OZEMPIC 1mg 1.34mg / ml injection for pre-filled pen medication leaflet

Ozempic 0.25 mg solution for injection in pre-filled pen

Ozempic 0.5 mg solution for injection in pre-filled pen

Ozempic 1 mg solution for injection in pre-filled pen

Ozempic 2 mg solution for injection in pre-filled pen

One ml of solution contains 1.34 mg of semaglutide*. One pre-filled pen contains 2 mg semaglutide*in 1.5 ml solution. Each dose contains 0.25 mg of semaglutide in 0.19 ml solution.

Ozempic 0.5 mg solution for injection1.5 mL: One ml aof solution contains 1.34 mg of semaglutide*. One pre-filled pen contains 2 mgsemaglutide* in 1.5 ml solution. Each dose contains 0.5 mg of semaglutide in 0.37 ml solution.

3 mL: One ml of solution contains 0.68 mg of semaglutide*. One pre-filled pen contains 2 mgsemaglutide* in 3 mL solution. Each dose contains 0.5 mg of semaglutide in 0.74 mL solution.

One ml of solution contains 1.34 mg of semaglutide*. One pre-filled pen contains 4 mg semaglutide*in 3 ml solution. Each dose contains 1 mg of semaglutide in 0.74 ml solution.

One ml of solution contains 2.68 mg of semaglutide*. One pre-filled pen contains 8 mg semaglutide*in 3 ml solution. Each dose contains 2 mg of semaglutide in 0.74 ml solution.

*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.

Solution for injection (injection).

Clear and colourless or almost colourless, isotonic solution; pH=7.4.

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

* as monotherapy when metformin is considered inappropriate due to intolerance orcontraindications

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

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

The starting dose is 0.25 mg semaglutide once weekly. After 4 weeks the dose should be increased to0.5 mg once weekly. After at least 4 weeks with a dose of 0.5 mg once weekly, the dose can beincreased to 1 mg once weekly to further improve glycaemic control. After at least 4 weeks with adose of 1 mg once weekly, the dose can be increased to 2 mg once weekly to further improveglycaemic control.

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

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 ofsulfonylurea or insulin should 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 Ozempic. Blood glucoseself-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when Ozempicis started and insulin is reduced. A stepwise approach to insulin reduction is recommended.

If a dose is missed, it should be administered as soon as possible and within 5 days after the misseddose. If more than 5 days have passed, the missed dose should be skipped, and the next dose should beadministered on the regularly scheduled day. In each case, patients can then resume their regular onceweekly dosing schedule.

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

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.

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 whentreating these patients with semaglutide (see section 5.2).

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

Subcutaneous use.

Ozempic is to be injected subcutaneously in the abdomen, in the thigh or in the upper arm. Theinjection site can be changed without dose adjustment. Ozempic should not be administeredintravenously 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.

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 in patients with type 1 diabetes mellitus or for the treatment ofdiabetic ketoacidosis. Semaglutide is not a substitute for insulin. Diabetic ketoacidosis has beenreported in insulin-dependent patients whom had rapid discontinuation or dose reduction of insulinwhen 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 istherefore not recommended in these patients.

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.

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 could cause a deterioration of renal function (see section 4.8).

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should beinformed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, semaglutide

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should be discontinued; if confirmed, semaglutide should not be restarted. Caution should be exercisedin patients with a history of pancreatitis.

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

In patients with diabetic retinopathy treated with insulin and semaglutide, an increased risk ofdeveloping diabetic retinopathy complications has been observed (see section 4.8). Caution should beexercised when using semaglutide in patients with diabetic retinopathy treated with insulin. Thesepatients should be monitored closely and treated according to clinical guidelines. Rapid improvementin glucose control has been associated with a temporary worsening of diabetic retinopathy, but othermechanisms cannot be excluded.

There is no experience with semaglutide 2 mg in patients with type 2 diabetes with uncontrolled orpotentially unstable diabetic retinopathy and semaglutide 2 mg is therefore not recommended in thesepatients.

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

Semaglutide delays gastric emptying and has the potential to impact the rate of absorption ofconcomitantly administered oral medicinal products. Semaglutide should be used with caution inpatients receiving oral medicinal products that require rapid gastrointestinal absorption.

Semaglutide delays the rate of gastric emptying as assessed by paracetamol pharmacokinetics during astandardised 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 observedwith semaglutide 2.4 mg, following 20 weeks of administration of semaglutide, probably due to atolerance effect. No dose adjustment of paracetamol is necessary when administered with semaglutide.

Semaglutide is not anticipated to decrease the effect of oral contraceptives as semaglutide did notchange the overall exposure of ethinylestradiol and levonorgestrel to a clinically relevant degree whenan oral contraceptive combination medicinal product (0.03 mg ethinylestradiol/0.15 mglevonorgestrel) 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 forany of the compounds.

Semaglutide did not change the overall exposure of atorvastatin following a single dose administrationof atorvastatin (40 mg). Atorvastatin Cmax was decreased by 38%. This was assessed not to beclinically relevant.

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

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

Semaglutide did not change the overall exposure or Cmax of R- and S-warfarin following a single doseof warfarin (25 mg), and the pharmacodynamic effects of warfarin as measured by the internationalnormalised 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 ofsemaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of

INR is recommended.

Women of childbearing potential are recommended to use contraception when treated 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 longhalf-life (see section 5.2).

In lactating rats, semaglutide was excreted in milk. As a risk to a breast-fed child cannot be excluded,semaglutide should not be used during breast-feeding.

