Vegzelma

Package Leaflet: Information for the User

Vegzelma 25 mg/mL concentrate for solution for infusion

bevacizumab
This medicinal product is subject to additional monitoring. This will allow any new safety information to be quickly identified. You can help by reporting any side effects you may experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What Vegzelma is and what it is used for
2. What you need to know before using Vegzelma
3. How to use Vegzelma
4. Possible side effects
5. How to store Vegzelma
6. Contents of the pack and other information

1. What Vegzelma is and what it is used for

Vegzelma contains the active substance bevacizumab, a humanised monoclonal antibody (a type of
protein normally produced by the immune system to help the body defend itself against infection and
cancer). Bevacizumab binds selectively to a protein called “human vascular endothelial growth factor”
(VEGF), which is present on the lining of the body’s blood and lymphatic vessels. The VEGF protein
promotes the growth of blood vessels within the tumour; these blood vessels supply the tumour with
nutrients and oxygen. Once bevacizumab binds to VEGF, tumour growth is inhibited by blocking the
development of blood vessels that supply nutrients and oxygen to the tumour.
Vegzelma is a medicine used to treat adult patients with advanced colorectal cancer, that is cancer of the
colon or rectum. Vegzelma will be administered in combination with a fluoropyrimidine-based
chemotherapy regimen.
Vegzelma is also used to treat adult patients with metastatic breast cancer. In patients with this type of
cancer, it will be administered with a chemotherapy regimen based on paclitaxel or capecitabine.
Vegzelma is also used to treat adult patients with advanced non-small cell lung cancer. Vegzelma will be
administered together with a platinum-based chemotherapy regimen.
Vegzelma is also used to treat adult patients with advanced non-small cell lung cancer when the tumour
cells have specific mutations in a protein called epidermal growth factor receptor (EGFR). Vegzelma will
be administered in combination with erlotinib.
Vegzelma is also used to treat adult patients with advanced renal cell carcinoma. In patients with this
type of cancer, bevacizumab will be administered together with another type of medicine called
interferon.
Vegzelma is also used to treat adult women with advanced epithelial ovarian cancer, fallopian tube
cancer, or primary peritoneal cancer. In patients with these types of cancer, bevacizumab will be
administered in combination with carboplatin and paclitaxel.
Vegzelma will be administered in combination with carboplatin and gemcitabine or with carboplatin
and paclitaxel when used in adult women with advanced epithelial ovarian cancer, fallopian tube
cancer, or primary peritoneal cancer whose disease has recurred at least 6 months after their last
treatment with a platinum-containing chemotherapy regimen.
Vegzelma will be administered in combination with paclitaxel, topotecan, or pegylated liposomal
doxorubicin when used in adult women with advanced epithelial ovarian cancer, fallopian tube cancer,
or primary peritoneal cancer whose disease has recurred within 6 months of their last treatment with a
platinum-containing chemotherapy regimen.
Vegzelma is also used to treat adult women with persistent, recurrent, or metastatic cervical cancer.
Vegzelma will be administered in combination with paclitaxel and cisplatin or, alternatively, with
paclitaxel and topotecan in women who cannot receive platinum-based therapy.

2. What you need to know before using Vegzelma

Do not use Vegzelma

• if you are allergic (hypersensitive) to bevacizumab or to any of the other ingredients of this medicine (listed in section 6).
• if you are allergic (hypersensitive) to products derived from Chinese hamster ovary (CHO) cells or to other recombinant human or humanized antibodies.
• if you are pregnant.

