This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

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

2. Qualitative and quantitative composition

Ozempic 0.25 mg solution for injection

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 injection

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 0.5 mg of semaglutide in 0.37 ml solution.

Ozempic 1 mg solution for injection

One ml of solution contains 1.34 mg of semaglutide*. One pre-filled pen contains 4 mg semaglutide* in 3.0 ml solution. Each dose contains 1 mg of semaglutide in 0.74 ml solution.

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection (injection).

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

4. Clinical particulars
4.1 Therapeutic indications

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

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

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

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

4.2 Posology and method of administration

Posology

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

Semaglutide 0.25 mg is not a maintenance dose. Weekly doses higher than 1 mg are not recommended.

When Ozempic is added to existing metformin and/or thiazolidinedione therapy, the current dose of metformin and/or thiazolidinedione can be continued unchanged.

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

Self-monitoring of blood glucose is not needed in order to adjust the dose of Ozempic. However, when initiating treatment with Ozempic in combination with a sulfonylurea or an insulin, blood glucose self-monitoring may become necessary to adjust the dose of the sulfonylurea or the insulin to reduce the risk of hypoglycaemia (see section 4.4).

Missed dose

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

Special populations

Elderly

No dose adjustment is required based on age. Therapeutic experience in patients ≥75 years of age is limited (see section 5.2).

Renal impairment

No dose adjustment is required for patients with mild, moderate or severe renal impairment. Experience with the use of semaglutide in patients with severe renal impairment is limited. Semaglutide is not recommended for use in patients with end-stage renal disease (see section 5.2).

Hepatic impairment

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

Paediatric population

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

Method of administration

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

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

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

For further information on administration, see section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Semaglutide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. Semaglutide is not a substitute for insulin.

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

Gastrointestinal effects

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. This should be considered when treating patients, with impaired renal function as nausea, vomiting, and diarrhoea may cause dehydration which could cause a deterioration of renal function (see section 4.8).

Acute pancreatitis

Acute pancreatitis has been observed with the use of GLP-1 receptor agonists. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, semaglutide should be discontinued; if confirmed, semaglutide should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Hypoglycaemia

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

Diabetic retinopathy

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

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

4.5 Interaction with other medicinal products and other forms of interaction

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

Paracetamol

Semaglutide delays the rate of gastric emptying as assessed by paracetamol pharmacokinetics during a standardised meal test. Paracetamol AUC0-60min and Cmax were decreased by 27% and 23%, respectively, following concomitant use of semaglutide 1 mg. The total paracetamol exposure (AUC0-5h) was not affected. No dose adjustment of paracetamol is necessary when administered with semaglutide.

Oral contraceptives

Semaglutide is not anticipated to decrease the effect of oral contraceptives as semaglutide did not change the overall exposure of ethinylestradiol and levonorgestrel to a clinically relevant degree when an oral contraceptive combination medicinal product (0.03 mg ethinylestradiol/0.15 mg levonorgestrel) was co-administered with semaglutide. Exposure of ethinylestradiol was not affected; an increase of 20% was observed for levonorgestrel exposure at steady state. Cmax was not affected for any of the compounds.

Atorvastatin

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

Digoxin

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

Metformin

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

Warfarin

Semaglutide did not change the overall exposure or Cmax of R- and S-warfarin following a single dose of warfarin (25 mg), and the pharmacodynamic effects of warfarin as measured by the international normalised ratio (INR) were not affected in a clinically relevant manner. However, upon initiation of semaglutide treatment in patients on warfarin or other coumarin derivatives, frequent monitoring of INR is recommended.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3). There are limited data from the use of semaglutide in pregnant women. Therefore, semaglutide should not be used during pregnancy. If a patient wishes to become pregnant, or pregnancy occurs, semaglutide should be discontinued. Semaglutide should be discontinued at least 2 months before a planned pregnancy due to the long half-life (see section 5.2).

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

Semaglutide has no or negligible influence on the ability to drive or use machines. When it is used in combination with a sulfonylurea or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines (see section 4.4).

4.8 Undesirable effects

Summary of safety profile

In 8 phase 3a trials 4,792 patients were exposed to semaglutide. The most frequently reported adverse reactions in clinical trials were gastrointestinal disorders, including nausea (very common), diarrhoea (very common) and vomiting (common). In general, these reactions were mild or moderate in severity and of short duration.