The effect of semaglutide on fertility in humans is unknown. Semaglutide did not affect male 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 or use machines. When it is used incombination with a sulfonylurea or insulin, patients should be advised to take precautions to avoidhypoglycaemia while driving and using machines (see section 4.4).

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In 8 phase 3a trials 4 792 patients were exposed to semaglutide up to 1 mg. The most frequentlyreported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (verycommon), diarrhoea (very common) and vomiting (common). In general, these reactions were mild ormoderate in severity and of short duration.

Table 1 lists adverse reactions identified in all phase 3 trials (including the long-term cardiovascularoutcomes trial) and post-marketing reports in patients with type 2 diabetes mellitus (further describedin 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 cardiovascularoutcomes trial (see text below the table for additional details).

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); very rare: (<1/10 000) and not known: (cannot be estimated from availabledata). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 1 Frequency of adverse reactions of semaglutide

MedDRA Very common Common Uncommon Rare Not knownsystem organclass

Immune Hypersensitivityc Anaphy-system lacticdisorders reaction

Metabolism Hypoglycaemiaa Hypoglycaemiaaand nutrition when used with when used withdisorders insulin or other oralsulfonylurea antidiabetics(OAD)

Decreasedappetite

Nervous Dizziness Dysgeusiasystemdisorders

Eye disorders Diabeticretinopathycomplicationsb

Cardiac Increased heartdisorders rate

Gastrointesti- Nausea Vomiting Acute pancreatitis Intestinalnal disorders Diarrhoea Abdominal pain Delayed gastric obstructiond

Abdominal emptyingdistension

Dyspepsia

Gastritis

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MedDRA Very common Common Uncommon Rare Not knownsystem organclass

Gastro-oesophagealreflux disease

Eructation

Flatulence

Hepatobiliary Cholelithiasisdisorders

Skin and Angioedemadsubcutaneoustissuedisorders

General Fatigue Injection sitedisorders and reactionsadministra-tion siteconditions

Investigations Increased lipase

Increasedamylase

Weightdecreaseda) Hypoglycaemia defined as severe (requiring the assistance of another person) or symptomatic in combinationwith a blood glucose <3.1 mmol/L.b) Diabetic retinopathy complications is a composite of: retinal photocoagulation, treatment with intravitrealagents, vitreous haemorrhage, diabetes-related blindness (uncommon). Frequency based on cardiovascularoutcomes trial.c) Grouped term covering also adverse events related to hypersensitivity such as rash and urticaria.d) From post-marketing reports.

In cardiovascular high risk population the adverse reaction profile was similar to that seen in the otherphase 3a trials (described in section 5.1).

No episodes of severe hypoglycaemia were observed when semaglutide was used as monotherapy.

Severe hypoglycaemia was primarily observed when semaglutide was used with a sulfonylurea (1.2%of subjects, 0.03 events/patient year) or insulin (1.5% of subjects, 0.02 events/patient year). Fewepisodes (0.1% of subjects, 0.001 events/patient year) were observed with semaglutide in combinationwith 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. Severehypoglycaemia 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 thehypoglycaemic episodes (45 out of 49 episodes) occurred when semaglutide was used in combinationwith sulfonylurea or insulin. Overall, there was no increased risk of hypoglycaemia with semaglutide2 mg.

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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 tomoderate 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 withsemaglutide.

In a 40-week phase 3b trial in patients receiving semaglutide 1 mg and 2 mg, nausea occurred insimilar proportions of patients when treated with semaglutide 1 mg and 2 mg, respectively. Diarrhoeaand vomiting occurred in higher proportions of patients when treated with semaglutide 2 mg comparedto semaglutide 1 mg. The gastrointestinal adverse reactions led to treatment discontinuation in similarproportions in the semaglutide 1 mg and 2 mg treatment groups.

In concomitant use with an SGLT2 inhibitor in SUSTAIN 9, constipation and gastro-oesophagealreflux disease occurred in 6.7% and 4% respectively of patients treated with semaglutide 1 mgcompared to no events for placebo-treated patients. The prevalence of these events did not decreaseover time.

The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was0.3% for semaglutide and 0.2% for the comparator, respectively. In the 2-year cardiovascularoutcomes trial the frequency of acute pancreatitis confirmed by adjudication was 0.5% for semaglutideand 0.6% for placebo (see section 4.4).

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 ofdiabetic retinopathy complications occurred in more patients treated with semaglutide (3%) comparedto placebo (1.8%). This was observed in insulin-treated patients with known diabetic retinopathy. Thetreatment difference appeared early and persisted throughout the trial. Systematic evaluation ofdiabetic retinopathy complication was only performed in the cardiovascular outcomes trial. In clinicaltrials up to 1 year involving 4 807 patients with type 2 diabetes, adverse events related to diabeticretinopathy were reported in similar proportions of subjects treated with semaglutide (1.7%) andcomparators (2.0%).

The incidence of discontinuation of treatment due to adverse events was 6.1% and 8.7% for patientstreated with semaglutide 0.5 mg and 1 mg, respectively, versus 1.5% for placebo. The most frequentadverse events leading to discontinuation were gastrointestinal.

Injection site reactions (e.g. injection site rash, erythema) have been reported by 0.6% and 0.5% ofpatients receiving semaglutide 0.5 mg and 1 mg, respectively. These reactions have usually been mild.

Consistent with the potentially immunogenic properties of medicinal products containing proteins orpeptides, patients may develop antibodies following treatment with semaglutide. The proportion ofpatients tested positive for anti-semaglutide antibodies at any time point post-baseline was low (1−3%)and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies withendogenous GLP-1 neutralising effect at end-of-trial.