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before using Vegzelma

• Vegzelma may increase the risk of developing intestinal wall perforations. If you have conditions causing abdominal inflammation (e.g. diverticulitis, gastric ulcers, chemotherapy-associated colitis), discuss this with your doctor.
• Vegzelma may increase the risk of developing an abnormal connection or passage between two organs or blood vessels. Persistent, recurrent, or metastatic cervical carcinoma may increase the risk of developing connections between the vagina and any section of the gastrointestinal tract.
• Vegzelma may increase the risk of bleeding or cause problems with wound healing after surgery. Do not take this medicine if you are scheduled for surgery, if you have undergone major surgery within the past 28 days, or if you have a surgical wound that has not yet healed.
• Vegzelma may increase the risk of developing severe skin infections or infections in deeper layers beneath the skin, especially if you have intestinal wall perforations or problems with wound healing.
• Vegzelma may increase the incidence of high blood pressure. If you have high blood pressure that is not well controlled with antihypertensive medications, discuss this with your doctor. It is important to ensure your blood pressure is under control before starting treatment with Vegzelma.
• If you have or have had an aneurysm (a bulge and weakening in the wall of a blood vessel) or a tear in the wall of a blood vessel.
• Vegzelma increases the risk of having protein in the urine, especially if you already have high blood pressure.
• The risk of developing blood clots in arteries (a type of blood vessel) may increase if you are over 65 years old, have diabetes, or have had previous arterial blood clots. Talk to your doctor, as blood clots can lead to heart attacks and strokes.
• Vegzelma may also increase the risk of developing blood clots in veins (a type of blood vessel).
• Vegzelma can cause bleeding, particularly tumor-related bleeding. Consult your doctor if you or members of your family tend to have problems with blood clotting or if you are taking blood-thinning medications for any reason.
• Vegzelma may cause bleeding within or around the brain. Consult your doctor if you have metastatic brain tumors.
• Vegzelma may increase the risk of bleeding in the lungs, including coughing up blood or blood in saliva. Discuss with your doctor if you have experienced these events in the past.
• Vegzelma may increase the risk of developing heart failure. It is important that your doctor knows if you have previously received treatment with anthracyclines (e.g. doxorubicin, a specific type of chemotherapy used to treat certain cancers) or thoracic radiotherapy, or if you have heart disease.
• Vegzelma may cause infections and a reduction in neutrophil count (a type of blood cell important for protection against bacteria).
• Vegzelma may cause hypersensitivity (including anaphylactic shock) and/or infusion reactions (reactions related to the injection of the medicine). Inform your doctor, pharmacist, or nurse if you have previously experienced problems after injections, such as dizziness/fainting, shortness of breath, swelling, or skin rashes.
• A rare neurological side effect called reversible posterior encephalopathy syndrome (PRES) has been associated with treatment with Vegzelma. If you experience headache, vision disturbances, confusion, or seizures with or without elevated blood pressure, contact your doctor immediately.

Contact your doctor even if any of the above conditions occurred only in the past.
Before starting or during treatment with Vegzelma:

• if you have had or currently have mouth, tooth, and/or jaw pain, swelling or inflammation in the mouth, numbness or heaviness in the jaw, or lose a tooth, inform your doctor and dentist immediately;
• if you need to undergo invasive dental treatment or dental surgery, inform your dentist that you are being treated with Vegzelma, especially if you have received or are receiving intravenous bisphosphonate injections.

