orally administered semaglutide is 25 mg. Orally administered semaglutide should always be taken as only one tablet per day. Taking more than one tablet, per day should not be done to achieve the effect of a higher dose.

Switching from subcutaneous to oral semaglutide

The effect of switching between subcutaneous and oral semaglutide cannot easily be predicted because oral semaglutide displays higher pharmacokinetic variability in absorption compared to subcutaneous semaglutide.

Patients treated with subcutaneous semaglutide 2.4 mg once weekly can be transitioned to oral semaglutide 25 mg once daily.
Patients can start oral semaglutide (Wegovy tablet) one week after their last dose of subcutaneous semaglutide.

Patients with type 2 diabetes

The risk of hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating treatment with semaglutide (see sections 4.4 and 4.8).

Missed dose

If a dose is missed, the missed dose should be skipped, and the next dose should be taken the following day.

Special populations

Elderly (≥ 65 years of age)
No dose adjustment is required based on age. Therapeutic experience in patients ≥ 85 years of age is limited.

Renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment. Experience with the use of semaglutide in patients with severe renal impairment is limited. Semaglutide is not recommended for use in patients with severe renal impairment (eGFR < 30 mL/min/1.73m2) including patients with end-stage renal disease (see sections 4.4, 4.8 and 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild or moderate hepatic impairment. 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 and should be used cautiously in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

Paediatric population
The safety and efficacy of orally administered semaglutide in children and adolescents below 18 years have not been established. No data is available.

Method of administration

Wegovy tablet is for oral use.

This medicinal product should be taken on an empty stomach after a recommended fasting period of at least 8 hours (see section 5.2).
It should be swallowed whole with a sip of water (up to half a glass of water equivalent to 120 mL). Tablets should not be split, crushed or chewed, as it is not known whether this impacts absorption of semaglutide.
Patients should wait at least 30 minutes before eating, drinking or taking other oral medicinal products. Waiting less than 30 minutes decreases the absorption of semaglutide (see sections 4.5 and 5.2).

4.3 Waist circumference (cm)

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Baseline
114.5
115.5
Change from baseline1
-9.4
-4.5
Difference from placebo1 [95% CI]
-4.9 [-6.0; -3.8]*
- Systolic blood pressure (mmHg)
Baseline
Change from baseline1
-3.9
-0.5
Difference from placebo1 [95% CI]
-3.4 [-5.6; -1.3]**
- HbA1c (mmol/mol (%))
Baseline

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.8 Undesirable effects

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Summary of safety profile

The most frequently reported adverse reactions were gastrointestinal disorders including nausea, diarrhoea, constipation, abdominal pain and vomiting. These reactions were mainly seen in the dose- escalation period (see Description of selected adverse reactions).

Tabulated list of adverse reactions

Table 3 lists adverse reactions identified in clinical studies in adults and post-marketing reports. The frequencies are based on a pool of four phase 3a trials (STEP 1-4), unless otherwise specified, where 2650 adult patients were exposed to Wegovy. The duration of the trials were 68 weeks.

Adverse reactions are listed by MedDRA 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). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 3 Adverse reactions
MedDRA system organ class
Very common
Common
Uncommo n
Rare

Very rare
Not known
Immune system disorders

Anaphylacti c reaction

Metabolism and nutrition disorders

Hypoglycaemia in patients with type 2 diabetesa

Nervous system disorders
Headacheb
Dizzinessb
Dysgeusiab,c
Dysaesthesiaa,c,f,g

Eye disorders

Diabetic retinopathy in patients with type 2 diabetesa

Non- arteritic anterior ischaemic optic neuropath y
(NAION)

Cardiac disorders

Increased heart ratea,c

Vascular disorders

Hypotensio n
Orthostatic hypotension

Gastrointestin al disorders
Vomitinga,b
Diarrhoeaa,b
Constipationa
,b
Nauseaa,b
Abdominal painb,c
Gastritisb,c
Gastrooesophage al reflux diseaseb
Dyspepsiab
Eructationb
Flatulenceb
Abdominal distensionb
Acute pancreatitisa
Delayed gastric emptying

Intestinal obstructionc,d
,e
Hepatobiliary disorders

Cholelithiasisa

Skin and subcutaneous tissue disorders

Hair lossa

Angioedem a

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 d) From post-marketing reports e) Grouped term covering PTs Intestinal obstruction, Ileus, small intestinal obstruction f) Frequency is based on the 3a program. An increased frequency has been observed with the 7.2 mg dose. Please refer to dysaesthesia subheading below for more information g) Grouped term covering PTs Dysaesthesia, Hyperaesthesia, Paraesthesia, Skin burning sensation, Burning sensation, Pain of skin, Sensitive skin, Skin discomfort, Skin sensitisation, Allodynia and Hyperpathia

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), vomiting in 24.5% (6.3% for placebo), and abdominal pain in 19.7% (10% 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 to < 60 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.