Tabulated list of adverse reactions

Table 1 lists adverse reactions identified in all phase 3a trials in patients with type 2 diabetes mellitus (further described in section 5.1). The frequencies of the adverse reactions are based on a pool of the phase 3a trials excluding the cardiovascular outcomes trial (see text below the table for additional details).

The reactions are listed below by system organ class and absolute frequency. Frequencies are defined as: very common: (≥1/10); common: (≥1/100 to <1/10); uncommon: (≥1/1,000 to <1/100); rare: (≥1/10,000 to <1/1,000) and very rare: (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1 Adverse reactions from long-term controlled phase 3a trials including the cardiovascular outcomes trial

MedDRA system organ class

Very common

Common

Uncommon

Rare

Immune system disorders

Anaphylactic reaction

Metabolism and nutrition disorders

Hypoglycaemiaa when used with insulin or sulfonylurea

Hypoglycaemiaa when used with other OADs

Decreased appetite

Nervous system disorders

Dizziness

Dysgeusia

Eye disorders

Diabetic retinopathy complicationsb

Cardiac disorders

Increased heart rate

Gastrointestinal disorders

Nausea

Diarrhoea

Vomiting

Abdominal pain

Abdominal distension

Constipation

Dyspepsia

Gastritis

Gastro-oesophageal reflux disease

Eructation

Flatulence

Hepatobiliary disorders

Cholelithiasis

General disorders and administration site conditions

Fatigue

Injection site reactions

Investigations

Increased lipase

Increased amylase

Weight decreased

a) Hypoglycaemia defined as severe (requiring the assistance of another person) or symptomatic in combination with a blood glucose <3.1 mmol/L

b) Diabetic retinopathy complications is a composite of: retinal photocoagulation, treatment with intravitreal agents, vitreous haemorrhage, diabetes-related blindness (uncommon). Frequency based on cardiovascular outcomes trial.

2-year cardiovascular outcomes and safety trial

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

Description of selected adverse reactions

Hypoglycaemia

No episodes of severe hypoglycaemia were observed when semaglutide was used as monotherapy. Severe hypoglycaemia was primarily observed when semaglutide was used with a sulfonylurea (1.2% of subjects, 0.03 events/patient year) or insulin (1.5% of subjects, 0.02 events/patient year). Few episodes (0.1% of subjects, 0.001 events/patient year) were observed with semaglutide in combination with oral antidiabetics other than sulfonylureas.

Gastrointestinal adverse reactions

Nausea occurred in 17.0% and 19.9% of patients when treated with semaglutide 0.5 mg and 1 mg, respectively, diarrhoea in 12.2% and 13.3% and vomiting in 6.4% and 8.4%. Most events were mild to moderate in severity and of short duration. The events led to treatment discontinuation in 3.9% and 5% of patients. The events were most frequently reported during the first months on treatment.

Patients with low body weight may experience more gastrointestinal side effects when treated with semaglutide.

Diabetic retinopathy complications

A 2-year clinical trial investigated 3,297 patients with type 2 diabetes, with high cardiovascular risk, long duration of diabetes and poorly controlled blood glucose. In this trial, adjudicated events of diabetic retinopathy complications occurred in more patients treated with semaglutide (3.0%) compared to placebo (1.8%). This was observed in insulin-treated patients with known diabetic retinopathy. The treatment difference appeared early and persisted throughout the trial. Systematic evaluation of diabetic retinopathy complication was only performed in the cardiovascular outcomes trial. In clinical trials up to 1 year involving 4,807 patients with type 2 diabetes, adverse events related to diabetic retinopathy were reported in similar proportions of subjects treated with semaglutide (1.7%) and comparators (2.0%).

Discontinuation due to an adverse event

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

Injection site reactions

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

Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop antibodies following treatment with semaglutide. The proportion of patients tested positive for anti-semaglutide antibodies at any time point post-baseline was low (1−2%) and no patients had anti-semaglutide neutralising antibodies or anti-semaglutide antibodies with endogenous GLP-1 neutralising effect at end-of-trial.

