RYBELSUS 3mg tablets medication leaflet

Rybelsus 1.5 mg tablets

Rybelsus 4 mg tablets

Rybelsus 9 mg tablets

Rybelsus 25 mg tablets

Rybelsus 50 mg tablets

Rybelsus 1.5 mg tablets

Each tablet contains 1.5 mg semaglutide*.

Rybelsus 4 mg tablets

Each tablet contains 4 mg semaglutide*.

Rybelsus 9 mg tablets

Each tablet contains 9 mg semaglutide*.

Rybelsus 25 mg tablets

Each tablet contains 25 mg semaglutide*.

Rybelsus 50 mg tablets

Each tablet contains 50 mg semaglutide*.

*human glucagon-like peptide-1 (GLP-1) analogue produced in Saccharomyces cerevisiae cells byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Tablet

Rybelsus 1.5 mg tablets

White to light yellow, round tablet (6.5 mm in diameter) debossed with ‘1.5’ on one side and ‘novo’on the other side.

Rybelsus 4 mg tablets

White to light yellow, round tablet (6.5 mm in diameter) debossed with ‘4’ on one side and ‘novo’ onthe other side.

Rybelsus 9 mg tablets

White to light yellow, round tablet (6.5 mm in diameter) debossed with ‘9’ on one side and ‘novo’ onthe other side.

Rybelsus 25 mg tablets

White to light yellow, oval shaped tablet (6.8 mm x 12 mm), debossed with ‘25’ on one side and‘novo’ on the other side.

Rybelsus 50 mg tablets

White to light yellow, oval shaped tablet (6.8 mm x 12 mm), debossed with ‘50’ on one side and‘novo’ on the other side.

Rybelsus is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitusto 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.

The starting dose of semaglutide is 1.5 mg once daily for one month. After one month, the dose shouldbe increased to a maintenance dose of 4 mg once daily. If needed, the dose can be escalated to the nexthigher dose after a minimum of one month on the current dose. The recommended single dailymaintenance 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 beused as one tablet per day. Taking more than one tablet a day should not be done to achieve the effectof a higher dose.

Switching from subcutaneous to oral semaglutide

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

Patients treated with subcutaneous semaglutide 0.5 mg once weekly can be transitioned to oralsemaglutide 4 mg or 9 mg once daily.

Patients treated with subcutaneous semaglutide 1 mg once weekly can be transitioned to oralsemaglutide 9 mg or 25 mg once daily.

Patients treated with subcutaneous semaglutide 2 mg once weekly can be transitioned to oralsemaglutide 25 mg or 50 mg once daily.

Patients can start oral semaglutide (Rybelsus) one week after their last dose of subcutaneoussemaglutide.

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

When semaglutide is used in combination with a sulfonylurea or with insulin, a reduction in the doseof sulfonylurea or insulin may be considered to reduce the risk of hypoglycaemia (see sections 4.4 and4.8).

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

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

No dose adjustment is required based on age.

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. Cautionshould be exercised when treating these patients with oral semaglutide (see section 5.2).

No dose adjustment is required for patients with hepatic impairment. Experience with the use ofsemaglutide in patients with severe hepatic impairment is limited. Caution should be exercised whentreating these patients with semaglutide (see section 5.2).

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

Rybelsus is a tablet for once-daily oral use.

- This medicinal product should be taken on an empty stomach after a recommended fastingperiod 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 to120 mL). Tablets should not be split, crushed or chewed, as it is not known whether this impactsabsorption of semaglutide.

- Patients should wait at least 30 minutes before eating, drinking or taking other oral medicinalproducts. Waiting less than 30 minutes decreases the absorption of semaglutide (see sections 4.5and 5.2).

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

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

Semaglutide should not be used for the treatment of diabetic ketoacidosis. Diabetic ketoacidosis hasbeen reported in insulin-dependent patients who had rapid discontinuation or dose reduction of insulinwhen 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

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonistsundergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastriccontent due to delayed gastric emptying (see section 4.8) should be considered prior to performingprocedures with general anaesthesia or deep sedation.

Gastrointestinal effects and dehydration

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This shouldbe considered when treating patients with impaired renal function, as nausea, vomiting, and diarrhoeamay cause dehydration, which in rare cases can lead to a deterioration of renal function (see section4.8). Patients treated with semaglutide should be advised of the potential risk of dehydration inrelation to gastrointestinal side effects and take precautions to avoid fluid depletion.

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should beinformed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, semaglutideshould be discontinued; if confirmed, semaglutide should not be restarted.

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

In patients with diabetic retinopathy treated with insulin and subcutaneous semaglutide, an increasedrisk of developing diabetic retinopathy complications has been observed, a risk that cannot beexcluded for orally administered semaglutide (see section 4.8). Caution should be exercised whenusing semaglutide in patients with diabetic retinopathy. These patients should be monitored closelyand treated according to clinical guidelines. Rapid improvement in glucose control has been associatedwith 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 withuncontrolled or potentially unstable diabetic retinopathy.

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Data from epidemiological studies indicates an increased risk for non-arteritic anterior ischaemic opticneuropathy (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 toophthalmological examination and treatment with semaglutide should be discontinued if NAION isconfirmed (see section 4.8).

Patients with gastroparesis

Semaglutide treated patients with gastroparesis may experience more serious or severe gastrointestinaladverse events. Semaglutide should be used with caution in these patients, and semaglutide is notrecommended if gastroparesis is severe (see section 4.8).