Your doctor or dentist may recommend a dental examination before starting treatment with Vegzelma.
Children and adolescents
Treatment with Vegzelma is not recommended in children and adolescents under 18 years of age, as neither safety nor benefit has been established in this patient population.
Bone tissue death (osteonecrosis) in bones other than the jaw has been observed in patients under 18 years of age treated with bevacizumab.
Other medicines and Vegzelma
Inform your doctor, pharmacist, or nurse if you are taking, have recently taken, or might take any other medicines.
Combining Vegzelma with another medicine called sunitinib malate (used for kidney and gastrointestinal cancers) may cause serious side effects. Discuss with your doctor to ensure you do not combine these medicines.
Inform your doctor if you are receiving platinum-based or taxane therapies for metastatic lung or breast cancer. These therapies in combination with Vegzelma may increase the risk of serious side effects.
Inform your doctor if you have recently received or are currently receiving radiotherapy.
Pregnancy, breastfeeding, and fertility
Do not use this medicine if you are pregnant. Vegzelma may harm the unborn baby, as it can interfere with the formation of new blood vessels. Your doctor will advise you to use adequate contraception during treatment with Vegzelma and for at least 6 months after the last dose of Vegzelma.
If you are pregnant, suspect you may be pregnant during treatment with this medicine, or are planning a pregnancy in the near future, speak to your doctor immediately.
You must not breastfeed during treatment with Vegzelma and for at least 6 months after the last dose of Vegzelma, as this medicine may interfere with the baby's growth and development.
Vegzelma may reduce female fertility. Consult your doctor for further information.
Ask your doctor, pharmacist, or nurse for advice before taking any medicine.
Driving and using machines
Vegzelma has not been shown to reduce the ability to drive or use tools or machines.
However, drowsiness and fainting have been reported with the use of Vegzelma. If you experience symptoms affecting your vision, concentration, or ability to react, do not drive or operate machinery until symptoms resolve.
Important information on some ingredients of Vegzelma
This medicine contains less than 1 mmol of sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.
This medicine contains 0.4 mg of polysorbate 20 per mL. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How to use Vegzelma

Dose and frequency of administration
The required dose of Vegzelma depends on your body weight and the type of tumour that needs to be
treated. The recommended dose is 5 mg, 7.5 mg, 10 mg or 15 mg per kilogram of body weight. Your
doctor will prescribe Vegzelma at the appropriate dose for you. Treatment with Vegzelma will be
administered once every 2 or 3 weeks. The number of infusions you will receive depends on your
response to treatment; however, you should continue receiving this treatment until Vegzelma is no
longer able to block the growth of your tumour. Your doctor will discuss this with you.
Method and route of administration
Vegzelma is a concentrate for solution for infusion. Depending on the prescribed dose, part of the
vial’s content or the entire vial of Vegzelma will be diluted with a sodium chloride solution before use.
Your doctor or nurse will administer this diluted Vegzelma solution as an intravenous infusion (a drip into a vein). The first infusion will be given over 90 minutes. If this is well tolerated, the second infusion may be given over 60 minutes. Subsequent infusions may be administered over 30 minutes.
Vegzelma administration must be temporarily interrupted

• if severe high blood pressure problems occur, requiring treatment with medicines to control blood pressure,
• if you have problems with wound healing after surgery,
• if you are scheduled to undergo a surgical procedure.

Vegzelma administration must be permanently discontinued if any of the following problems occur

• severe high blood pressure that cannot be controlled with antihypertensive medications, or sudden and severe increase in blood pressure,
• presence of protein in the urine associated with oedema (swelling of the body),
• perforation of the intestinal wall,
• an abnormal connection or passage between the trachea and oesophagus, internal organs and skin, vagina and any part of the gastrointestinal tract, or between other tissues not normally connected (fistula), considered by the doctor as severe,
• severe skin infections or infections of deeper layers beneath the skin,
• blood clots in the arteries,
• blood clots in the pulmonary blood vessels,
• severe bleeding of any kind.

If too much Vegzelma is administered

• You may experience severe headache. In this case, contact your doctor, pharmacist or nurse immediately.

If you forget to receive a dose of Vegzelma

• Your doctor will decide the most appropriate time to administer your next dose of Vegzelma. Discuss this with your doctor.

If you stop treatment with Vegzelma
Stopping treatment with Vegzelma may cause the tumour growth control effect to cease. Do not stop
treatment with Vegzelma without first discussing it with your doctor.
If you have any doubts about how to use this medicine, consult your doctor, pharmacist or
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody will experience them.
If you experience any side effect, including those not listed in this leaflet, speak to your doctor, pharmacist or nurse.
The side effects listed below have been observed in patients treated with Vegzelma in combination with chemotherapy. This does not mean that these side effects were necessarily caused by Vegzelma.