Acute pancreatitis

The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical studies 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.

Acute gallstone disease/Cholelithiasis

Cholelithiasis was reported in 1.6% and led to cholecystitis in 0.6% of patients treated with semaglutide in phase 3a clinical studies. Cholelithiasis and cholecystitis was reported in 1.1% and 0.3%, respectively, of patients treated with placebo.

Hair loss

In phase 3a clinical studies, hair loss was reported in 2.5% of patients treated with semaglutide and in 1.0% of patients treated with placebo. In STEP UP trials, hair loss was reported in 5.3% of patients treated with semaglutide 7.2 mg and in 1.0% of patients on 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 studies, 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 2.9 - 10.9% for semaglutide 2.4 mg and 15.3% for semaglutide 7.2 mg. No patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect. 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.
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).

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 semaglutide, 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).

Dysaesthesia

In phase 3 a clinical studies, 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.

In STEPUP, dysaesthesia-related events were reported by 21.6% of patients treated with semaglutide 7.2 mg and 0.3% of patients on placebo. Most events in the 7.2 mg group were mild to moderate and 85% (368 out of 434 events) recovered while on treatment. 28% (123 of all 434 events) in the semaglutide 7.2 mg subcutaneous group recovered after changes in the dose of the trial product.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

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.

Paediatric population

In a clinical trial conducted in adolescents of 12 years to below 18 years of age with obesity or overweight with at least one weight-related comorbidity, 133 patients were exposed to semaglutide.
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.

Other special populations

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.

Reporting of suspected adverse reactions

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Summary of safety profile

The most frequently reported adverse reactions were gastrointestinal disorders including nausea, diarrhoea, constipation, abdominal pain, dyspepsia and vomiting. These reactions were mainly seen in the dose-escalation period (see Description of selected adverse reactions).

The safety profile of oral semaglutide was consistent with the safety profile of subcutaneous semaglutide.

Tabulated list of adverse reactions

Table 1 lists adverse reactions identified in clinical studies in adults and post-marketing reports. The frequencies are based, unless otherwise specified, on a pool of the subcutaneous semaglutide phase 3a trials (STEP 1-4), where 2650 adult patients were exposed to Wegovy. The duration of the trials was 68 weeks. The adverse reactions in OASIS 4 (204 adults with obesity or overweight with at least one weight-related comorbidity were exposed to oral semaglutide for 64 weeks) had similar frequencies to the subcutaneous phase 3a trials, except for dyspepsia which had a higher frequency category. Events not relevant for oral administration are omitted in the following overview.

Adverse reactions are listed by MedDRA 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). Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions
MedDRA system organ class
Very common
Common
Uncommo n
Rare
Very rare
Not known
Immune system disorders

Anaphylacti c reaction

Metabolism and nutrition disorders

Hypoglycaemia in patients with type 2 diabetesa

Nervous system disorders
Headacheb
Dizzinessb
Dysgeusiab,c
Dysaesthesiaa,c,g

MedDRA system organ class
Very common
Common
Uncommo n
Rare
Very rare
Not known
Eye disorders

Diabetic retinopathy in patients with type 2 diabetesa

Non- arteritic anterior ischaemic optic neuropath y
(NAION)

Cardiac disorders

Increased heart ratea,c

Vascular disorders

Hypotensio n
Orthostatic hypotension

Gastrointestin al disorders
Vomitinga,b
Diarrhoeaa,b
Constipationa
,b
Dyspepsiab,d
Nauseaa,b
Abdominal painb,c
Gastritisb,c
Gastrooesophage al reflux diseaseb
Eructationb
Flatulenceb
Abdominal distensionb
Acute pancreatitisa
Delayed gastric emptying

Intestinal obstructionc, e,f
Hepatobiliary disorders

Cholelithiasisa

Skin and subcutaneous tissue disorders

Hair lossa

Angioedem a

General disorders and administration site conditions
Fatigueb,c

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) The frequency is based on the OASIS 4 phase 3 trial with oral semaglutide.
e) From post-marketing reports f) Grouped term covering PTs Intestinal obstruction, Ileus, small intestinal obstruction g) Grouped term covering PTs Dysaesthesia, Hyperaesthesia, Paraesthesia, Skin burning sensation, Burning sensation, Pain of skin, Sensitive skin, Skin discomfort, Skin sensitisation, Allodynia and Hyperpathia

Description of selected adverse reactions

The below adverse reactions are applicable for oral semaglutide. Frequencies on specific adverse reactions, unless otherwise specified, pertains to the OASIS 4 phase 3 trial.