Increased heart rate has been observed with GLP-1 receptor agonists. In the phase 3a trials, meanincreases of 1 to 6 beats per minute (bpm) from a baseline of 72 to 76 bpm were observed in subjects

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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 onplacebo after 2 years of 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.

Overdoses of up to 4 mg in a single dose, and up to 4 mg in a week have been reported in clinicaltrials. The most commonly reported adverse reaction was nausea. All patients recovered withoutcomplications.

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

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATCcode: 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, in thecardiovascular system and in the kidneys. The glucose and appetite effects are specifically mediatedvia GLP-1 receptors 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.

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 also expressed in the heart, vasculature, immune system and kidneys. Themechanism of action of semaglutide is likely multifactorial. Indirect effects are indicated by thebeneficial effect of semaglutide on plasma lipids, lowered systolic blood pressure and reducedinflammation in clinical studies but direct effects are likely also involved. In animal studies,semaglutide attenuates the development of atherosclerosis by preventing aortic plaque progression andreducing inflammation in the plaque.

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

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

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 frombaseline (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 glucoseconcentration (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.

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

Semaglutide lowers the fasting and postprandial glucagon concentrations. In patients with type 2diabetes, semaglutide resulted in the following relative reductions in glucagon compared to placebo:fasting glucagon (8-21%), postprandial glucagon response (14-15%) and mean 24 hour glucagonconcentration (12%).

Semaglutide lowered high blood glucose concentrations by stimulating insulin secretion and loweringglucagon secretion in a glucose dependent manner. With semaglutide, the insulin secretion rate inpatients with type 2 diabetes was comparable to that of healthy subjects.

During induced hypoglycaemia, semaglutide compared to placebo did not alter the counter regulatoryresponses of increased glucagon and did not impair the decrease of C-peptide in patients with type2-diabetes.

Semaglutide caused a minor delay of early postprandial gastric emptying, thereby reducing the rate atwhich glucose appears in the circulation postprandially.

Semaglutide compared to placebo lowered the energy intake of 3 consecutive ad libitum meals by18-35%. This was supported by a semaglutide-induced suppression of appetite in the fasting state aswell as postprandially, improved control of eating, less food cravings and a relative lower preferencefor high fat food.

Semaglutide compared to placebo lowered fasting triglyceride and very low density lipoproteins(VLDL) cholesterol concentrations by 12% and 21%, respectively. The postprandial triglyceride and

VLDL cholesterol response to a high fat meal was reduced by >40%.

The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. Semaglutidedid not prolong QTc intervals at dose levels up to 1.5 mg at steady state.

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Improvement of glycaemic control, reduction of cardiovascular morbidity and mortality, weight lossand risk reduction of chronic kidney disease progression are integral parts of the treatment of type 2diabetes.

The efficacy and safety of semaglutide 0.5 mg and 1 mg once weekly were evaluated in sixrandomised controlled phase 3a trials that included 7 215 patients with type 2 diabetes mellitus(4 107 treated with semaglutide). Five trials (SUSTAIN 1-5) had the glycaemic efficacy assessment asthe primary objective, while one trial (SUSTAIN 6) had cardiovascular outcome as the primaryobjective.

The efficacy and safety of semaglutide 2 mg once weekly was evaluated in a phase 3b trial (SUSTAIN

FORTE) including 961 patients.

In addition, a phase 3b trial (SUSTAIN 7) including 1 201 patients was conducted to compare theefficacy and safety of semaglutide 0.5 mg and 1 mg once weekly to dulaglutide 0.75 mg and 1.5 mgonce weekly, respectively. A phase 3b trial (SUSTAIN 9), was conducted to investigate the efficacyand safety of semaglutide as add-on to SGLT2 inhibitor treatment.

Treatment with semaglutide demonstrated sustained, statistically superior and clinically meaningfulreductions in HbA1c and body weight for up to 2 years compared to placebo and active controltreatment (sitagliptin, insulin glargine, exenatide ER and dulaglutide).

The efficacy of semaglutide was not impacted by age, gender, race, ethnicity, BMI at baseline, bodyweight (kg) at baseline, diabetes duration and level of renal function impairment.

Results target the on-treatment period in all randomised subjects (analyses based on mixed models forrepeated measurements or multiple imputation).

In addition, a phase 3b trial (SUSTAIN 11), was conducted to investigate the effect of semaglutideversus insulin aspart, both as add-on to metformin and optimised insulin glargine (U100).

A phase 3b kidney outcomes trials (FLOW) including 3 533 patients was conducted to investigate theeffects of semaglutide 1 mg once weekly versus placebo on the progression of kidney impairment inpatients with type 2 diabetes and chronic kidney disease.

Detailed information is provided below.

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SUSTAIN 1 - Monotherapy

In a 30-week double-blind placebo-controlled trial, 388 patients inadequately controlled with diet andexercise, were randomised to semaglutide 0.5 mg or semaglutide 1 mg once weekly or placebo.

Table 2 SUSTAIN 1: Results at week 30

Semaglutide Semaglutide Placebo0.5 mg 1 mg

Intent-to-Treat (ITT) Population (N) 128 130 129

HbA1c (%)

Baseline (mean) 8.1 8.1 8.0

Change from baseline at week 30 -1.5 -1.6 0

Difference from placebo [95% -1.4 [-1.7, -1.1]a -1.5 [-1.8, -1.2]a -

CI]

Patients (%) achieving HbA1c <7% 74 72 25

FPG (mmol/L)

Baseline (mean) 9.7 9.9 9.7

Change from baseline at week 30 -2.5 -2.3 -0.6

Body weight (kg)

Baseline (mean) 89.8 96.9 89.1

Change from baseline at week 30 -3.7 -4.5 -1.0

Difference from placebo [95% -2.7 [-3.9, -1.6]a -3.6 [-4.7, -2.4]a -

CI]ap <0.0001 (2-sided) for superiority

SUSTAIN 2 - Semaglutide vs. sitagliptin both in combination with 1-2 oral antidiabetic medicinalproducts (metformin and/or thiazolidinediones)

In a 56-week active-controlled double-blind trial, 1 231 patients were randomised to semaglutide0.5 mg once weekly, semaglutide 1 mg once weekly or sitagliptin 100 mg once daily, all incombination with metformin (94%) and/or thiazolidinediones (6%).