Compliance with the dosing regimen is recommended for optimal effect of semaglutide. If thetreatment response with semaglutide is lower than expected, the treating physician should be awarethat the absorption of semaglutide is highly variable and may be minimal (2-4% of patients will nothave any exposure), and that the absolute bioavailability of semaglutide is low.

Sodium content1.5 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.

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

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

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 reportedduring concomitant use of acenocoumarol and semaglutide. Upon initiation of semaglutide treatmentin patients on warfarin or other coumarin derivatives, frequent monitoring of INR is recommended.

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 notconsidered clinically relevant.

No clinically relevant change in AUC or Cmax of digoxin, oral contraceptives (containingethinylestradiol and levonorgestrel), metformin or furosemide was observed when concurrentlyadministered with semaglutide.

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

No clinically relevant change in AUC or Cmax of semaglutide was observed when taken withomeprazole.

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 multipletablets 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 oralmedicinal products (see section 4.2).

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

Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data from theuse 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).

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 breastmilk at low concentrations. As a risk to a breast-fed child cannot be excluded, Rybelsus should not beused during breast-feeding.

The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male fertilityin rats. In female rats, an increase in oestrous length and a small reduction in number of ovulationswere observed at doses associated with maternal body weight loss (see section 5.3).

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 bedone cautiously if dizziness occurs.

When it is used in combination with a sulfonylurea or insulin, patients should be advised to takeprecautions to avoid hypoglycaemia while driving and using machines (see section 4.4).

In 10 phase 3a trials, 5 707 patients were exposed to semaglutide alone or in combination with otherglucose-lowering medicinal products. The duration of the treatment ranged from 26 weeks to78 weeks. The most frequently reported adverse reactions in clinical trials were gastrointestinaldisorders, including nausea (very common), diarrhoea (very common) and vomiting (common).

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 apool of the phase 3a trials excluding the cardiovascular outcomes trial.

The reactions are listed below by system organ class and absolute frequency. Frequencies are definedas: 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 theavailable data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1 Frequency of adverse reactions of oral semaglutide

MedDRA Very Common Uncommon Rare Very Notsystem organ common Rare knownclass

Immune Hypersensitiv Anaphylacsystem ityc ticdisorders reaction

Metabolism Hypoglycae Hypoglycaeand mia when mia whennutrition used with used withdisorders insulin or other oralsulfonylurea antidiabetica productsa

Decreasedappetite

Nervous Dizziness Dysgeusiasystem Dysaesthesiadisorders e

Eye Diabetic Non-disorders retinopathy arteriticcomplication anteriorsb ischaemicopticneuropathy(NAION)

Cardiac Increaseddisorders heart rate

Gastrointesti Nausea Vomiting Eructation Acute Intestinalnal disorders Diarrhoea Abdominal Delayed pancreatiti obstructiopain gastric s nd,f

Abdominal emptyingdistension

Dyspepsia

Gastritis

Gastro-oesophageal

MedDRA Very Common Uncommon Rare Very Notsystem organ common Rare knownclassrefluxdisease

Flatulence

Hepatobiliar Cholelithiasisy disorders

General Fatiguedisordersandadministration siteconditions

Investigation Increased Weights lipase decreased

Increasedamylasea) 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, vitreoushaemorrhage and diabetes-related blindness (uncommon). Frequency is based on the cardiovascular outcomes trial withsubcutaneous semaglutide, but it cannot be excluded that the risk of diabetic retinopathy complications identified also appliesto 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 subheadingbelow 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’.

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/patientyear). Few episodes (0.1% of subjects, 0.001 events/patient year) were observed with semaglutide incombination with oral antidiabetics other than sulfonylurea.

Nausea occurred in 15%, diarrhoea in 10%, and vomiting in 7% of patients when treated withsemaglutide. Most events were mild to moderate in severity and of short duration. The events led totreatment discontinuation in 4% of subjects. The events were most frequently reported during the firstmonths on treatment.

In PIONEER PLUS when treated with semaglutide 25 mg and 50 mg nausea occurred in 27% and27%, diarrhoea in 13% and 14%, and vomiting in 17% and 18% of patients, respectively. These eventsled 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 frequentlyreported during dose escalation the first months on treatment.

Patients with gastroparesis may experience more serious or severe gastrointestinal effects when treatedwith 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 ofacute pancreatitis confirmed by adjudication was 0.1% for semaglutide and 0.2% for placebo (seesection 4.4.). In phase 3b cardiovascular outcomes trial SOUL, the frequency of acute pancreatitisconfirmed by adjudication was 0.4% for semaglutide and 0.4% for placebo.

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 thistrial, adjudicated events of diabetic retinopathy complications occurred in more patients treated withsubcutaneous semaglutide (3.0%) compared to placebo (1.8%). This was observed in insulin-treatedpatients with known diabetic retinopathy. The treatment difference appeared early and persistedthroughout the trial. Systematic evaluation of diabetic retinopathy complication was only performed inthe cardiovascular outcomes trial with subcutaneous semaglutide. In clinical trials with Rybelsus of upto 18 months duration involving 6 352 patients with type 2 diabetes, adverse events related to diabeticretinopathy were reported in similar proportions in subjects treated with semaglutide (4.2%) andcomparators (3.8%).

Non-arteritic anterior ischaemic optic neuropathy (NAION)

Results from several large epidemiological studies suggest that exposure to semaglutide in adults withtype 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.

Consistent with the potential immunogenic properties of medicinal products containing proteins orpeptides, patients may develop antibodies following treatment with semaglutide. The proportion ofsubjects 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 withneutralising effect on endogenous GLP-1 at end-of-trial.