Allergic reactions
If you experience an allergic reaction, tell your doctor or a healthcare professional immediately. Signs may include: difficulty breathing or chest pain. Skin redness or flushing, rash, chills and shivering, feeling unwell (nausea) or vomiting, swelling, dizziness, rapid heartbeat, and loss of consciousness may also occur.

If you experience any of the side effects described below, seek immediate medical help.

Serious side effects that may be very common (may affect more than 1 in 10 people) include:

• high blood pressure,
• numbness or tingling in the hands or feet,
• reduction in blood cells, including white blood cells, which fight infections (this may be accompanied by fever), and cells involved in blood clotting,
• feeling weak and lacking energy,
• fatigue,
• diarrhoea, nausea, vomiting, and abdominal pain.

Serious side effects that may be common (may affect up to 1 in 10 people) include:

• intestinal perforation,
• bleeding, including bleeding in the lungs in patients with non-small cell lung cancer,
• blocked arteries due to a blood clot,
• blocked veins due to a blood clot,
• blocked pulmonary blood vessels due to a blood clot,
• blocked leg veins due to a blood clot,
• heart failure,
• problems with wound healing after surgery,
• redness, peeling, soreness, pain, or blistering on the palms of the hands or soles of the feet,
• reduction in the number of red blood cells,
• lack of energy,
• stomach and intestinal disorders,
• muscle and joint pain, muscle weakness,
• dry mouth associated with thirst and/or reduced or dark urine,
• inflammation of the mucous membranes of the mouth, intestine, lungs and airways, reproductive and urinary tract,
• mouth and oesophageal ulcers that may cause pain and difficulty swallowing,
• pain, including headache, back pain, and pain in the pelvic and anal area,
• localized abscesses,
• infections, particularly blood or bladder infections,
• reduced blood flow to the brain or stroke,
• drowsiness,
• nosebleeds,
• increased heart rate (pulsations),
• intestinal obstruction,
• changes in urine tests (presence of protein in the urine),
• shortness of breath or reduced oxygen levels in the blood,
• skin infections or infections of deeper skin layers,
• fistulas: abnormal tubular connections between internal organs and the skin or other tissues that are not normally connected, including connections between the vagina and gastrointestinal tract in patients with cervical cancer,
• allergic reactions (signs may include difficulty breathing, facial redness, rash, low or high blood pressure, low oxygen levels in the blood, chest pain, or nausea/vomiting).

Serious side effects that may be rare (may affect up to 1 in 1,000 people) include:

• sudden and severe allergic reaction with difficulty breathing, swelling, dizziness, rapid heartbeat, sweating, and loss of consciousness (anaphylactic shock).

Serious side effects with unknown frequency (frequency cannot be estimated from the available data) include:

• severe skin infections or infections of deeper layers beneath the skin, especially if you have had intestinal wall perforations or wound healing problems,
• a negative effect on women's ability to have children (see the sections following the list of side effects for further recommendations),
• a brain condition with symptoms such as seizures, headache, confusion, and vision changes (reversible posterior encephalopathy syndrome (PRES)),
• symptoms suggesting changes in normal brain function (headache, visual disturbances, confusion or seizures) and high blood pressure,
• dilation and weakening of the wall of a blood vessel or a tear in the blood vessel wall (aneurysms and arterial dissections),
• blockage of small blood vessel(s) in the kidney,
• abnormally high blood pressure in the blood vessels of the lungs, making the right side of the heart work harder than normal,
• perforation of the cartilage wall separating the nostrils,
• perforation of the stomach or intestine,
• an open wound or perforation in the lining of the stomach or small intestine (signs may include abdominal pain, feeling of bloating, black tarry stools, blood in the stool or blood in vomit),
• bleeding from the lower part of the large intestine,
• gum lesions with exposure of jawbone that do not heal, possibly associated with pain and inflammation of surrounding tissue (see the sections following the list of side effects for further recommendations),
• gallbladder perforation (symptoms and signs may include abdominal pain, fever, and nausea/vomiting).