Table 3 SUSTAIN 2: Results at week 56

Semaglutide Semaglutide Sitagliptin0.5 mg 1 mg 100 mg

Intent-to-Treat (ITT) Population (N) 409 409 407

HbA1c (%)

Baseline (mean) 8.0 8.0 8.2

Change from baseline at week 56 -1.3 -1.6 -0.5

Difference from sitagliptin [95% -0.8 [-0.9, -0.6]a -1.1 [-1.2, -0.9]a -

CI]

Patients (%) achieving HbA1c <7% 69 78 36

FPG (mmol/L)

Baseline (mean) 9.3 9.3 9.6

Change from baseline at week 56 -2.1 -2.6 -1.1

Body weight (kg)

Baseline (mean) 89.9 89.2 89.3

Change from baseline at week 56 -4.3 -6.1 -1.9

Difference from sitagliptin [95% -2.3 [-3.1, -1.6]a -4.2 [-4.9, -3.5]a -

CI]ap <0.0001 (2-sided) for superiority

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Time since randomisation (week) Time since randomisation (week)

Semaglutide 0.5 mg Semaglutide 1 mg Semaglutide 0.5 mg Semaglutide 1 mg

Sitagliptin Sitagliptin

Figure 1 Mean change in HbA1c (%) and body weight (kg) from baseline to week 56

SUSTAIN 7 - Semaglutide vs. dulaglutide both in combination with metformin

In a 40-week, open-label trial, 1 201 patients on metformin were randomised 1:1:1:1 to once weeklysemaglutide 0.5 mg, dulaglutide 0.75 mg, semaglutide 1 mg or dulaglutide 1.5 mg, respectively .

The trial compared 0.5 mg of semaglutide to 0.75 mg of dulaglutide and 1 mg of semaglutide to1.5 mg of dulaglutide.

Gastrointestinal disorders were the most frequent adverse events, and occurred in similar proportion ofpatients receiving semaglutide 0.5 mg (129 patients [43%]), semaglutide 1 mg (133 [44%]), anddulaglutide 1.5 mg (143 [48%]); fewer patients had gastrointestinal disorders with dulaglutide 0.75 mg(100 [33%]).

At week 40, the increase in pulse rate for semaglutide (0.5 mg and 1 mg) and dulaglutide (0.75 mg and1.5 mg) was 2.4, 4.0, and 1.6, 2.1, beats/min, respectively.

Table 4 SUSTAIN 7: Results at week 40

Semaglutide Semaglutide Dulaglutide Dulaglutide0.5 mg 1 mg 0.75 mg 1.5 mg

Intent-to-Treat (ITT) 301 300 299 299

Population(N)

HbA1c (%)

Baseline (mean) 8.3 8.2 8.2 8.2

Change from baseline at week 40 -1.5 -1.8 -1.1 -1.4

Difference from dulaglutide -0.4b -0.4c - -[95% CI] [-0.6, -0.2]a [-0.6, -0.3]a

Patients (%) achieving HbA1c <7% 68 79 52 67

FPG (mmol/L)

Baseline (mean) 9.8 9.8 9.7 9.6

Change from baseline at week 40 -2.2 -2.8 -1.9 -2.2

Body weight (kg)

Baseline (mean) 96.4 95.5 95.6 93.4

Change from baseline at week 40 -4.6 -6.5 -2.3 -3.0

Difference from dulaglutide -2.3b -3.6c - -[95% CI] [-3.0, -1.5]a [-4.3, -2.8]aap <0.0001 (2-sided) for superiorityb semaglutide 0.5 mg vs dulaglutide 0.75 mgc semaglutide 1 mg vs dulaglutide 1.5 mg

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HbA1c (%)

Change from baseline

Body weight (kg)

Change from baseline... . . .

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Time since randomisation (week) Time since randomisation (week)

Semaglutide 0.5 mg Semaglutide 1 mg Semaglutide 0.5 mg Semaglutide 1 mg

Dulaglutide 0.75 mg Dulaglutide 1.5 mg Dulaglutide 0.75 mg Dulaglutide 1.5 mg

Figure 2 Mean change in HbA1c (%) and body weight (kg) from baseline to week 40

SUSTAIN 3 - Semaglutide vs. exenatide ER both in combination with metformin or metformin withsulfonylurea

In a 56-week open-label trial, 813 patients on metformin alone (49%), metformin with sulfonylurea(45%) or other (6%) were randomised to semaglutide 1 mg or exenatide ER 2 mg once weekly.