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

Dysaesthesia

Events related to a clinical picture of altered skin sensation such as paraesthesia, pain of skin, sensitiveskin, dysaesthesia and burning skin sensation were reported in 2.1% and 5.2% of patients treated withoral semaglutide 25 mg and 50 mg, respectively. The events were mild to moderate in severity andmost patients recovered while on continued treatment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Effects of overdose with semaglutide in clinical studies may be associated with gastrointestinaldisorders. In the event of overdose, appropriate supportive treatment should be initiated according tothe patient’s clinical signs and symptoms. A prolonged period of observation and treatment of thesymptoms may be necessary, taking into account the long half-life of semaglutide of approximately1 week (see section 5.2). There is no specific antidote for overdose with semaglutide.

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

ATC code: A10BJ06

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts asa GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target fornative GLP-1.

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

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

Semaglutide reduces body weight and body fat mass through lowered energy intake, involving anoverall 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 hasa beneficial effect on plasma lipids, lowers systolic blood pressure and reduces inflammation inclinical studies. In animal studies, semaglutide attenuates the development of atherosclerosis bypreventing aortic plaque progression and reducing inflammation in the plaque.

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

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

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] forfasting glucose and 29% [19; 37] for postprandial glucose.

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].

Semaglutide causes a minor delay in early postprandial gastric emptying, with paracetamol exposure(AUC0-1h) 31% [13; 46] lower in the first hour after the meal, thereby reducing the rate at whichglucose appears in the circulation postprandially.

Semaglutide compared to placebo lowered fasting triglyceride and very-low-density lipoproteins(VLDL) cholesterol concentrations by 19% [8; 28] and 20% [5; 33], respectively. The postprandialtriglyceride and VLDL cholesterol response to a high fat meal was reduced by 24% [9; 36] and 21%[7; 32], respectively. ApoB48 was reduced both in fasting and postprandial state by 25% [2; 42] and30% [15; 43], respectively.

The efficacy and safety of Rybelsus have been evaluated in eight global randomised controlled phase3a trials. Phase 3a studies were conducted with tablets containing 3 mg, 7 mg and 14 mg semaglutidewhich are bioequivalent to 1.5 mg, 4 mg and 9 mg semaglutide, respectively. In seven trials, theprimary objective was the assessment of the glycaemic efficacy; in one trial (PIONEER 6), theprimary objective was the assessment of cardiovascular outcomes.

The trials included 8 842 randomised patients with type 2 diabetes (5 169 treated with semaglutide),including 1 165 patients with moderate renal impairment. Patients had an average age of 61 years(range 18 to 92 years), with 40% of patients ≥ 65 years of age and 8% ≥ 75 years of age. The efficacyof semaglutide was compared with placebo or active controls (sitagliptin, empagliflozin andliraglutide).

The efficacy and safety of semaglutide 25 mg and 50 mg once daily was evaluated in a phase 3b trial(PIONEER PLUS) including 1 606 randomised patients.

A phase 3b cardiovascular outcomes trial (SOUL) including 9 650 patients was conducted todemonstrate that oral semaglutide lowers the risk of major adverse cardiovascular events (MACE)compared to placebo in addition to standard of care, in patients with type 2 diabetes and establishedcardiovascular disease and/or chronic kidney disease.

The efficacy of semaglutide was not impacted by baseline age, gender, race, ethnicity, body weight,

BMI, diabetes duration, upper gastrointestinal disease and level of renal function.

PIONEER 1 - Monotherapy

In a 26-week double-blind trial, 703 patients with type 2 diabetes inadequately controlled with diet andexercise were randomised to semaglutide 3 mg, semaglutide 7 mg, semaglutide 14 mg or placebo oncedaily.

Table 2 Results of a 26-week monotherapy trial comparing semaglutide with placebo (PIONEER1)

Semaglutide Semaglutide Placebo7 mg2 14 mg2(Bioequivalent to 4 mg) (Bioequivalent to 9 mg)

Full analysis set (N) 175 175 178

HbA1c (%)

Baseline 8.0 8.0 7.9

Change from baseline1 ‑1.2 ‑1.4 ‑0.3

Difference from placebo1 [95% CI] ‑0.9 [‑1.1; ‑0.6]* ‑1.1 [‑1.3; ‑0.9]* -

Patients (%) achieving HbA1c < 7.0% 69§ 77§ 31

FPG (mmol/L)

Baseline 9.0 8.8 8.9

Change from baseline1 ‑1.5 ‑1.8 ‑0.2

Difference from placebo1 [95% CI] ‑1.4 [‑1.9; ‑0.8]§ ‑1.6 [‑2.1; ‑1.2]§ -

Body weight (kg)

Baseline 89.0 88.1 88.6

Change from baseline1 ‑2.3 ‑3.7 ‑1.4

Semaglutide Semaglutide Placebo7 mg2 14 mg2(Bioequivalent to 4 mg) (Bioequivalent to 9 mg)

Difference from placebo1 [95% CI] ‑0.9 [‑1.9; 0.1] ‑2.3 [‑3.1; ‑1.5]* -1 Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. 2 Bioequivalence has been confirmedbetween 4 mg and 7 mg doses, as well as, between 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER 2 - Semaglutide vs. empagliflozin, both in combination with metformin

In a 52-week open-label trial, 822 patients with type 2 diabetes were randomised to semaglutide 14 mgonce daily or empagliflozin 25 mg once daily, both in combination with metformin.