Gastrointestinal adverse reactions

The events were most frequently reported during dose escalation. Over the 64 weeks trial period, nausea occurred in 46.6% of patients when treated with oral semaglutide (18.6% for placebo), vomiting in 30.9% (5.9% for placebo), dyspepsia in 18.1% (8.8% for placebo), diarrhoea in 17.6% (8.8% for placebo), and abdominal pain in 16.7% (7.8% for placebo). Most events were mild to

moderate in severity and of short duration. Constipation occurred in 20.1% of patients treated with semaglutide (9.8% for placebo) and was mild to moderate in severity and of longer duration.

Patients with a history of gastroparesis may experience more serious or severe gastrointestinal effects when treated with semaglutide.

Patients with moderate renal impairment (eGFR ≥ 30 to < 60 mL/min/1.73 m2) may experience more gastrointestinal effects when treated with semaglutide.

The gastrointestinal events led to permanent treatment discontinuation in 3.4% of patients treated with oral semaglutide.

Acute pancreatitis

Acute pancreatitis was reported in 0 % of patients treated with oral semaglutide and 1.0 % of patients treated with placebo. The frequency of adjudication-confirmed acute pancreatitis reported in the STEP phase 3a clinical studies 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.

Acute gallstone disease/Cholelithiasis

Cholelithiasis was reported in 2.5 % and led to cholecystitis in 0 % of patients treated with oral semaglutide. Cholelithiasis and cholecystitis were reported in 1 % and 0 %, respectively, of patients treated with placebo.

Hair loss

Hair loss was reported in 6.4 % of patients treated with oral semaglutide and in 2.0 % of patients treated with placebo. All events were mild or moderate and half of them recovered by end of the trial.
Hair loss was reported more frequently in patients with a greater weight loss (≥ 20 %).

Increased heart rate

A mean increase of 2 beats per minute (bpm) from a baseline mean of 72 bpm was observed in patients treated with oral semaglutide. The proportions of subjects with an increase in pulse from baseline ≥ 20 bpm at any timepoint during the on-treatment period were 26.5 % in the semaglutide group vs. 20.8 % 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 with oral semaglutide 14 mg and 50 mg at any time post-baseline was low (0.5 % and 0.3 % for Rybelsus and Wegovy tablets, respectively) and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect. 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 anti-semaglutide antibodies, the presence of antibodies had 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 2.4 mg s.c 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 subcutaneous 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 semaglutide 2.4 mg, 6.2 % of patients treated with subcutaneous 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).

Dysaesthesia

Events related to a clinical picture of altered skin sensation such as sensitive skin, hyperaesthesia, paraesthesia, skin burning sensation and allodynia were reported in 4.9% of patients treated with oral semaglutide. No events were reported in patients treated with placebo. The events were mild to moderate in severity and most patients recovered while on continued treatment.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Other special populations

In the SELECT trial, in adults with established cardiovascular disease, the adverse reaction profile was similar to that seen in subcutaneous semaglutide in the weight management phase 3a trials.

Reporting of suspected adverse reactions

4.4 Special warnings and precautions for use

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Aspiration in association with general anaesthesia or deep sedation

Gastrointestinal effects and dehydration

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 in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Acute pancreatitis

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Patients with type 2 diabetes

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.

Hypoglycaemia in patients with type 2 diabetes

Diabetic retinopathy in patients with type 2 diabetes

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.

Patients with gastroparesis

Semaglutide treated patients with gastroparesis may experience more serious or severe gastrointestinal adverse reactions. Semaglutide should be used with caution in these patients, and semaglutide is not recommended if gastroparesis is severe (see section 4.8).

Populations not studied

The safety and efficacy of Wegovy have not been investigated in patients:
- treated with other products for weight management,
- with type 1 diabetes,
- with severe renal impairment (see section 4.2),
- with moderate or severe hepatic impairment and metabolic dysfunction-associated steatohepatitis (MASH),
- with congestive heart failure New York Heart Association (NYHA) class IV.
Use in these patients is not recommended.

There is limited experience with Wegovy in patients:
- aged 85 years or more (see section 4.2),
- with mild, moderate or severe hepatic impairment (see section 4.2),
- with inflammatory bowel disease.
Use with caution in these patients.