Table 5 SUSTAIN 3: Results at week 56

Semaglutide Exenatide ER1 mg 2 mg

Intent-to-Treat (ITT) Population (N) 404 405

HbA1c (%)

Baseline (mean) 8.4 8.3

Change from baseline at week 56 -1.5 -0.9

Difference from exenatide [95% CI] -0.6 [-0.8, -0.4]a -

Patients (%) achieving HbA1c <7% 67 40

FPG (mmol/L)

Baseline (mean) 10.6 10.4

Change from baseline at week 56 -2.8 -2.0

Body weight (kg)

Baseline (mean) 96.2 95.4

Change from baseline at week 56 -5.6 -1.9

Difference from exenatide [95% CI] -3.8 [-4.6, -3.0]a -ap <0.0001 (2-sided) for superiority

SUSTAIN 4 - Semaglutide vs. insulin glargine both in combination with 1-2 oral antidiabeticmedicinal products (metformin or metformin and sulfonylurea)

In a 30-week open-label comparator trial 1 089 patients were randomised to semaglutide 0.5 mg onceweekly, semaglutide 1 mg once weekly, or insulin glargine once-daily on a background of metformin(48%) or metformin and sulfonylurea (51%).

Table 6 SUSTAIN 4: Results at week 30

Semaglutide Semaglutide Insulin0.5 mg 1 mg Glargine

Intent-to-Treat (ITT) Population (N) 362 360 360

HbA1c (%)

Baseline (mean) 8.1 8.2 8.1

Change from baseline at week 30 -1.2 -1.6 -0.8

Difference from insulin glargine [95% CI] -0.4 [-0.5, -0.2]a -0.8 [-1.0, -0.7]a -

Patients (%) achieving HbA1c <7% 57 73 38

FPG (mmol/L)

VV-LAB-123016 1.0 .

HbA1c (%)

Change from baseline

Body weight (kg)

Change from baseline

Semaglutide Semaglutide Insulin0.5 mg 1 mg Glargine

Baseline (mean) 9.6 9.9 9.7

Change from baseline at week 30 -2.0 -2.7 -2.1

Body weight (kg)

Baseline (mean) 93.7 94.0 92.6

Change from baseline at week 30 -3.5 -5.2 +1.2

Difference from insulin glargine [95% CI] -4.6 [-5.3, -4.0]a -6.34 [-7.0, -5.7]a -ap <0.0001 (2-sided) for superiority

SUSTAIN 5 - Semaglutide vs. placebo both in combination with basal insulin

In a 30-week double-blind placebo-controlled trial, 397 patients inadequately controlled with basalinsulin with or without metformin were randomised to semaglutide 0.5 mg once weekly, semaglutide1 mg once weekly or placebo.

Table 7 SUSTAIN 5: Results at week 30

Semaglutide Semaglutide Placebo0.5 mg 1 mg

Intent-to-Treat (ITT) Population (N) 132 131 133

HbA1c (%)

Baseline (mean) 8.4 8.3 8.4

Change from baseline at week 30 -1.4 -1.8 -0.1

Difference from placebo [95% -1.4 [-1.6, -1.1]a -1.8 [-2.0, -1.5]a -

CI]

Patients (%) achieving HbA1c <7% 61 79 11

FPG (mmol/L)

Baseline (mean) 8.9 8.5 8.6

Change from baseline at week 30 -1.6 -2.4 -0.5

Body weight (kg)

Baseline (mean) 92.7 92.5 89.9

Change from baseline at week 30 -3.7 -6.4 -1.4

Difference from placebo [95% -2.3 [-3.3, -1.3]a -5.1 [-6.1, -4.0]a -

CI]ap <0.0001 (2-sided) for superiority

SUSTAIN FORTE - Semaglutide 2 mg vs. semaglutide 1 mg

In a 40-week double-blind trial, 961 patients inadequately controlled with metformin with or withoutsulfonylurea were randomised to semaglutide 2 mg once weekly or semaglutide 1 mg once weekly.

Treatment with semaglutide 2 mg resulted in a statistically superior reduction in HbA1c after 40 weeksof treatment compared to semaglutide 1 mg.

Table 8 SUSTAIN FORTE: Results at week 40

Semaglutide Semaglutide1 mg 2 mg

Intent-to-Treat (ITT) Population (N) 481 480

HbA1c (%)

Baseline (mean) 8.8 8.9

Change from baseline at week 40 -1.9 -2.2

Difference from semaglutide 1 mg - -0.2 [-0.4, -0.1]a[95% CI]

Patients (%) achieving HbA1c <7% 58 68

FPG (mmol/L)

Baseline (mean) 10.9 10.7

VV-LAB-123016 1.0 .

Semaglutide Semaglutide1 mg 2 mg

Change from baseline at week 40 -3.1 -3.4

Body weight (kg)

Baseline (mean) 98.6 100.1

Change from baseline at week 40 -6.0 -6.9

Difference from semaglutide 1 mg -0.9 [-1.7, -0.2]b[95% CI]ap<0.001 (2-sided) for superioritybp<0.05 (2-sided) for superiority

SUSTAIN 9 - Semaglutide vs. placebo as add-on to SGLT2 inhibitor ± metformin or sulfonylurea

In a 30-week double-blind placebo-controlled trial, 302 patients inadequately controlled with SGLT2inhibitor with or without metformin or sulfonylurea were randomised to semaglutide 1 mg onceweekly or placebo.

Table 9 SUSTAIN 9: Results at week 30

Semaglutide Placebo1 mg

Intent-to-Treat (ITT) Population (N) 151 151

HbA1c (%)

Baseline (mean) 8.0 8.1

Change from baseline at week 30 -1.5 -0.1

Difference from placebo [95% CI] -1.4 [-1.6, -1.2]a -

Patients (%) achieving HbA1c <7% 78.7 18.7

FPG (mmol/L)

Baseline (mean) 9.1 8.9

Change from baseline at week 30 -2.2 0.0

Body weight (kg)

Baseline (mean) 89.6 93.8

Change from baseline at week 30 -4.7 -0.9

Difference from placebo [95% CI] -3.8 [-4.7, -2.9]a -ap < 0.0001 (2-sided) for superiority, adjusted regarding multiplicity based on hierarchical testing of the HbA1cvalue and body weight

SUSTAIN 11 - Semaglutide vs. insulin aspart as add-on to insulin glargine + metformin

In a 52-week open-label trial, 1748 subjects with inadequately controlled T2D after a 12-week run-inperiod on insulin glargine and metformin were randomised to 1:1 to receive either semaglutide once-weekly (0.5 mg or 1.0 mg) or insulin aspart three times daily. The included population had a meandiabetes duration of 13.4 years and a mean HbA1c of 8.6%, with a target HbA1c of 6.5-7.5%.