Heart rate increase

Increased heart rate has been observed with GLP-1 receptor agonists. In the phase 3a trials, mean increases of 1 to 6 beats per minute (bpm) from a baseline of 72 to 76 bpm were observed in subjects treated with Ozempic. In a long-term trial in subjects with cardiovascular risk factors, 16% of Ozempic-treated subjects had an increase in heart rate of >10 bpm compared to 11% of subjects on placebo after 2 years of treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9 Overdose

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

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

5. Pharmacological properties
5.1 Pharmacodynamic properties

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

Mechanism of action

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

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

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

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

GLP-1 receptors are also expressed in the heart, vasculature, immune system and kidneys.

Semaglutide had a beneficial effect on plasma lipids, lowered systolic blood pressure and reduced inflammation in clinical studies. In animal studies, semaglutide attenuates the development of atherosclerosis by preventing aortic plaque progression and reducing inflammation in the plaque.

Pharmacodynamic effects

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

Fasting and postprandial glucose

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

Beta-cell function and insulin secretion

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

Glucagon secretion

Semaglutide lowers the fasting and postprandial glucagon concentrations. In patients with type 2 diabetes, 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 glucagon concentration (12%).

Glucose dependent insulin and glucagon secretion

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

During induced hypoglycaemia, semaglutide compared to placebo did not alter the counter regulatory responses of increased glucagon and did not impair the decrease of C-peptide in patients with type 2-diabetes.

Gastric emptying

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

Appetite, energy intake and food choice

Semaglutide compared to placebo lowered the energy intake of 3 consecutive ad libitum meals by 18-35%. This was supported by a semaglutide-induced suppression of appetite in the fasting state as well as postprandially, improved control of eating, less food cravings and a relative lower preference for high fat food.

Fasting and postprandial lipids

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%.

Cardiac electrophysiology (QTc)

The effect of semaglutide on cardiac repolarization was tested in a thorough QTc trial. Semaglutide did not prolong QTc intervals at supra-therapeutic dose levels (up to 1.5 mg at steady state).

Clinical efficacy and safety

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are an integral part of the treatment of type 2 diabetes.

The efficacy and safety of Ozempic 0.5 mg and 1 mg once weekly were evaluated in six randomised 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 as the primary objective, while one trial (SUSTAIN 6) had cardiovascular outcome as the primary objective.

An additional trial including 1,201 patients was conducted to compare the efficacy and safety of Ozempic 0.5 mg and 1 mg once weekly to dulaglutide 0.75 mg and 1.5 mg once weekly, respectively.

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

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

SUSTAIN 1 – Monotherapy

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

Table 2 SUSTAIN 1: Results at week 30

Semaglutide

0.5 mg

Semaglutide

1 mg

Placebo

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% CI]

-1.4 [-1.7, -1.1]a

-1.5 [-1.8, -1.2]a

-

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% CI]

-2.7 [-3.9, -1.6]a

-3.6 [-4.7, -2.4]a

-

ap <0.0001 (2-sided) for superiority

SUSTAIN 2 – Ozempic vs. sitagliptin both in combination with 1–2 oral antidiabetic drugs (metformin and/or thiazolidinediones)

In a 56-week active-controlled double-blind trial, 1,231 patients were randomised to Ozempic 0.5 mg once weekly, Ozempic 1 mg once weekly or sitagliptin 100 mg once daily, all in combination with metformin (94%) and/or thiazolidinediones (6%).

Table 3 SUSTAIN 2: Results at week 56

Semaglutide

0.5 mg

Semaglutide

1 mg

Sitagliptin

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% CI]

-0.8 [-0.9, -0.6]a

-1.1 [-1.2, -0.9]a

-

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% CI]

-2.3 [-3.1, -1.6]a

-4.2 [-4.9, -3.5]a

-

ap <0.0001 (2-sided) for superiority

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

SUSTAIN 7 – Ozempic 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 weekly Ozempic 0.5 mg, dulaglutide 0.75 mg , Ozempic 1 mg or dulaglutide 1.5 mg, respectively. The trial compared 0.5 mg of Ozempic to 0.75 mg of dulaglutide and 1 mg of Ozempic to 1.5 mg of dulaglutide.

Gastrointestinal disorders were the most frequent adverse events, and occurred in similar proportion of patients receiving Ozempic 0.5 mg (129 patients [43%]), Ozempic 1 mg (133 [44%]), and dulaglutide 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 Ozempic (0.5 mg and 1 mg) and dulaglutide (0.75 mg and 1.5 mg) was 2.4, 4.0, and 1.6, 2.1, beats/min, respectively.