Table 3 Results of a 52-week trial comparing semaglutide with empagliflozin (PIONEER 2)

Semaglutide Empagliflozin14 mg2 25 mg(Bioequivalent to 9 mg)

Full analysis set (N) 411 410

Week 26

HbA1c (%)

Baseline 8.1 8.1

Change from baseline1 ‑1.3 ‑0.9

Difference from empagliflozin1 [95% CI] ‑0.4 [‑0.6; ‑0.3]* -

Patients (%) achieving HbA1c < 7.0% 67§ 40

FPG (mmol/L)

Baseline 9.5 9.7

Change from baseline1 ‑2.0 ‑2.0

Difference from empagliflozin1 [95% CI] 0.0 [‑0.2; 0.3] -

Body weight (kg)

Baseline 91.9 91.3

Change from baseline1 ‑3.8 ‑3.7

Difference from empagliflozin1 [95% CI] ‑0.1 [‑0.7; 0.5] -

Week 52

HbA1c (%)

Change from baseline1 ‑1.3 ‑0.9

Difference from empagliflozin1 [95% CI] ‑0.4 [‑0.5; ‑0.3]§ -

Patients (%) achieving HbA1c < 7.0% 66§ 43

Body weight (kg)

Change from baseline1 ‑3.8 ‑3.6

Difference from empagliflozin1 [95% CI] ‑0.2 [‑0.9; 0.5] -1 Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. 2 Bioequivalence has been confirmedbetween 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER 3 - Semaglutide vs. sitagliptin, both in combination with metformin or metformin withsulfonylurea

In a 78-week, double-blind, double-dummy trial, 1 864 patients with type 2 diabetes were randomisedto semaglutide 3 mg, semaglutide 7 mg, semaglutide 14 mg or sitagliptin 100 mg once daily, all incombination with metformin alone or metformin and sulfonylurea. Reductions in HbA1c and bodyweight were sustained throughout the trial duration of 78 weeks.

Table 4 Results of a 78-week trial comparing semaglutide with sitagliptin (PIONEER 3)

Semaglutide Semaglutide Sitagliptin7 mg2 14 mg2 100 mg(Bioequivalent to 4 mg) (Bioequivalent to 9 mg)

Full analysis set (N) 465 465 467

Week 26

HbA1c (%)

Baseline 8.4 8.3 8.3

Change from baseline1 ‑1.0 ‑1.3 ‑0.8

Difference from sitagliptin1 [95% CI] ‑0.3 [‑0.4; ‑0.1]* ‑0.5 [‑0.6; ‑0.4]* -

Patients (%) achieving HbA1c < 7.0% 44§ 56§ 32

FPG (mmol/L)

Baseline 9.4 9.3 9.5

Change from baseline1 ‑1.2 ‑1.7 ‑0.9

Difference from sitagliptin1 [95% CI] ‑0.3 [‑0.6; 0.0]§ ‑0.8 [‑1.1; ‑0.5]§ -

Body weight (kg)

Baseline 91.3 91.2 90.9

Change from baseline1 ‑2.2 ‑3.1 ‑0.6

Difference from sitagliptin1 [95% CI] ‑1.6 [‑2.0; ‑1.1]* ‑2.5 [‑3.0; ‑2.0]* -

Week 78

HbA1c (%)

Change from baseline1 ‑0.8 ‑1.1 ‑0.7

Difference from sitagliptin1 [95% CI] ‑0.1 [‑0.3; 0.0] ‑0.4 [‑0.6; ‑0.3]§ -

Patients (%) achieving HbA1c < 7.0% 39§ 45§ 29

Body weight (kg)

Change from baseline1 ‑2.7 ‑3.2 ‑1.0

Difference from sitagliptin1 [95% CI] ‑1.7 [‑2.3; ‑1.0]§ ‑2.1 [‑2.8; ‑1.5]§ -1 Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. 2 Bioequivalence has been confirmedbetween 4 mg and 7 mg doses, as well as, between 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER 4 - Semaglutide vs. liraglutide and placebo, all in combination with metformin ormetformin with an SGLT2 inhibitor

In a 52-week double-blind, double-dummy trial, 711 patients with type 2 diabetes were randomised tosemaglutide 14 mg, liraglutide 1.8 mg subcutaneous injection or placebo once daily, all incombination with metformin or metformin and an SGLT2 inhibitor.

Table 5 Results of a 52-week trial comparing semaglutide with liraglutide and placebo(PIONEER 4)

Semaglutide Liraglutide Placebo14 mg2 1.8 mg(Bioequivalent to 9 mg)

Full analysis set (N) 285 284 142

Week 26

HbA1c (%)

Baseline 8.0 8.0 7.9

Change from baseline1 ‑1.2 ‑1.1 ‑0.2

Difference from liraglutide1 [95% CI] ‑0.1 [‑0.3; 0.0] - -

Difference from placebo1 [95% CI] ‑1.1 [‑1.2; ‑0.9]* - -

Patients (%) achieving HbA1c < 7.0% 68§,a 62 14

FPG (mmol/L)

Baseline 9.3 9.3 9.2

Change from baseline1 ‑2.0 ‑1.9 ‑0.4

Difference from liraglutide1 [95% CI] ‑0.1 [‑0.4; 0.1] - -

Semaglutide Liraglutide Placebo14 mg2 1.8 mg(Bioequivalent to 9 mg)

Difference from placebo1 [95% CI] ‑1.6 [‑2.0; ‑1.3]§ - -

Body weight (kg)

Baseline 92.9 95.5 93.2

Change from baseline1 ‑4.4 ‑3.1 ‑0.5

Difference from liraglutide1 [95% CI] ‑1.2 [‑1.9; ‑0.6]* - -

Difference from placebo1 [95% CI] ‑3.8 [‑4.7; ‑3.0]* - -

Week 52

HbA1c (%)