Treatment with semaglutide resulted in reduction in HbA1c at week 52 (-1.5% for semaglutide vs. -1.2% for insulin aspart).

The number of severe hypoglycaemic episodes in both treatment arms was low (4 episodes withsemaglutide vs. 7 episodes with insulin aspart).

Mean baseline body weight decreased with semaglutide (-4.1 kg) and increased with insulin aspart(+2.8 kg) and the estimated treatment difference was -6.99 kg (95%CI -7.41 to -6.57) at week 52.

In SUSTAIN 6 (see subsection “Cardiovascular disease”) 123 patients were on sulfonylureamonotherapy at baseline. HbA1c at baseline was 8.2%, 8.4% and 8.4% for semaglutide 0.5 mg,

VV-LAB-123016 1.0 .

semaglutide 1 mg, and placebo, respectively. At week 30, the change in HbA1c was -1.6%, -1.5% and0.1% for semaglutide 0.5 mg, semaglutide 1 mg, and placebo, respectively.

Combination with premix insulin ± 1-2 OADs

In SUSTAIN 6 (see subsection “Cardiovascular disease”) 867 patients were on premix insulin (with orwithout OAD(s)) at baseline. HbA1c at baseline was 8.8%, 8.9% and 8.9% for semaglutide 0.5 mg,semaglutide 1 mg, and placebo, respectively. At week 30, the change in HbA1c was -1.3%, -1.8% and -0.4% for semaglutide 0.5 mg, semaglutide 1 mg, and placebo, respectively.

In a 104-week double-blind trial (SUSTAIN 6), 3 297 patients with type 2 diabetes mellitus at highcardiovascular risk were randomised to either semaglutide 0.5 mg once weekly, semaglutide 1 mgonce weekly or corresponding placebo in addition to standard-of-care hereafter followed for 2 years.

In total 98% of the patients completed the trial and the vital status was known at the end of the trial for99.6% of the patients.

The trial population was distributed by age as: 1 598 patients (48.5%) ≥65 years, 321 (9.7%)≥75 years, and 20 (0.6%) ≥85 years. There were 2 358 patients with normal or mild renal impairment,832 with moderate and 107 with severe or end stage renal impairment. There were 61% males, themean age was 65 years and mean BMI was 33 kg/m2. The mean duration of diabetes was 13.9 years.

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 primary component MACE endpoints was 254, including 108 (6.6%) withsemaglutide and 146 (8.9%) with placebo. See figure 4 for results on primary and secondarycardiovascular endpoints. Treatment with semaglutide resulted in a 26% risk reduction in the primarycomposite outcome of death from cardiovascular causes, non-fatal myocardial infarction or non-fatalstroke. The total numbers of cardiovascular deaths, non-fatal myocardial infarctions and non-fatalstrokes were 90, 111, and 71, respectively, including 44 (2.7%), 47 (2.9%), and 27 (1.6%),respectively, with semaglutide (figure 4). The risk reduction in the primary composite outcome wasmainly driven by decreases in the rate of non-fatal stroke (39%) and non-fatal myocardial infarction(26%) (figure 3).

HR: 0.7495% CI 0.58: 0.95

Number of subjects at risk

Semaglutide

Placebo

Time from randomisation (week)

Semaglutide Placebo

VV-LAB-123016 1.0 .

Patients with event (%)

Figure 3 Kaplan-Meier plot of time to first occurrence of the composite outcome: cardiovasculardeath, non-fatal myocardial infarction or non-fatal stroke (SUSTAIN 6)

Hazard Ratio Semaglutide Placebo(95% CI) N (%) N (%)

FAS 1648 1649(100) (100)0.74

Primary endpoint - MACE 108 146(0.58- 0.95) (6.6) (8.9)

Components of MACE

Cardiovascular death 0.98 44(0.65-1.48) (2.7) (2.8)0.61 27 44

Non-fatal stroke (0.38-0.99) (1.6) (2.7)

Non-fatal myocardial infarction 0.74 47 64(0.51-1.08) (2.9) (3.9)

Other secondary endpoints1.05 62 60

All cause death (0.74-1.50) (3.8) (3.6)0.2 1 5

Favours Semaglutide Favours placebo

Figure 4 Forest plot: analyses of time to first occurrence of the composite outcome, itscomponents and all cause death (SUSTAIN 6)

There were 158 events of new or worsening nephropathy. The hazard ratio [95% CI] for time tonephropathy (new onset of persistent macroalbuminuria, persistent doubling of serum creatinine, needfor continuous renal replacement therapy and death due to renal disease) was 0.64 [0.46; 0.88] drivenby new onset of persistent macroalbuminuria.

Kidney outcomes

In a double-blind kidney outcomes trial (FLOW), 3 533 patients with type 2 diabetes mellitus andchronic kidney disease with eGFR of 50-75 ml/min/1.73 m2 and UACR >300 and <5000 mg/g, oreGFR 25-<50 ml/min/1.73 m2 and UACR of >100 and <5000 mg/g were randomised to eithersemaglutide 1 mg once weekly or corresponding placebo in addition to standard-of-care.