Table 4 SUSTAIN 7: Results at week 40

Semaglutide

0.5 mg

Semaglutide

1 mg

Dulaglutide

0.75 mg

Dulaglutide

1.5 mg

Intent-to-Treat (ITT)

Population(N)

301

300

299

299

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

[95% CI]

-0.4b

[-0.6, -0.2]a

-0.4c

[-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

[95% CI]

-2.3b

[-3.0, -1.5]a

-3.6c

[-4.3, -2.8]a

-

-

ap <0.0001 (2-sided) for superiority

b Ozempic 0.5 mg vs dulaglutide 0.75 mg

c Ozempic 1 mg vs dulaglutide 1.5 mg

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

SUSTAIN 3 – Ozempic vs. exenatide ER both in combination with metformin or metformin with sulfonylurea

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

Table 5 SUSTAIN 3: Results at week 56

Semaglutide

1 mg

Exenatide ER

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 – Ozempic vs. insulin glargine both in combination with 1–2 oral antidiabetic drugs (metformin or metformin and sulfonylurea)

In a 30-week open-label comparator trial 1,089 patients were randomised to Ozempic 0.5 mg once weekly, Ozempic 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

0.5 mg

Semaglutide

1 mg

Insulin 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)

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 – Ozempic vs. placebo both in combination with basal insulin

In a 30-week double-blind placebo-controlled trial, 397 patients inadequately controlled with basal insulin with or without metformin were randomised to Ozempic 0.5 mg once weekly, Ozempic 1 mg once weekly or placebo.

Table 7 SUSTAIN 5: Results at week 30

Semaglutide

0.5 mg

Semaglutide

1 mg

Placebo

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% CI]

-1.4 [-1.6, -1.1]a

-1.8 [-2.0, -1.5]a

-

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% CI]

-2.3 [-3.3, -1.3]a

-5.1 [-6.1, -4.0]a

-

ap <0.0001 (2-sided) for superiority

Combination with sulfonylurea monotherapy

In SUSTAIN 6 (see subsection Cardiovascular disease) 123 patients were on sulfonylurea monotherapy at baseline. HbA1c at baseline was 8.2%, 8.4% and 8.4% for Ozempic 0.5 mg, Ozempic 1 mg, and placebo, respectively. At week 30, the change in HbA1c was -1.6%, -1.5% and 0.1% for Ozempic 0.5 mg, Ozempic 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 or without OAD(s)) at baseline. HbA1c at baseline was 8.8%, 8.9% and 8.9% for Ozempic 0.5 mg, Ozempic 1 mg, and placebo, respectively. At week 30, the change in HbA1c was -1.3%, -1.8% and -0.4% for Ozempic 0.5 mg, Ozempic 1 mg, and placebo, respectively.

Cardiovascular disease

In a 104-week double-blind trial (SUSTAIN 6), 3,297 patients with type 2 diabetes mellitus at high cardiovascular risk were randomised to either Ozempic 0.5 mg once weekly, Ozempic 1 mg once 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 for 99.6% 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, the mean 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 adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction or non-fatal stroke.

The total number of primary component MACE endpoints was 254, including 108 (6.6%) with semaglutide and 146 (8.9%) with placebo. See figure 4 for results on primary and secondary cardiovascular endpoints. Treatment with semaglutide resulted in a 26% risk reduction in the primary composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. The total numbers of cardiovascular deaths, non-fatal myocardial infarctions and non-fatal strokes 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 was mainly driven by decreases in the rate of non-fatal stroke (39%) and non-fatal myocardial infarction (26%) (figure 3).

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

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

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

Body weight

After one year of treatment, a weight loss of ≥5% and ≥10% was achieved for more subjects with Ozempic 0.5 mg (46% and 13%) and 1 mg (52 – 62% and 21 – 24%) compared with the active comparators 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 subjects with Ozempic 0.5 mg (44% and 14%) compared with dulaglutide 0.75 mg (23% and 3%) and Ozempic 1 mg (up to 63% and 27%) compared with dulaglutide 1.5 mg (30% and 8%).