If you experience any of the side effects described below, seek medical help as soon as possible.

Non-serious side effects that are very common (may affect more than 1 in 10 people) include:

• constipation,
• loss of appetite,
• fever,
• eye problems (including increased tear production),
• changes in speech,
• altered sense of taste,
• runny nose,
• dry, peeling, and inflamed skin, changes in skin colour,
• loss of body weight,
• nosebleeds.

Non-serious side effects that are common (may affect up to 1 in 10 people) include:

• changes in voice and hoarseness.

Patients over 65 years of age have an increased risk of the following side effects:

• blood clots in arteries, which may lead to stroke or heart attack,
• reduction in white blood cells and cells involved in blood clotting,
• diarrhoea,
• feeling unwell,
• headache,
• feeling of fatigue,
• high blood pressure.

Vegzelma may also cause changes in laboratory test results prescribed by your doctor. These include: a reduction in white blood cells, particularly neutrophils (a type of white blood cell that helps protect against infections), presence of protein in the urine, reduced levels of potassium, sodium or phosphorus (a mineral) in the blood, increased blood glucose levels, increased alkaline phosphatase (an enzyme) in the blood; increased serum creatinine (a protein measured in blood tests to assess kidney function); reduced haemoglobin (found in red blood cells and transports oxygen), which may be severe.

Pain in the mouth, teeth and/or jaw, swelling or blisters in the mouth, numbness or heaviness in the jaw, or tooth loss. These may be signs and symptoms of damage to the jawbone (osteonecrosis). Inform your doctor and dentist immediately if any of these effects occur.

Women of premenopausal age (women who have menstrual cycles) may notice menstrual irregularities, absence of menstruation, and may experience negative effects on fertility. If you are considering having children, you should discuss this with your doctor before starting treatment.

Vegzelma has been developed and manufactured for the treatment of cancer via intravenous injection. It has not been developed or manufactured for administration by injection into the eye. Therefore, this route of administration is not authorised. When bevacizumab is injected directly into the eye (unapproved use), the following side effects may occur:

• infection or inflammation of the eyeball,
• eye redness, appearance of floating particles or spots in the visual field ("floaters"), eye pain,
• flashes of light and "floaters" progressing to partial loss of vision,
• increased eye pressure,
• eye haemorrhages.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, speak to your doctor, pharmacist or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Vegzelma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the outer packaging and
on the label of the vial after the abbreviation “Exp./EXP”. The expiry date refers to the last day of that month.
Store in a refrigerator (2°C–8°C).
Do not freeze.
Keep the vial in the outer packaging to protect the medicine from light.
Diluted infusion solutions should be used immediately. If immediate use is not possible, the user is responsible for the storage duration and conditions, which normally should not exceed 24 hours at a temperature between 2°C and 8°C, unless the infusion solutions have been prepared under sterile conditions. If dilution has been performed under sterile conditions, Vegzelma is stable for 60 days at a temperature between 2°C and 8°C plus an additional 7 days at a temperature between 2°C and 30°C.
Do not use Vegzelma if you notice particulate matter or changes in colour before administration.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

What Vegzelma contains

• The active substance is bevacizumab. Each mL of concentrate contains 25 mg of bevacizumab, corresponding to 1.4–16.5 mg/mL when diluted as recommended. Each 4 mL vial contains 100 mg of bevacizumab, corresponding to 1.4 mg/mL when diluted as recommended. Each 16 mL vial contains 400 mg of bevacizumab, corresponding to 16.5 mg/mL when diluted as recommended.
• The other components are trehalose dihydrate, sodium phosphate, polysorbate 20, and water for injections.

Description of the appearance of Vegzelma and contents of the pack
Vegzelma is a concentrate for solution for infusion. The concentrate is a clear liquid, colourless to pale brown, in a glass vial closed with a rubber stopper. Each vial contains 100 mg of bevacizumab in 4 mL of solution or 400 mg of bevacizumab in 16 mL of solution. Each pack of Vegzelma contains 1, 2, or 10 vials.