The study was stopped early for efficacy following the planned interim analysis based on arecommendation by the independent Data Monitoring Committee. The median follow-up time was40.9 months.

The mean age of the population was 66.6 years and 69.7% were male. The mean baseline BMI was32.0 kg/m2. The mean duration of diabetes at baseline was 17.4 years and mean baseline HbA1c was7.8% (61.5 mmol/mol). The mean baseline eGFR was 47 ml/min/1.73 m2 and the median UACR was568 mg/g. At baseline, about 95% of the patients were treated with renin-angiotensin-aldosteronesystem inhibitors and 16% with SGLT2 inhibitors.

Semaglutide was superior to placebo, in addition to standard-of-care, in preventing the primarycomposite outcome of persistent ≥50% reduction in eGFR, onset of persistent eGFR<15 ml/min/1.73 m2, initiation of chronic kidney replacement therapy, kidney death or cardiovasculardeath with a hazard ratio of 0.76 [0.66; 0.88]95% CI, corresponding to a relative risk reduction in kidneydisease progression of 24% (see Figure 5). The individual components of the primary compositecontributed to the treatment effect but there were few kidney deaths (see Figure 6).

Semaglutide showed superiority over placebo, in addition to standard-of-care, in reducing the yearlyrate of change in eGFR with an estimated treatment difference of 1.16 (ml/min/1.73m2/year) [0.86;1.47]95% CI. Treatment with semaglutide improved overall survival with a significant reduction in all-cause mortality (see Figure 6).

VV-LAB-123016 1.0 .

HR: 0.7695% CI [0.66 - 0.88]

Number of subjects at risk

Semaglutide

Placebo

Time from randomisation (months)

Semaglutide Placebo

Figure 5 Cumulative incidence function of time to first occurrence of the primary compositeoutcome: onset of persistent ≥50% reduction in eGFR, onset of persistent eGFR<15 ml/min/1.73 m2, initiation of chronic kidney replacement therapy, kidney death orcardiovascular death (FLOW)

Number of events/analysed subjects

HR [95% CI] (Sema 1.0 mg; Placebo)

Primary endpoint 0.76 [0.66; 0.88] 331/1767; 410/1766

Persistent >=50% reduction in eGFR 0.73 [0.59; 0.89] 165/1766; 213/1766

Persistent eGFR<15 0.80 [0.61; 1.06] 92/1767; 110/1766

Renal-replacement therapy 0.84 [0.63; 1.12] 87/1767; 100/1766

Renal death 0.97 [0.27; 3.49] 5/1767; 5/1766

CV death 0.71 [0.56; 0.89] 123/1767; 169/1766

MACE 0.82 [0.68; 0.98] 212/1767; 254/1766

Non-fatal MI 0.80 [0.55; 1.15] 52/1767; 64/1766

Non-fatal stroke 1.22 [0.84; 1.77] 63/1767; 51/1766

CV death 0.71 [0.56; 0.89] 123/1767; 169/1766

All-cause death 0.80 [0.67; 0.95] 227/1767; 279/1766

Favors Favors

Sema 1.0 mg Placebo0.2 0.5 1 2 5

Figure 6 Forest plot: analyses of time to first occurrence of the primary composite outcome andits components, first occurrence of MACE and its components and all cause death (FLOW)

After one year of treatment, a weight loss of ≥5% and ≥10% was achieved for more subjects withsemaglutide 0.5 mg (46% and 13%) and 1 mg (52-62% and 21-24%) compared with the activecomparators sitagliptin (18% and 3%) and exenatide ER (17% and 4%).

In the 40-week trial versus dulaglutide a weight loss of ≥5% and ≥10% was achieved for more subjectswith semaglutide 0.5 mg (44% and 14%) compared with dulaglutide 0.75 mg (23% and 3%) andsemaglutide 1 mg (up to 63% and 27%) compared with dulaglutide 1.5 mg (30% and 8%).

VV-LAB-123016 1.0 .

Patients with event (%)

A significant and sustained reduction in body weight from baseline to week 104 was observed withsemaglutide 0.5 mg and 1 mg vs placebo 0.5 mg and 1 mg, in addition to standard-of-care (-3.6 kgand -4.9 kg vs -0.7 kg and -0.5 kg , respectively) in SUSTAIN 6.

In the kidney outcomes trial FLOW, treatment with semaglutide 1 mg resulted in a sustained reductionin body weight at week 104 vs placebo, in addition to standard-of-care (-5.6 kg for semaglutideand -1.4 kg for placebo).

Significant reductions in mean systolic blood pressure were observed when semaglutide 0.5 mg(3.5-5.1 mmHg) and 1 mg (5.4-7.3 mmHg) were used in combination with oral antidiabetic medicinalproducts or basal insulin. For diastolic blood pressure, there were no significant differences betweensemaglutide and comparators. The observed reductions in systolic blood pressure for semaglutide2 mg and 1 mg at week 40 were 5.3 mmHg and 4.5 mmHg, respectively.

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

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

Compared to native GLP-1, semaglutide has a prolonged half-life of around 1 week making it suitablefor once weekly subcutaneous administration. The principal mechanism of protraction is albuminbinding, which results in decreased renal clearance and protection from metabolic degradation.

Furthermore, semaglutide is stabilised against degradation by the DPP-4 enzyme.

