Ozempic 0.25 mg solution for injection in pre-filled pen

 Section 4.5: Interaction with Warfarin and other coumarin derivatives paragraph updated to mention cases of decreased INR with concomitant administration of semaglutide and acenocoumarol.

Section 4.8: Intestinal obstruction added as an Adverse Reaction (with a frequency of ‘not known’). 

Section 4 - Update to include 'Bowel obstruction' , in line with SmPC update

Section 4 - Removal of Northern Ireland adverse event reporting details

Change to section 4.8:

Delayed gastric emptying

New text inserted under section 4:

•       a delay in the emptying of the stomach.

Section 2 - Driving and using machines

Wording update: 'sulphonylurea' updated to 'sulfonylurea'.

Other minor formatting updates along the text.

(Re-upload to add a reference to 'Instructions on how to use Ozempic 0.25 mg solution for injection in pre-filled pen' section updated)

Removal of Black Inverted Triangle.

Section 1:

Text updated from:

'Ozempic is used:

• on its own – if your blood sugar is not controlled well enough by diet and exercise alone, and you cannot use metformin (another diabetes medicine) or

• with other medicines for diabetes – when they are not enough to control your blood sugar levels. These other medicines may include: oral antidiabetics (such as metformin, thiazolidinediones, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitor) or insulin.'

To:

'Ozempic is used to treat adults (aged 18 years and older) with type 2 diabetes when diet and exercise is not enough:

• on its own – when you cannot use metformin (another diabetes medicine) or

• with other medicines for diabetes – when they are not enough to control your blood sugar levels. These may be medicines you take by mouth or inject such as insulin.

Section 2, Warnings and precautions:

'This medicine is not an insulin and should not be used if:' updated to 'This medicine is not the same as insulin and you should not use it if:'

'Hypoglycaemia' updated to 'Low blood sugar (hypoglycaemia)'

Section 2, Children and adolescents:

'This medicine is not recommended in children and adolescents under 18 years as the safety and efficacy in this age group have not yet been established.' updated to 'This medicine is not recommended in children and adolescents aged under 18 years as the safety and efficacy in this age group have not yet been established.'

Section 2, Other medicines and Ozempic:

'Warfarin or other similar medicines taken by mouth to reduce blood clotting (oral anti-coagulants). Frequent blood testing to determine the ability of your blood to clot may be required.' updated to 'Warfarin or other similar medicines taken by mouth to reduce blood clotting (oral anti-coagulants). You may need frequent blood tests to check how quickly your blood clots.'

Section 2, Pregnancy and breast-feeding:

'This medicine should not be used during pregnancy, as it is not known if it may affect your unborn child. Therefore, it is recommended to use contraception while using this medicine. If you wish to become pregnant, you should stop using this medicine at least two months in advance. If you become pregnant when using this medicine, talk to your doctor right away, as your treatment will need to be changed.' updated to 'This medicine should not be used during pregnancy, as it is not known if it affects an unborn baby. Therefore, use of contraception is recommended while using this medicine. If you wish to become pregnant, discuss how to change your treatment with your doctor as you should stop using this medicine at least 2 months in advance. If you become pregnant while using this medicine, talk to your doctor right away, as your treatment will need to be changed.'

Section 2, Driving and using machines:

'Avoid driving or using machines if you get any signs of low blood sugar.' updated to 'Do not drive or use machines if you get any signs of low blood sugar.'

Section 3, How Ozempic is given:

'Detailed instructions for use are on the other side of this leaflet.' updated to 'Detailed instructions for use are on the other side of this package leaflet.'

Section 4, Possible side effects:

Common: 'you should inform your doctor if you experience eye problems, such as changes in vision, during treatment with this medicine.' updated to 'you should tell your doctor if you get eye problems, such as changes in vision, during treatment with this medicine.'

Rare: 'You should seek immediate medical help...' updated to 'You must get immediate medical help...'

Other side effects, Very common: sentence added 'low blood sugar (hypoglycaemia) when this medicine is used with medicines that contain a sulfonylurea or insulin'.

Other side effects, Common: 'low blood sugar (hypoglycaemia) when this medicine is used with another antidiabetic medicine' updated to 'low blood sugar (hypoglycaemia) when this medicine is used with oral diabetes medicine other than sulfonylurea or insulin'

Section 5, How to store Ozempic:

Before opening: 'Keep away from the cooling element.

Protect from light.' updated to 'Keep away from the cooling element. Keep the pen cap on in order to protect from light.'

Section 6, This leaflet was last revised:

Updated to 09/2022

Instructions on how to use Ozempic 0.25 mg solution for injection in pre-filled pen:

Multiple updates along the text.