Change from baseline1 ‑1.2 ‑0.9 ‑0.2

Difference from liraglutide1 [95% CI] ‑0.3 [‑0.5; ‑0.1]§ - -

Difference from placebo1 [95% CI] ‑1.0 [‑1.2; ‑0.8]§ - -

Patients (%) achieving HbA1c < 7.0% 61§,a 55 15

Body weight (kg)

Change from baseline1 ‑4.3 ‑3.0 ‑1.0

Difference from liraglutide1 [95% CI] ‑1.3 [‑2.1; ‑0.5]§ - -

Difference from placebo1 [95% CI] ‑3.3 [‑4.3; ‑2.4]§ - -1 Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. a vs placebo. 2 Bioequivalence has beenconfirmed between 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER 5 - Semaglutide vs. placebo, both in combination with basal insulin alone, metformin andbasal insulin or metformin and/or sulfonylurea, in patients with moderate renal impairment

In a 26-week double-blind trial, 324 patients with type 2 diabetes and moderate renal impairment(eGFR 30-59 mL/min/1.73 m2) were randomised to semaglutide 14 mg or placebo once daily. Trialproduct was added to the patient’s stable pre-trial antidiabetic regimen.

Table 6 Results of a 26-week trial comparing semaglutide with placebo in patients with type 2diabetes and moderate renal impairment (PIONEER 5)

Semaglutide Placebo14 mg2(Bioequivalent to 9 mg)

Full analysis set (N) 163 161

HbA1c (%)

Baseline 8.0 7.9

Change from baseline1 ‑1.0 ‑0.2

Difference from placebo1 [95% CI] ‑0.8 [‑1.0; ‑0.6]* -

Patients (%) achieving HbA1c < 7.0% 58§ 23

FPG (mmol/L)

Baseline 9.1 9.1

Change from baseline1 ‑1.5 ‑0.4

Difference from placebo1 [95% CI] ‑1.2 [‑1.7; ‑0.6]§ -

Body weight (kg)

Baseline 91.3 90.4

Change from baseline1 ‑3.4 ‑0.9

Difference from placebo1 [95% CI] ‑2.5 [‑3.2; ‑1.8]* -1 Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. 2 Bioequivalence has been confirmedbetween 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER 7 - Semaglutide vs. sitagliptin, both in combination with metformin, SGLT2 inhibitors,sulfonylurea or thiazolidinediones. Flexible-dose-adjustment trial

In a 52-week open-label trial, 504 patients with type 2 diabetes were randomised to semaglutide(flexible dose adjustment of 3 mg, 7 mg, and 14 mg once daily) or sitagliptin 100 mg once daily, all incombination with 1-2 oral glucose-lowering medicinal products (metformin, SGLT2 inhibitors,sulfonylurea or thiazolidinediones). The dose of semaglutide was adjusted every 8 weeks based onpatient’s glycaemic response and tolerability. The sitagliptin 100 mg dose was fixed. The efficacy andsafety of semaglutide were evaluated at week 52.

At week 52, the proportion of patients on treatment with semaglutide 3 mg, 7 mg and 14 mg wasapproximately 10%, 30% and 60%, respectively.

Table 7 Results of a 52-week flexible-dose-adjustment trial comparing semaglutide withsitagliptin (PIONEER 7)

Semaglutide Sitagliptin

Flexible dose2 100 mg

Full analysis set (N) 253 251

HbA1c (%)

Baseline 8.3 8.3

Patients (%) achieving HbA1c < 7.0%1 58* 25

Body weight (kg)

Baseline 88.9 88.4

Change from baseline1 ‑2.6 ‑0.7

Difference from sitagliptin1 [95% CI] ‑1.9 [‑2.6; ‑1.2]* -1 Irrespective of treatment discontinuation (16.6% of the patients with semaglutide flexible dose and 9.2% with sitagliptin,where 8.7% and 4.0%, respectively, were due to AEs) or initiation of rescue medication (pattern mixture model usingmultiple imputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity (for ‘Patients achieving

HbA1c < 7.0%’, the p-value is for the odds ratio). 2Bioequivalence has been confirmed between 1.5 mg and 3 mg, between4 mg and 7 mg and between 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER 8 - Semaglutide vs. placebo, both in combination with insulin with or without metformin

In a 52-week double-blind trial, 731 patients with type 2 diabetes inadequately controlled on insulin(basal, basal/bolus or premixed) with or without metformin were randomised to semaglutide 3 mg,semaglutide 7 mg, semaglutide 14 mg or placebo once daily.

Table 8 Results of a 52-week trial comparing semaglutide with placebo in combination withinsulin (PIONEER 8)

Semaglutide Semaglutide Placebo7 mg2 14 mg2(Bioequivalent to 4 mg) (Bioequivalent to 9 mg)

Full analysis set (N) 182 181 184

Week 26 (insulin dose capped to baselinelevel)

HbA1c (%)

Baseline 8.2 8.2 8.2

Change from baseline1 ‑0.9 ‑1.3 ‑0.1

Difference from placebo1 [95% CI] ‑0.9 [‑1.1; ‑0.7]* ‑1.2 [‑1.4; ‑1.0]* -

Patients (%) achieving HbA1c < 7.0% 43§ 58§ 7

FPG (mmol/L)

Baseline 8.5 8.3 8.3

Change from baseline1 ‑1.1 ‑1.3 0.3

Difference from placebo1 [95% CI] ‑1.4 [‑1.9; ‑0.8]§ ‑1.6 [‑2.2; ‑1.1]§ -

Body weight (kg)