Excipient with known effect

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Aspiration in association with general anaesthesia or deep sedation

Gastrointestinal effects and dehydration

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 in rare cases can lead to a deterioration of renal function (see section 4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration in relation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Acute pancreatitis

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Patients with type 2 diabetes

Semaglutide should not be used as a substitute for insulin in patients with type 2 diabetes.

Compliance with the dosing regimen is recommended for the optimal effect of semaglutide. If the treatment response with semaglutide is lower than expected, the treating physician should be aware that the absorption of semaglutide is highly variable and may be minimal, and that the absolute bioavailability of semaglutide is low.
Furthermore, patients with diabetes have been predicted to have lower drug exposure and less weight reduction than patients without diabetes.

In patients with type 2 diabetes with an inadequate response to oral semaglutide, consider switching to subcutaneous semaglutide.

Hypoglycaemia in patients with type 2 diabetes

Diabetic retinopathy in patients with type 2 diabetes

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.

Patients with gastroparesis

Populations not studied

The safety and efficacy of subcutaneous or oral semaglutide have not been investigated in patients:
- treated with other products for weight management,
- with type 1 diabetes,
- with severe renal impairment (see section 4.2),
- with severe hepatic impairment (see section 4.2),
- with congestive heart failure New York Heart Association (NYHA) class IV.
Use in these patients is not recommended.

There is limited experience with subcutaneous or oral semaglutide in patients:
- aged 85 years or more (see section 4.2),
- with mild or moderate hepatic impairment (see section 4.2),
- with inflammatory bowel disease,
- with type 2 diabetes and HbA1c < 8% for the 25 mg oral semaglutide,
- with type 2 diabetes on concomitant insulin for the 25 mg oral semaglutide.
Use with caution in these patients.

Excipient with known effect

Sodium

Wegovy 1.5 mg, 4 mg and 9 mg tablets contain less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Wegovy 25 mg tablets contain 23 mg sodium per tablet, equivalent to 1% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

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. The effect of semaglutide

7.2 mg on the rate of gastric emptying has not been investigated. Semaglutide should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption.

Paracetamol

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.

Oral contraceptives

Atorvastatin

Digoxin

Semaglutide did not change the overall exposure or Cmax of digoxin following a single dose of digoxin (0.5 mg).

Metformin

Semaglutide did not change the overall exposure or Cmax of metformin following dosing of 500 mg twice daily over 3.5 days.

Warfarin and other coumarin derivatives

Paediatric population

Interaction studies have only been performed in adults.

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Semaglutide delays gastric emptying which may influence the absorption of other oral medicinal products.

Effects of semaglutide on other medicinal products

Interactions with medicinal products with very low bioavailability (1%) have not been evaluated.

Effects of other medicinal products on semaglutide

Omeprazole
No clinically relevant change in AUC or Cmax of semaglutide was observed when taken with omeprazole.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Women of childbearing potential

Women of childbearing potential are recommended to use contraception when treated with semaglutide (see section 4.5).

Pregnancy

Breast-feeding

In lactating rats, semaglutide was excreted in milk. A risk to the newborns/infants cannot be excluded.
Wegovy should not be used during breast-feeding.

Fertility

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Women of childbearing potential

Women of childbearing potential are recommended to use contraception when treated with semaglutide (see section 4.5).

Pregnancy

Breast-feeding

No measurable concentrations of semaglutide were found in breast milk of lactating women.
Salcaprozate sodium was present in breast milk and some of its metabolites were excreted in breast milk at low concentrations. A risk to newborns/infants cannot be excluded. Wegovy should not be used during breast-feeding.

Fertility

4.7 Effects on ability to drive and use machines

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen · Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

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.

Patients with type 2 diabetes

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).

4.9 Overdose

Overdose with semaglutide may be associated with gastrointestinal disorders which could lead to dehydration. In the event of overdose the patient should be observed for clinical signs and appropriate supportive treatment initiated.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Pharmacotherapeutic group: Medicinal product used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ06

Mechanism of action

GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.

Animal studies show that semaglutide works in the brain through the GLP-1 receptor. Semaglutide has direct effects on areas in the brain involved in homeostatic regulation of food intake in the hypothalamus and the brainstem. Semaglutide may affect the hedonic reward system through direct and indirect effects in brain areas including the septum, thalamus and amygdala.

Clinical studies show that semaglutide reduces energy intake, increases feelings of satiety, fullness and control of eating, reduces feelings of hunger, and frequency and intensity of cravings. In addition, semaglutide reduces the preference for high fat foods.