Removal of Black Inverted Triangle.

Section 1:

Text updated from:

'Ozempic is used:

• on its own – if your blood sugar is not controlled well enough by diet and exercise alone, and you cannot use metformin (another diabetes medicine) or

• with other medicines for diabetes – when they are not enough to control your blood sugar levels. These other medicines may include: oral antidiabetics (such as metformin, thiazolidinediones, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitor) or insulin.'

To:

'Ozempic is used to treat adults (aged 18 years and older) with type 2 diabetes when diet and exercise is not enough:

• on its own – when you cannot use metformin (another diabetes medicine) or

• with other medicines for diabetes – when they are not enough to control your blood sugar levels. These may be medicines you take by mouth or inject such as insulin.

Section 2, Warnings and precautions:

'This medicine is not an insulin and should not be used if:' updated to 'This medicine is not the same as insulin and you should not use it if:'

'Hypoglycaemia' updated to 'Low blood sugar (hypoglycaemia)'

Section 2, Children and adolescents:

'This medicine is not recommended in children and adolescents under 18 years as the safety and efficacy in this age group have not yet been established.' updated to 'This medicine is not recommended in children and adolescents aged under 18 years as the safety and efficacy in this age group have not yet been established.'

Section 2, Other medicines and Ozempic:

'Warfarin or other similar medicines taken by mouth to reduce blood clotting (oral anti-coagulants). Frequent blood testing to determine the ability of your blood to clot may be required.' updated to 'Warfarin or other similar medicines taken by mouth to reduce blood clotting (oral anti-coagulants). You may need frequent blood tests to check how quickly your blood clots.'

Section 2, Pregnancy and breast-feeding:

'This medicine should not be used during pregnancy, as it is not known if it may affect your unborn child. Therefore, it is recommended to use contraception while using this medicine. If you wish to become pregnant, you should stop using this medicine at least two months in advance. If you become pregnant when using this medicine, talk to your doctor right away, as your treatment will need to be changed.' updated to 'This medicine should not be used during pregnancy, as it is not known if it affects an unborn baby. Therefore, use of contraception is recommended while using this medicine. If you wish to become pregnant, discuss how to change your treatment with your doctor as you should stop using this medicine at least 2 months in advance. If you become pregnant while using this medicine, talk to your doctor right away, as your treatment will need to be changed.'

Section 2, Driving and using machines:

'Avoid driving or using machines if you get any signs of low blood sugar.' updated to 'Do not drive or use machines if you get any signs of low blood sugar.'

Section 3, How Ozempic is given:

'Detailed instructions for use are on the other side of this leaflet.' updated to 'Detailed instructions for use are on the other side of this package leaflet.'

Section 4, Possible side effects:

Common: 'you should inform your doctor if you experience eye problems, such as changes in vision, during treatment with this medicine.' updated to 'you should tell your doctor if you get eye problems, such as changes in vision, during treatment with this medicine.'

Rare: 'You should seek immediate medical help...' updated to 'You must get immediate medical help...'

Other side effects, Very common: sentence added 'low blood sugar (hypoglycaemia) when this medicine is used with medicines that contain a sulfonylurea or insulin'.

Other side effects, Common: 'low blood sugar (hypoglycaemia) when this medicine is used with another antidiabetic medicine' updated to 'low blood sugar (hypoglycaemia) when this medicine is used with oral diabetes medicine other than sulfonylurea or insulin'

Section 5, How to store Ozempic:

Before opening:

'Keep away from the cooling element. Protect from light.' updated to 'Keep away from the cooling element. Keep the pen cap on in order to protect from light.'

Section 6, This leaflet was last revised:

Updated to 09/2022

Removal of Black Inverted Triangle.

Section 4.8:

Table 1, Metabolism and nutrition disorders - 'oral antidiabetics' added before 'OAD'.

Minor formatting updates.

Section 5.1:

Figure 4 - Format updated.

Section 6.3:

'Store below 30 °C or in a refrigerator (2 °C–8 °C). Do not freeze Ozempic and do not use Ozempic if it has been frozen.' updated to 'Store below 30 °C or in a refrigerator (2 °C–8 °C). Do not freeze Ozempic.'

Sentence deleted: '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.'

Section 6.4:

'Before first use: Store in a refrigerator (2 °C–8 °C). Keep away from the cooling element. Do not freeze Ozempic and do not use Ozempic if it has been frozen.' updated to 'Store in a refrigerator (2 °C–8 °C). Keep away from the cooling element. Do not freeze Ozempic.'

Section 6.6:

Sentence deleted: 'Needles and other waste material should be disposed of in accordance with local requirements.'

'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.' updated to '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 with local requirements.' 