Baseline 87.1 84.6 86.0

Change from baseline1 ‑2.4 ‑3.7 ‑0.4

Semaglutide Semaglutide Placebo7 mg2 14 mg2(Bioequivalent to 4 mg) (Bioequivalent to 9 mg)

Difference from placebo1 [95% CI] ‑2.0 [‑3.0; ‑1.0]* ‑3.3 [‑4.2; ‑2.3]* -

Week 52 (uncapped insulin dose)+

HbA1c (%)

Change from baseline1 ‑0.8 ‑1.2 ‑0.2

Difference from placebo1 [95% CI] ‑0.6 [‑0.8; ‑0.4]§ ‑0.9 [‑1.1; ‑0.7]§ -

Patients (%) achieving HbA1c < 7.0% 40§ 54§ 9

Body weight (kg)

Change from baseline1 ‑2.0 ‑3.7 0.5

Difference from placebo1 [95% CI] ‑2.5 [‑3.6; ‑1.4]§ ‑4.3 [‑5.3; ‑3.2]§ -1 Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. + The total daily insulin dose wasstatistically significantly lower with semaglutide than with placebo at week 52. 2 Bioequivalence has been confirmed between4 mg and 7 mg doses, as well as, between 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

PIONEER PLUS - Efficacy and safety of semaglutide 25 mg and 50 mg compared with semaglutide14 mg once daily in subjects with type 2 diabetes

In a 68-week double-blinded clinical trial 1 606 patients with type 2 diabetes on stable doses of 1-3oral anti-diabetic drugs (metformin, sulfonylureas, SGLT2 inhibitors or DPP-4 inhibitors*) wererandomized to receive maintenance doses of either semaglutide 14 mg, semaglutide 25 mg orsemaglutide 50 mg once daily.

*DPP-4 inhibitors were to be discontinued at randomisation.

Treatment with semaglutide 25 mg and 50 mg once daily was superior in reducing HbA1c and bodyweight compared to semaglutide 14 mg (see Table 9). Week 68 data support a sustained effect of oralsemaglutide 14 mg, 25 mg and 50 mg on HbA1c and body weight (see Figure 1).

Time since randomisation (weeks)

Time since randomisation (weeks)

Oral sema 14 mg Oral sema 25 mg Oral sema 50 mg Oral sema 14 mg Oral sema 25 mg Oral sema 50 mg

Figure 1 Mean HbA1c and mean body weight (kg) from baseline to week 68

Table 9 Results of a 52-week trial comparing semaglutide 25 mg and 50 mg with semaglutide14 mg (PIONEER PLUS)

Semaglutide Semaglutide Semaglutide14 mg2 25 mg 50 mg(Bioequivalentto 9 mg)

Full analysis set (N) 536 535 535

Week 52

HbA1c (%)

Baseline 8.9 9.0 8.9

Change from baseline1 ‑1.5 ‑1.8 ‑2.0

HbA1c (%)

Body Weight (kg)

Semaglutide Semaglutide Semaglutide14 mg2 25 mg 50 mg(Bioequivalentto 9 mg)

Difference from Rybelsus 14 mg 1 ‑0.27 [‑0.42; ‑0.12]* ‑0.53[95% CI] [‑0.68: ‑0.38]*

Patients (%) achieving HbA1c < 7.0% 39.0§ 50.5§ 63.0§

Patients (%) achieving HbA1c ≤ 6.5% 25.8§ 39.6§ 51.2§

FPG (mmol/L)

Baseline 10.8 11.0 10.8

Change from baseline1 ‑2.3 ‑2.8 ‑3.2

Difference from Rybelsus 14 mg 1 ‑0.46 [‑0.79; ‑0.13]§ ‑0.82 [‑1.15; ‑0.49]§[95% CI]

Body weight (kg)

Baseline 96.4 96.6 96.1

Change from baseline1 ‑4.4 ‑6.7 -8.0

Difference from Rybelsus 14 mg 1 ‑2.32 [‑3.11: ‑1.53]* ‑3.63[95% CI] [‑4.42; ‑2.84]*1Irrespective of treatment discontinuation or initiation of rescue medication (pattern mixture model using multipleimputation). * p< 0.001 (unadjusted 2-sided) for superiority, controlled for multiplicity. § p< 0.05, not controlled formultiplicity; for ‘Patients achieving HbA1c < 7.0%’, the p-value is for the odds ratio. 2 Bioequivalence has been confirmedbetween 9 mg and 14 mg doses, see section 5.2 Pharmacokinetic properties.

Cardiovascular outcomes

SOUL: Cardiovascular outcomes trial in patients with type 2 diabetes

In a double-blind, placebo-controlled, event driven trial, 9 650 patients, 50 years of age or older withtype 2 diabetes at high cardiovascular risk, defined as having established cardiovascular disease and/orchronic kidney disease, were randomised to either semaglutide 14 mg (bioequivalent to semaglutide9 mg) once-daily or placebo once daily added to standard of care.

In total, 5 468 patients (56.7%) had established cardiovascular disease without chronic kidney disease,1 241 (12.9%) had chronic kidney disease only and 2 620 (27.2%) had both cardiovascular disease andkidney disease. The mean age at baseline was 66.1 years, and 71.1% of the patients were men. Themean duration of diabetes was 15.4 years, the mean HbA1c was 8.0%, the mean BMI was 31.1 kg/m2,and the mean eGFR was 73.8 mL/min/1.73 m2. Medical history included stroke (15.4%), myocardialinfarction (40.0%), and peripheral artery disease (15.7%). At baseline, 26.9% of the patients weretreated with sodium-glucose cotransporter2 (SGLT2) inhibitors.