Maximum concentration was reached 1 to 3 days post dose. Steady state exposure was achievedfollowing 4-5 weeks of once weekly administration. In patients with type 2 diabetes, the mean steadystate concentrations following subcutaneous administration of 0.5 mg and 1 mg semaglutide wereapproximately 16 nmol/L and 30 nmol/L, respectively. In the trial comparing semaglutide 1 mg and2 mg, the mean steady state concentrations were 27 nmol/L and 54 nmol/L, respectively. Semaglutideexposure increased in a dose proportional manner for doses of 0.5 mg, 1 mg and 2 mg. Similarexposure was achieved with subcutaneous administration of semaglutide in the abdomen, thigh, orupper arm. Absolute bioavailability of subcutaneous semaglutide was 89%.

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

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

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

VV-LAB-123016 1.0 .

semaglutide-related material were excreted in urine and approximately 1/3 in faeces. Approximately3% of the dose was excreted as intact semaglutide via urine. In patients with type 2 diabetes clearanceof semaglutide was approximately 0.05 L/h. With an elimination half-life of approximately 1 week,semaglutide will be present in the circulation for about 5 weeks after the last dose.

Special population

Age had no effect on the pharmacokinetics of semaglutide based on data from phase 3a studiesincluding patients of 20-86 years of age.

Gender, race (White, Black or African-American, Asian) and ethnicity (Hispanic or Latino, non-

Hispanic or -Latino) had no effect on the pharmacokinetics of semaglutide.

Body weight has an effect on the exposure of semaglutide. Higher body weight results in lowerexposure; a 20% difference in body weight between individuals will result in an approximate 16%difference in exposure. Semaglutide doses of 0.5 mg and 1 mg provide adequate systemic exposureover a body weight range of 40-198 kg.

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

This was shown with a single dose of 0.5 mg semaglutide for patients with different degrees of renalimpairment (mild, moderate, severe or patients in dialysis) compared with subjects with normal renalfunction. This was also shown for subjects with type 2 diabetes and with renal impairment based ondata from phase 3a studies, although the experience in patients with end-stage renal disease waslimited.

Hepatic impairment did not have any impact on the exposure of semaglutide. The pharmacokinetics ofsemaglutide were evaluated in patients with different degrees of hepatic impairment (mild, moderate,severe) compared with subjects with normal hepatic function in a trial with a single-dose of 0.5 mgsemaglutide.

Semaglutide has not been studied in paediatric patients.

Development of anti-semaglutide antibodies when treated with semaglutide 1 mg and 2.4 mg occurredinfrequently (see section 4.8) and the response did not appear to influence semaglutidepharmacokinetics.

Preclinical data reveal no special hazards for humans based on conventional studies of safetypharmacology, repeat-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.

VV-LAB-123016 1.0 .

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 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.

Disodium phosphate dihydrate

Phenol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

In the absence of compatibility studies this medicinal product must not be mixed with other medicinalproducts.

Ozempic 0.25 mg, 0.5 mg, 1 mg and 2 mg3 years.

VV-LAB-123016 1.0 .

In-use shelf life: 6 weeks.

Store below 30 °C or in a refrigerator (2 °C-8 °C). Do not freeze Ozempic. Keep the pen cap on whenthe pen is not in use in order to protect it from light.

Store in a refrigerator (2 °C-8 °C). Keep away from the cooling element.

Do not freeze Ozempic.

Keep the pen cap on in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

1.5 ml or 3 ml glass cartridge (type I glass) closed at the one end with a rubber plunger (chlorobutyl)and at the other end with an aluminium cap with a laminated rubber sheet (bromobutyl/polyisoprene)inserted. The cartridge is assembled into a disposable pre-filled pen made of polypropylene,polyoxymethylene, polycarbonate and acrylonitrile butadiene styrene.

Each pre-filled pen contains 1.5 ml of solution, delivering 4 doses of 0.25 mg.1 pre-filled pen and 4 disposable NovoFine Plus needles

Ozempic 0.5 mg solution for injection1.5 mL: Each pre-filled pen contains 1.5 ml of solution, delivering 4 doses of 0.5 mg.1 pre-filled pen and 4 disposable NovoFine Plus needles3 pre-filled pens and 12 disposable NovoFine Plus needles3 mL: Each pre-filled pen contains 3 mL of solution, delivering 4 doses of 0.5 mg.1 pre-filled pen and 4 disposable NovoFine Plus needles3 pre-filled pens and 12 disposable NovoFine Plus needles

Each pre-filled pen contains 3 ml of solution, delivering 4 doses of 1 mg.1 pre-filled pen and 4 disposable NovoFine Plus needles3 pre-filled pens and 12 disposable NovoFine Plus needles

Each pre-filled pen contains 3 ml of solution, delivering 4 doses of 2 mg.1 pre-filled pen and 4 disposable NovoFine Plus needles3 pre-filled pens and 12 disposable NovoFine Plus needles

Not all pack sizes may be marketed.

The patient should be advised to discard the injection needle after each injection and store the penwithout an injection needle attached. This may prevent blocked needles, contamination, infection,leakage of solution and inaccurate dosing.

VV-LAB-123016 1.0 .

The pen is for use by one person only.

Ozempic should not be used if it does not appear clear and colourless or almost colourless.

Ozempic should not be used if it has been frozen.

Ozempic can be administered with 30G, 31G, and 32G disposable needles up to a length of 8 mm.

Any unused medicinal product and other waste material should be disposed of in accordance withlocal requirements.

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

EU/1/17/1251/002

EU/1/17/1251/003

EU/1/17/1251/004

EU/1/17/1251/005

EU/1/17/1251/006

EU/1/17/1251/010

EU/1/17/1251/011

EU/1/17/1251/012

EU/1/17/1251/013

Date of first authorisation: 08 February 2018

Date of latest renewal: 21 September 2022

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

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

VV-LAB-123016 1.0 .