Semaglutide orchestrates the homeostatic and hedonic contributions with executive function to regulate caloric intake, appetite, reward and food choice.

In addition, in clinical studies semaglutide have shown to reduce blood glucose in a glucose dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high.
The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys.
Semaglutide has a beneficial effect on plasma lipids, lowered systolic blood pressure and reduced inflammation in clinical studies. Furthermore, animal studies have shown that semaglutide attenuated the development of atherosclerosis and had an anti-inflammatory action in the cardiovascular system.

The mechanism of action of semaglutide for cardiovascular risk reduction is likely multifactorial, in part driven by weight loss effects and effects on known cardiovascular risk factors (reduction in blood pressure, improvements in lipid profile and glucose metabolism, and anti-inflammatory effects as demonstrated by reductions in high-sensitivity C-reactive protein (hsCRP)). The exact mechanism of cardiovascular risk reduction has not been established.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Pharmacotherapeutic group: Medicinal product used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ06.

Mechanism of action

GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.

Semaglutide orchestrates the homeostatic and hedonic contributions with executive function to regulate caloric intake, appetite, reward and food choice.

In addition, in clinical studies semaglutide has shown to reduce blood glucose in a glucose dependent manner by stimulating insulin secretion and lowering glucagon secretion when blood glucose is high.
The mechanism of blood glucose lowering also involves a minor delay in gastric emptying in the early postprandial phase. During hypoglycaemia, semaglutide diminishes insulin secretion and does not impair glucagon secretion.

Pharmacodynamic effects

Appetite, energy intake and food choice

Semaglutide reduces appetite by increasing feelings of fullness and satiety, while lowering hunger and prospective food consumption.

Fasting and postprandial lipids

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Applies to: Wegovy 0.25 mg solution for injection in pre-filled pen / Wegovy 0.5 mg solution for injection in pre-filled pen / Wegovy 1 mg solution for injection in pre-filled pen

Absorption

The average semaglutide steady state concentration following subcutaneous administration of the 2.4 mg and 7.2 mg semaglutide maintenance doses was approximately 75 nmol/L and 236 nmol/L, respectively, in patients with overweight (BMI ≥ 27 kg/m2 to < 30 kg/m2) or obesity (BMI ≥ 30 kg/m2) based on data from phase 3a trials, where 90% of patients had average concentrations between 51 nmol/L and 110 nmol/L and between 164 nmol/L and 332 nmol/L, respectively. The steady state exposure of semaglutide increased proportionally with doses from 0.25 mg up to 7.2 mg once weekly.
Steady state exposure was stable with time as assessed up to week 72. Similar exposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, or upper arm. The absolute bioavailability of semaglutide was 89%.

Distribution

The mean volume of distribution of semaglutide following subcutaneous administration in patients with overweight or obesity was approximately 12.4 L. Semaglutide is extensively bound to plasma albumin (> 99%).

Metabolism/biotransformation

Elimination

The primary excretion routes of semaglutide-related material are via the urine and faeces.
Approximately 3% of the absorbed dose was excreted in the urine as intact semaglutide.

Excerpt – full text in the original document. Original document (PDF, EMA)

Applies to: Wegovy 1.5 mg tablets / Wegovy 4 mg tablets / Wegovy 9 mg tablets

Absorption

The pharmacokinetic profile of orally administered semaglutide has been characterised in healthy people and patients with overweight or obesity using population PK modelling. Following oral administration, maximum plasma concentration of semaglutide occurred 1 hour post dose. The half- life of semaglutide is approximately 1 week indicating that steady-state exposure will be reached after 4-5 weeks of once-daily administration. Average predicted concentration was approximately 77 nmol/L with 90% of subjects treated with semaglutide 25 mg having an average concentration between 27 and 186 nmol/L.

The steady-state concentrations increased approximately proportionally with doses up to 25 mg once daily. The total within and between participant variability in AUC following oral semaglutide dosing was estimated at 166% after a single dose. In steady state conditions, the variability in AUC is reduced due to daily dosing and the long half-life of semaglutide, resulting in 68% total variability (33% within participant variability).

Based on in vitro data, salcaprozate sodium facilitates absorption of semaglutide. The absorption of semaglutide predominantly occurs in the stomach.

The estimated absolute bioavailability of semaglutide is approximately 1-2% following oral administration.

Absorption of orally administered semaglutide is decreased if taken with food or large volumes of water. Different dosing schedules of semaglutide have been investigated. Studies show that longer pre- and post-dose fasting period results in higher absorption.

Distribution

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.