Marketing Authorisation Holder
Celltrion Healthcare Hungary Kft.
1062 Budapest
Váci út 1-3. WestEnd Office Building B tower
Hungary

Manufacturer
Nuvisan GmbH
Wegenerstraße 13
89231 Neu-Ulm
Germany
Nuvisan France SARL
2400, Route des Colles
06410, Biot
France
Kymos S.L.
Ronda Can Fatjó 7B
(Parc Tecnològic del Vallès) Cerdanyola del Vallès
08290 Barcelona
Spain
Midas Pharma GmbH
Rheinstraße 49
55218 Ingelheim am Rhein
Germany

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Celltrion Healthcare Belgium BVBA Celltrion Healthcare Hungary Kft.
Tél/Tel: +32 1528 7418 Tel.: +36 1 231 0493

България Luxembourg/Luxemburg
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Belgium BVBA
Teл.: +36 1 231 0493 Tél/Tel: +32 1528 7418

Česká republika Magyarország
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Tel: +36 1 231 0493 Tel.: +36 1 231 0493

Danmark Malta
Celltrion Healthcare Denmark ApS Mint Health Ltd.
Tlf: +45 3535 2989 Tel: +356 2093 9800
[email protected]

Deutschland Nederland
Celltrion Healthcare Deutschland GmbH Celltrion Healthcare Netherlands B.V.
Tel: +49 (0)30 346494150 Tel: +31 20 888 7300
[email protected]

Eesti Norge
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Norway AS
Tel: +36 1 231 0493 [email protected]

España Österreich
CELLTRION FARMACEUTICA (ESPAÑA) S.L. Astro-Pharma GmbH
Tel: +34 910 498 478 Tel: +43 1 97 99 860

Ελλάδα Polska
ΒΙΑΝΕΞ Α.Ε. Celltrion Healthcare Hungary Kft.
Τηλ: +30 210 8009111 - 120 Tel.: +36 1 231 0493

France Portugal
CELLTRION HEALTHCARE FRANCE SAS CELLTRION PORTUGAL, UNIPESSOAL LDA
Tél.: +33 (0)1 71 25 27 00 Tel: +351 21 936 8542

Hrvatska România
Oktal Pharma d.o.o. Celltrion Healthcare Hungary Kft.
Tel: +385 1 6595 777 Tel: +36 1 231 0493

Ireland Slovenija
Celltrion Healthcare Ireland Limited OPH Oktal Pharma d.o.o.
Tel: +353 1 223 4026 Tel.: +386 1 519 29 22

Ísland Slovenská republika
Celltrion Healthcare Hungary Kft. Celltrion Healthcare Hungary Kft.
Sími: +36 1 231 0493 Tel: +36 1 231 0493

Italia Suomi/Finland
Celltrion Healthcare Italy S.R.L. Celltrion Healthcare Finland Oy.
Tel: +39 0247927040 Puh/Tel: +358 29 170 7755
[email protected]

Κύπρος Sverige
C.A. Papaellinas Ltd Celltrion Sweden AB
Τηλ: +357 22741741 Tel: +46 8 80 11 77
[email protected]

Latvija
Celltrion Healthcare Hungary Kft.
Tālr.: +36 1 231 0493

Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu

ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS OF THE
MARKETING AUTHORISATIONS

Scientific conclusions
Taking into account the assessment by the Pharmacovigilance Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for bevacizumab, the PRAC's scientific conclusions are as follows:
In view of the available data on hyaline glomerular occlusive microangiopathy reported in the literature, including some cases with positive dechallenge, and in view of a plausible mechanism of action, the PRAC considers that a causal relationship between bevacizumab and hyaline glomerular occlusive microangiopathy is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing bevacizumab should therefore be amended accordingly.
Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and the rationale of the recommendation.

Reasons for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions for bevacizumab, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing bevacizumab remains favourable, subject to the proposed changes to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation(s).