Section 9:

Sentence added 'Date of latest renewal:'

Section 10:

Date of revision of the text updated to '09/2022'

Section 5.1; New text added:

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

"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-in period 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 mean diabetes duration of 13.4 years and a mean HbA_1c of 8.6%, with a target HbA_1c of 6.5-7.5%.

Treatment with semaglutide resulted in reduction in HbA_1c 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 with semaglutide 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."

Section 10: Revision date updated to '04/2022'

Section 2.

New text:

‘Severe and on-going stomach pain which could be due to acute pancreatitis’: Please see section 4 for the warning signs of inflamed pancreas.

‘Diabetic eye disease (retinopathy)’: In case you have potentially unstable diabetic eye disease, it is not recommended that you use Ozempic® 2 mg.

‘Driving and using machines’: Ozempic® is unlikely to affect your ability to drive and use machines.

Text update:

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

Section 3.

New text:

‘How much to use’: Your doctor may increase your dose to 2 mg once a week if your blood sugar is not controlled well enough with a dose of 1 mg once a week.

Text update:

‘If you forget to use Ozempic®’: Do not use a double dose to make up for a forgotten dose.

Section 4.

Text update:

United Kingdom updated to United Kingdom (Northern Ireland)

Section 6.

New text:

‘What Ozempic® contains’: See also section 2, ‘Sodium content’.

‘What Ozempic® looks like and contents of the pack’: Each pre‑filled pen contains 1.5 ml of solution, delivering 4 doses of 0.25 mg.

Date leaflet was last revised updated to 01/2022.

Minor formatting updates along the text.

Section 1. Name of the Medicinal Product

New text: Ozempic 2 mg solution for injection in pre-filled pen

Section 2. Qualitative and Quantitative Composition

New text:

Ozempic 2 mg solution for injection

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.

Section 4.1. Therapeutic indications

Text updated to: For trial 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.

Section 4.2. Posology and method of administration

New text:

After at least 4 weeks with a dose of 1 mg once weekly, the dose can be increased to 2 mg once weekly to further improve glycaemic control.

Subcutaneous use.

Text updated to: Weekly doses higher than 2 mg are not recommended.

Text moved to from 'Method of Administration' to 'Posology':

Changing the dosing day

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

Section 4.4. Special Warnings and Precautions

Text added to 'Diabetic rethinopathy': There is no experience with semaglutide 2 mg in patients with type 2 diabetes with uncontrolled or potentially unstable diabetic retinopathy and semaglutide 2 mg is therefore not recommended in these patients. 

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

Section 4.5. Interactions with other medicinal products and other forms of interaction

Text added to 'Paracetamol': No clinically relevant effect on the rate of gastric emptying was observed with semaglutide 2.4 mg, following 20 weeks of administration of semaglutide, probably due to a tolerance effect.

Section 4.8. Undesirable effects

Multiple text updates, including 'Ozempic' updated to 'semaglutide' where relevant. 

Text update in 'Immunogeniticity': The proportion of patients tested positive for anti-semaglutide antibodies at any time point post-baseline was low (1−3%)

Section 5.1. Pharmacodynamic properties

Text and image updates, including 'Ozempic' updated to 'semaglutide' where relevant.

Section 5.2. Pharmacokinetic properties

Text added:

Absorption: In the trial comparing semaglutide 1 mg and 2 mg, the mean steady state concentrations were 27 nmol/L and 54 nmol/L, respectively. Semaglutide exposure increased in a dose proportional manner for doses of 0.5 mg, 1 mg and 2 mg.

Immunogenicity

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

Text update: Metabolism updated to Biotransformation.

Section 6.3. Shelf life

Text update:

Before first use

Ozempic 0.25 mg, 0.5 mg and 1 mg

3 years.

Ozempic 2 mg

2 years.

After first opening

Section 6.4. Special precautions for use

Formatting updates.

Section 6.5. Nature and contents of container

Text added:

Ozempic 2 mg solution for injection

Each pre-filled pen contains 3 ml of solution, delivering 4 doses of 2 mg.

1 pre-filled pen and 4 disposable NovoFine Plus needles

3 pre-filled pens and 12 disposable NovoFine Plus needles

Section 8. Marketing Authorisation Numbers

Text added:

EU/1/17/1251/010

EU/1/17/1251/011

Section 10. Date of Revision of the Text

Text updated to: 

01/2022

Multiple formatting updates along the text.

Section 4. Possible side effects

Text updated:

"Rare: may affect up to 1 in 1,000 people

•           severe allergic reactions (anaphylactic reactions, angioedema). You should seek immediate medical help and inform your doctor straight away if you get symptoms such as breathing problems, swelling of face, lips, tongue and/or throat with difficulty swallowing and a fast heartbeat."