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

Blood pressure

Significant reductions in mean systolic blood pressure were observed when Ozempic 0.5 mg (3.5-5.1 mmHg) and 1 mg (5.4–7.3 mmHg) were used in combination with oral antidiabetic medicinal products or basal insulin. For diastolic blood pressure, there were no significant differences between semaglutide and comparators.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with semaglutide in one or more subsets of the paediatric population in type 2 diabetes (see section 4.2).

5.2 Pharmacokinetic properties

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

Absorption

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

Distribution

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

Metabolism/Biotransformation

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

Elimination

In a study with a single subcutaneous dose of radiolabelled semaglutide, it was found that the primary excretion routes of semaglutide-related material were via urine and faeces; approximately 2/3 of semaglutide-related material were excreted in urine and approximately 1/3 in faeces. Approximately 3% of the dose was excreted as intact semaglutide via urine. In patients with type 2 diabetes clearance of 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

Elderly

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

Gender, race and ethnicity

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

Body weight has an effect on the exposure of semaglutide. Higher body weight results in lower exposure; 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 exposure over a body weight range of 40–198 kg.

Renal impairment

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 renal impairment (mild, moderate, severe or patients in dialysis) compared with subjects with normal renal function. This was also shown for subjects with type 2 diabetes and with renal impairment based on data from phase 3a studies, although the experience in patients with end-stage renal disease was limited.

Hepatic impairment

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

Paediatric population

Semaglutide has not been studied in paediatric patients.

5.3 Preclinical safety data

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, 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 at clinically relevant exposures. No other treatment-related tumours were observed. The rodent C-cell tumours are caused by a non-genotoxic, specific GLP-1 receptor mediated mechanism to which rodents are particularly sensitive. The relevance for humans is considered to be low, but cannot be completely excluded.

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

In embryo-foetal development studies in rats, semaglutide caused embryotoxicity below clinically relevant exposures. Semaglutide caused marked reductions in maternal body weight and reductions in embryonic 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. Mechanistic evaluations indicated that the embryotoxicity involved a GLP-1 receptor mediated impairment of the nutrient supply to the embryo across the rat yolk sac. Due to species differences in yolk sac anatomy and 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 of semaglutide on the foetus cannot be excluded.

In developmental toxicity studies in rabbits and cynomolgus monkeys, increased pregnancy loss and slightly increased incidence of foetal abnormalities were observed at clinically relevant exposures. The findings coincided with marked maternal body weight loss of up to 16%. Whether these effects are related 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 slightly smaller at delivery, but recovered during the lactation period.

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

6. Pharmaceutical particulars
6.1 List of excipients

Disodium phosphate dihydrate

Propylene glycol

Phenol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

3 years.

In-use shelf life: 6 weeks.

After first use: Store below 30°C or in a refrigerator (2°C to 8°C). Do not freeze Ozempic and do not use Ozempic if it has been frozen. Keep the pen cap on when the pen is not in use in order to protect it from light.

Always remove the injection needle after each injection and store the pen without a needle attached. This may prevent blocked needles, contamination, infection, leakage of solution and inaccurate dosing.

6.4 Special precautions for storage

Before first use: Store in a refrigerator (2°C to 8°C). Keep away from the cooling element.

Do not freeze Ozempic and do not use Ozempic if it has been frozen.

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

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

6.5 Nature and contents of container

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.

Pack sizes:

Ozempic 0.25 mg solution for injection: 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 injection: 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 needles

3 pre-filled pens and 12 disposable NovoFine Plus needles

Ozempic 1 mg solution for injection: Each pre-filled pen contains 3 ml of solution, delivering 4 doses of 1 mg.

1 pre-filled pen and 4 disposable NovoFine Plus needles

3 pre-filled pens and 12 disposable NovoFine Plus needles

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The patient should be advised to discard the injection needle after each injection and store the pen without an injection needle attached. This may prevent blocked needles, contamination, infection, leakage of solution and inaccurate dosing. Needles and other waste material should be disposed of in accordance with local requirements.

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 needles up to a length of 8 mm. The pen is designed to be used with NovoFine or NovoTwist disposable needles. NovoFine Plus needles are included in the package.

7. Marketing authorisation holder

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

8. Marketing authorisation number(s)

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

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 08 February 2018

10. Date of revision of the text

10/2018

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