The primary endpoint was time from randomisation to first occurrence of a major adversecardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction, or non-fatalstroke. The primary endpoint, time to first MACE, occurred in 1 247 of the 9 650 included patients,579 first MACE (12.0%) were recorded among the 4 825 patients treated with semaglutide, comparedto 668 first MACE (13.8%) among the 4 825 patients treated with placebo.

Superiority of semaglutide versus placebo for MACE was confirmed with a hazard ratio of 0.86[0.77; 0.96] [95% CI], corresponding to a relative risk reduction in MACE of 14% (see Figure 2). Thereduction of MACE with semaglutide was consistent across subgroups of age, sex, race, ethnicity,

BMI at baseline, or level of kidney function impairment.

Analysis of the first composite kidney event (the first confirmatory secondary endpoint) resulted in ahazard ratio of 0.91 [0.80; 1.05] [95% CI].

Placebo

Oral Semaglutide

HR: 0.8695% CI [0.77 - 0.96]

Time from randomization (months)

Patients at risk

Oral Semaglutide

Placebo

Data from the in-trial period and based on full analysis set. Cumulative incidence estimates are based on time from randomisation to first

EAC-confirmed MACE with non-CV death modelled as competing risk using the Aalen-Johansen estimator. Subjects without events ofinterest were censored at the end of their in-trial observation period. Time from randomisation to first MACE was analysed using a Coxproportional hazards model with treatment as categorical fixed factor. The hazard ratio and confidence interval are adjusted for the groupsequential design using the likelihood ratio ordering.

CV: cardiovascular, EAC: event adjudication committee, MACE: major adverse cardiovascular event.

Figure 2: Time from randomisation to first MACE Cumulative incidence function plot

Patients with Event (%)

Number of events/analysed subjects

HR [95% CI] (Oral sema; Placebo)

Primary endpoint and components

Primary endpoint (MACE) 0.86 [0.77; 0.96] 579/4 825; 668/4 825

CV death 0.93 [0.80; 1.09] 301/4 825; 320/4 825

Non-fatal MI 0.74 [0.61; 0.89] 191/4 825; 253/4 825

Non-fatal stroke 0.88 [0.70; 1.11] 144/4 825; 161/4 825

Other secondary endpoints

Composite kidney event 0.91 [0.80; 1.05] 403/4 825; 435/4 825

MALE 0.71 [0.52; 0.96] 71/4 825; 99/4 825

All-cause death Favours Favoursplacebo 0.91 [0.80; 1.02] 528/4 825; 577/4 825sema0.6 0.8 1.0

Data from the in-trial period and based on full analysis set. Time from randomisation to each endpoint was analysed using a Cox proportionalhazards model with treatment as categorical fixed factor. Subjects without events of interest were censored at the end of their in-trial period.

For the primary endpoint the HR and CI were adjusted for the group sequential design using likelihood ratio ordering. CV death includesboth cardiovascular death and undetermined cause of death.

HR: hazard ratio CI: Confidence interval CV: cardiovascular, MI: myocardial infarction.

Composite kidney event: endpoint consisting of cardiovascular death, kidney death, onset of persistent ≥ 50% reduction in estimatedglomerular filtration rate (CKD-EPI) compared with baseline, onset of persistent eGFR (CKD-EPI) < 15 mL/min/1.73 m2 or initiation ofchronic kidney replacement therapy (dialysis or kidney transplantation).

MALE: major adverse limb events; composite endpoint consisting of acute or chronic limb ischemia hospitalisation.

Figure 3: Treatment effect for the primary endpoint, its components and other secondaryendpoints (SOUL)

PIONEER 6: Cardiovascular outcomes trial in patients with type 2 diabetes

In a double-blind trial (PIONEER 6), 3 183 patients, 50 years of age or older with type 2 diabetes athigh cardiovascular risk were randomised to semaglutide 14 mg (bioequivalent to semaglutide 9 mg)once daily or placebo in addition to standard-of-care. The median observation period was 16 months.

PIONEER 6 was a pre−approval CVOT designed to establish CV safety.

The primary endpoint was time from randomisation to first occurrence of a major adversecardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction or non-fatalstroke.

The total number of first MACE was 137: 61 (3.8%) with semaglutide and 76 (4.8%) with placebo.

The analysis of time to first MACE resulted in a HR of 0.79 [0.57; 1.11]95% CI.

By end-of-treatment, 27-65.7% of the patients had achieved a weight loss of ≥ 5% and 6-34.7% hadachieved a weight loss of ≥ 10% with semaglutide, compared with 12-39% and 2-8%, respectively,with the active comparators.

In the cardiovascular outcomes trial SOUL, a reduction in body weight from baseline to week 104 wasobserved with semaglutide vs. placebo, in addition to standard-of-care (‑4.22 kg vs. ‑1.27 kg).

Treatment with semaglutide had reduced systolic blood pressure by 2-7 mmHg.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Rybelsus in one or more subsets of the paediatric population in type 2 diabetes (see section 4.2 forinformation on paediatric use).

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 twoformulations 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 mg9 mg Equal effect to 14 mg

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

The pharmacokinetics of semaglutide have been extensively characterised in healthy subjects andpatients with type 2 diabetes. Following oral administration, maximum plasma concentration ofsemaglutide occurred approximately 1 hour post dose. Steady-state exposure was reached after4-5 weeks of once-daily administration. In patients with type 2 diabetes, the average steady-stateconcentrations were approximately as listed below:4 mg (bioequivalent to 7 mg): Average concentration was 7 nmol/L with 90% of subjects treated withsemaglutide 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 treatedwith 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 mghaving 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 mghaving an average concentration between 23 and 279 nmol/L.