Section 4.8:

Table 1 updated to list 'angioedema' as an undesirable effect with a frequency of 'Not known', in the system organ class, 'Skin and subcutaneous tissue disorders'.

Data is 'From post-marketing reports'

Section 1 - What Ozempic is and what it is used for

Text update to:

Ozempic is used:

•        on its own – if your blood sugar is not controlled well enough by diet and exercise alone, and you cannot use metformin (another diabetes medicine) or

•        with other medicines for diabetes – when they are not enough to control your blood sugar levels. These other medicines may include: oral antidiabetics (such as metformin, thiazolidinediones, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitor) or insulin.

Section 4.2

Posology:

New text in following sentence:

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.

Section 4.8, Hypoglycaemia

New text:

ADA classified hypoglycaemia occurred in 11.3% (0.3 events/patient year) of patients when semaglutide 1.0 mg was added to SGLT2 inhibitor in SUSTAIN 9 compared to 2.0% (0.04 events/patient year) of placebo-treated patients. Severe hypoglycaemia was reported in 0.7% (0.01 events/patient year) and 0% of patients, respectively.

Section 4.8, Gastrointestinal adverse reactions

New text:

In concomitant use with an SGLT2 inhibitor in SUSTAIN 9, constipation and gastro-oesophageal reflux disease occurred in 6.7% and 4% respectively of patients treated with semaglutide 1.0 mg compared to no events for placebo-treated patients. The prevalence of these events did not decrease over time.

Section 5.1, Clinical efficacy and safety

New text:

In An additional a phase 3b trial (SUSTAIN 7) 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. A phase 3b trial (SUSTAIN 9), was conducted to investigate the efficacy and safety of semaglutide as add-on to SGLT2 inhibitor treatment.

SUSTAIN 9 – Ozempic vs. placebo as add-on to SGLT2 inhibitor ± metformin or SU

In a 30-week double-blind placebo-controlled trial, 302 patients inadequately controlled with SGLT2 inhibitor with or without metformin or SU were randomised to semaglutide 1.0 mg once weekly or placebo.

Table 8 SUSTAIN 9: Results at week 30

^ap < 0.0001 (2-sided) for superiority, adjusted regarding multiplicity based on hierarchical testing of the HbA1c value and body weight

Section 4, Possible side effects

New text:

Uncommon: allergic reactions like rash, itching or hives

Section 4, Special warnings and precautions for use

New text:

Traceability

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

Section 4.8 Undesirable effects

New text:

Uncommon: Hypersensitivity^c)

^c) Grouped term covering also adverse events related to hypersensitivity such as rash and urticaria.

Removed sentence 'Needles are medical devices' from IFU

Section 2, Warnings and precautions:

Ozempic® is not an insulin and should therefore not be used as a substitute for insulin.

Section 2, Other medicines and Ozempic®:

If you are using insulin, your doctor will tell you how to reduce the dose of insulin and will recommend you to monitor your blood sugar more frequently, in order to avoid hyperglycaemia (high blood sugar) and diabetic ketoacidosis (a complication of diabetes that occurs when the body is unable to break down glucose because there is not enough insulin).

Section 4.8:

Uncommon: may affect up to 1 in 100 people

•           Inflamed pancreas (acute pancreatitis) which could cause severe pain in the stomach and back which does not go away. You should see a doctor immediately if you experience such symptoms.

Section 4.8, reporting of side effects

Malta added

Instructions for Use:

Needles are medical devices.

Check the paper tab and the outer needle cap for damages that could affect sterility. If any damage is seen use a new needle.

If the paper tab is broken, do not use the needle, as sterility is not guaranteed.

Section 4.2

Posology:

Blood glucose self-monitoring is necessary to adjust the dose of sulfonylurea and insulin, particularly when Ozempic is started and insulin is reduced. A stepwise approach to insulin reduction is recommended. 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).

Section 4.4:

Diabetic ketoacidosis has been reported in insulin-dependent patients whom had rapid discontinuation or dose reduction of insulin when treatment with a GLP-1 receptor agonist is started (see section 4.2).

Section 4.8:

New uncommon ADR in Table 1: Acute pancreatitis

Description of selected adverse reactions:

Acute pancreatitis

The frequency of adjudication-confirmed acute pancreatitis reported in phase 3a clinical trials was 0.3% for semaglutide and 0.2% for the comparator, respectively. In the 2-year cardiovascular outcomes trial the frequency of acute pancreatitis confirmed by adjudication was 0.5% for semaglutide and 0.6% for placebo (see section 4.4).

Section 4.8, how to report a side effect

UK removed, Malta added