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

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

The estimated bioavailability of semaglutide is approximately 1-2% following oral administration. Thebetween-subject variability in absorption was high (coefficient of variation was approximately 100%).

The estimation of the within-subject variability in bioavailability was not reliable.

Absorption of semaglutide is decreased if taken with food or large volumes of water. Different dosingschedules of semaglutide have been investigated. Studies show that longer pre- and post-dose fastingperiod results in higher absorption (see section 4.2).

The estimated absolute volume of distribution is approximately 8 L in subjects with type 2 diabetes.

Semaglutide is extensively bound to plasma proteins (> 99%).

Semaglutide is 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 beinvolved in the metabolism of semaglutide.

The primary excretion routes of semaglutide-related material are via the urine and faeces.

Approximately 3% of the absorbed dose is excreted as intact semaglutide via the urine.

With an elimination half-life of approximately 1 week, semaglutide will be present in the circulationfor about 5 weeks after the last dose. The clearance of semaglutide in patients with type 2 diabetes isapproximately 0.04 L/h.

Age had no effect on the pharmacokinetics of semaglutide based on data from clinical trials, whichstudied patients up to 92 years of age.

Gender had no clinically meaningful effects on the pharmacokinetics of semaglutide.

Race (White, Black or African-American, Asian) and ethnicity (Hispanic or Latino, not Hispanic or

Latino) had no clinically meaningful effect on the pharmacokinetics of semaglutide.

Body weight had an effect on the exposure of semaglutide. Higher body weight was associated withlower exposure. Semaglutide provided adequate systemic exposure over the body weight range of40-212 kg evaluated in the clinical trials.

Renal impairment did not impact the pharmacokinetics of semaglutide in a clinically relevant manner.

The pharmacokinetics of semaglutide were evaluated in patients with mild, moderate or severe renalimpairment and patients with end-stage renal disease on dialysis compared with subjects with normalrenal function in a study with 10 consecutive days of once-daily doses of semaglutide. This was alsoshown for subjects with type 2 diabetes and renal impairment based on data from phase 3a studies.

Hepatic impairment did not impact the pharmacokinetics of semaglutide in a clinically relevantmanner. The pharmacokinetics of semaglutide were evaluated in patients with mild, moderate orsevere hepatic impairment compared with subjects with normal hepatic function in a study with 10consecutive days of once-daily doses of semaglutide.

Upper GI tract disease (chronic gastritis and/or gastroesophageal reflux disease) did not impact thepharmacokinetics of semaglutide in a clinically relevant manner. The pharmacokinetics wereevaluated in patients with type 2 diabetes with or without upper GI tract disease dosed for 10consecutive days with once-daily doses of semaglutide. This was also shown for subjects with type 2diabetes and upper GI tract disease based on data from phase 3a studies.

Semaglutide has not been studied in paediatric patients.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity or genotoxicity.

Non-lethal thyroid C-cell tumours observed in rodents are a class effect for GLP-1 receptor agonists.

In 2-year carcinogenicity studies in rats and mice, semaglutide caused thyroid C-cell tumours atclinically relevant exposures. No other treatment-related tumours were observed. The rodent C-celltumours are caused by a non-genotoxic, specific GLP-1 receptor mediated mechanism to whichrodents are particularly sensitive. The relevance for humans is considered to be low, but cannot becompletely excluded.

In fertility studies in rats, semaglutide did not affect mating performance or male fertility. In femalerats, an increase in oestrous cycle length and a small reduction in corpora lutea (ovulations) wereobserved at doses associated with maternal body weight loss.

In embryo-foetal development studies in rats, semaglutide caused embryotoxicity below clinicallyrelevant exposures. Semaglutide caused marked reductions in maternal body weight and reductions inembryonic survival and growth. In foetuses, major skeletal and visceral malformations were observed,including effects on long bones, ribs, vertebrae, tail, blood vessels and brain ventricles. Mechanisticevaluations indicated that the embryotoxicity involved a GLP-1 receptor mediated impairment of thenutrient supply to the embryo across the rat yolk sac. Due to species differences in yolk sac anatomyand function, and due to the lack of GLP-1 receptor expression in the yolk sac of non-human primates,this mechanism is considered unlikely to be of relevance to humans. However, a direct effect ofsemaglutide on the foetus cannot be excluded.

In developmental toxicity studies in rabbits and cynomolgus monkeys, increased pregnancy loss andslightly increased incidence of foetal abnormalities were observed at clinically relevant exposures. Thefindings coincided with marked maternal body weight loss of up to 16%. Whether these effects arerelated to the decreased maternal food consumption as a direct GLP-1 effect is unknown.

Postnatal growth and development were evaluated in cynomolgus monkeys. Infants were slightlysmaller at delivery, but recovered during the lactation period.

In juvenile rats, semaglutide caused delayed sexual maturation in both males and females. Thesedelays had no impact upon fertility and reproductive capacity of either sex, or on the ability of thefemales to maintain pregnancy.

Salcaprozate sodium

Magnesium stearate

Not applicable.

3 years

Store in the original blister package in order to protect from light and moisture.

This medicinal product does not require any special temperature storage conditions.

Alu/Alu blisters.

Pack sizes of: 10, 30, 60, 90 and 100 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novo Nordisk A/S

Novo Allé

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Date of first authorisation: 03 April 2020

Date of latest renewal: 22 November 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu