Gadovist

Package leaflet: Information for the patient

Gadovist 1.0 mmol/ml solution for injection

Gadobutrol
Please read all of this leaflet carefully before you are given 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, the person who will administer Gadovist (the radiologist), or hospital/ MRI centre staff.
• If you get any side effects, including those not listed in this leaflet, tell your doctor or radiologist. See section 4.

Contents of this leaflet:

1. What Gadovist is and what it is used for
2. What you need to know before you are given Gadovist
3. How you will be given Gadovist
4. Possible side effects
5. How to store Gadovist
6. Contents of the pack and other information

1. What Gadovist is and what it is used for

Gadovist is a contrast agent for Magnetic Resonance Imaging (MRI) used in the diagnosis of the brain,
spinal cord, and blood vessels.
Gadovist may also help your doctor determine the nature of a known or suspected abnormality (benign or malignant)
in the liver and kidneys.
Gadovist may also be used in magnetic resonance imaging (MRI) to investigate abnormalities in other parts of the body.
Gadovist enhances the visibility of abnormal structures or lesions and helps to differentiate between
healthy and diseased tissue. It is indicated for adults and children of all ages (including full-term newborns).
How Gadovist works
MRI is an imaging diagnostic technique that exploits the behavior of water molecules in normal and abnormal tissues.
This technique relies on a complex system of magnets and radio waves. Computers record the signals and convert them into images.
Gadovist is administered by intravenous injection. This medicinal product is for diagnostic use only and
will be administered solely by healthcare professionals experienced in clinical MRI practice.

2. What you need to know before receiving Gadovist

Do NOT use Gadovist if

• you are allergic to gadobutrol or to any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor before you are given Gadovist if

• you suffer or have suffered from an allergy (e.g. hay fever, hives) or asthma
• you have previously experienced reactions to any contrast agent
• you have severely impaired kidney function
• you suffer from brain disorders with seizures (epileptic crises) or other diseases of the nervous system
• you have a pacemaker or if there are implants or clips containing iron in your body

Your doctor will decide whether or not you can undergo the planned examination.

• Allergic-type reactions or other types of reactions causing heart problems, breathing difficulties, or skin reactions may occur after the use of Gadovist. Severe reactions are possible. Many of these reactions occur within half an hour after administration of Gadovist; therefore, you will be monitored after the procedure. Delayed reactions (after hours or days) have been observed (see section 4).

Kidneys/liver
Inform your doctor if

• your kidneys are not functioning properly
• you have recently had, or are scheduled to have a liver transplant in the near future.

Your doctor may decide to perform a blood test to assess whether your kidneys are functioning properly before deciding to use Gadovist, especially if you are 65 years of age or older.

Newborns and infants
Since kidney function is not yet fully matured in children up to 4 weeks of age and in infants up to 1 year of age, Gadovist will only be used in these patients after careful evaluation by the doctor.

Other medicines and Gadovist
Inform your doctor if you are taking, have recently taken, or might take any other medicines.

Pregnancy and breastfeeding

• Pregnancy Gadobutrol may cross the placenta. It is not known whether this affects the unborn child. Inform your doctor if you think you may be pregnant or if you are planning a pregnancy. Gadovist must not be used during pregnancy unless strictly necessary.
• Breastfeeding Inform your doctor if you are breastfeeding or intend to start breastfeeding. Your doctor will decide whether you can continue breastfeeding or whether you should interrupt breastfeeding for a period of 24 hours after administration of Gadovist.

Gadovist contains sodium
This medicine contains less than 23 mg of sodium per dose (based on the average amount administered to a 70 kg person), i.e. essentially ‘sodium-free’.

3. How Gadovist is administered

Gadovist is injected intravenously through a small needle by a healthcare professional. The MRI examination can begin immediately.
After the injection, you will be monitored for at least 30 minutes.
Standard dose
The appropriate dose for you depends on your body weight and the body region being examined by MRI:
In adults, a single injection of 0.1 millilitre of Gadovist per kg of body weight is recommended (this means that for a 70 kg person the dose would be 7 millilitres). However, an additional injection of up to 0.2 millilitres per kg of body weight may be given within 30 minutes of the first injection. A total dose of up to 0.3 millilitres of Gadovist per kg of body weight is permitted as the maximum dose (this means that for a 70 kg person the dose would be 21 millilitres) for imaging of the central nervous system (CNS) and CE-MRA. A minimum dose of 0.075 millilitres of Gadovist per kg of body weight is permitted (this means that for a 70 kg person the dose would be 5.25 millilitres) for CNS imaging.
Further information on the administration and handling of Gadovist is provided at the end of this leaflet.
Dosing in special patient populations
The use of Gadovist is not recommended in patients with severe kidney problems and in patients who have recently undergone or are about to undergo a liver transplant. However, if use is required, only one dose of Gadovist should be administered during the examination, and a second administration must not be given within at least 7 days.
Newborns, infants, children and adolescents

• In children of all ages (including full-term newborns), a single dose of 0.1 millilitre of Gadovist per kg of body weight is recommended for all types of diagnostic examinations (see section 1).
• Since renal function is not yet mature in children up to 4 weeks of age and in infants up to 1 year of age, Gadovist should be used in these patients only after careful medical evaluation. Newborns and infants should receive only one dose of Gadovist during the examination and should not receive a second injection within at least 7 days.

Elderly
No dose adjustment is necessary if you are 65 years of age or older, but you may undergo a blood test to assess whether your kidneys are functioning properly.
If you receive more Gadovist than you should
An overdose is unlikely. If it does occur, your doctor will treat any symptoms and may use renal dialysis to remove Gadovist from your body. There is no evidence that this can prevent the development of Nephrogenic Systemic Fibrosis (NSF; see section 4). Therefore, renal dialysis should not be used as a treatment for this condition. In some cases, your heart may be monitored.
If you have any doubts about the use of this medicine, consult your doctor or radiologist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them. Most of these reactions occur within half an hour after administration of Gadovist. In rare cases, delayed allergic or other adverse reactions have been observed, occurring from hours to several days after administration of Gadovist. If this happens to you, inform your doctor or radiologist immediately.

The most serious side effects (which have been fatal or life-threatening in some cases) are:

• Heart stops beating ( cardiac arrest ), a severe lung disease ( acute respiratory distress syndrome ) / fluid in the lungs ( pulmonary edema ), and a severe allergic-like reaction ( anaphylactoid ) (including respiratory arrest and shock)

In addition, the following side effects have been associated with fatal or life-threatening outcomes in some cases:

• Shortness of breath ( dyspnea ), loss of consciousness, severe allergic-like reaction, severe drop in blood pressure that may lead to collapse, respiratory arrest, fluid in the lungs, swelling of the mouth and throat, and low blood pressure.

In rare cases:

• Allergic-type reactions (hypersensitivity and anaphylaxis), including severe reactions (shock), requiring immediate medical intervention.

If you notice:

• swelling of the face, lips, tongue or throat,
• coughing and sneezing
• difficulty breathing
• itching
• runny nose
• hives

inform the MRI department staff immediately. These may be the first signs of an impending serious reaction. The examination may need to be stopped and you may require additional treatment.

The most commonly observed side effects (may affect 5 or more subjects per 1,000) are:

• headache, feeling unwell (nausea), and dizziness.

Most of the observed side effects are mild to moderate.

The possible side effects observed in clinical studies prior to the approval of Gadovist are listed below according to their likelihood of occurrence:

Common: (may affect up to 1 in 10 people)

• headache
• feeling unwell ( nausea )

Uncommon: (may affect up to 1 in 100 people)

• Allergic-like reactions, for example:
  • low blood pressure
  • hives
  • facial swelling
  • swelling (edema) of the eyelid
  • redness

The frequency of the following allergic-like reactions is not known:

• a severe allergic-like reaction (anaphylactic shock)
• marked drop in blood pressure that may lead to collapse (shock)
• respiratory arrest
• breathing difficulties (bronchospasm)
• blue lips
• swelling of the mouth and throat
• swelling of the throat
• increase in blood pressure
• chest pain
• swelling of the face, throat, mouth, lips and/or tongue (angioedema)
• conjunctivitis
• increased sweating
• cough
• sneezing
• burning sensation
• pale skin (pallor)
• dizziness, altered taste sensation, numbness and tingling
• shortness of breath ( dyspnea )
• vomiting
• redness of the skin ( erythema )
• itching including generalized itching ( pruritus )
• skin rash (including generalized rash, flat red spots [ macular rash ], small, localized, raised lesions [ papular rash ], and itchy skin rash [pruritic exanthem])
• various types of injection site reactions (e.g., extravasation into surrounding tissues, burning, cold sensation, warm sensation, redness, rash, pain or bruising)
• sensation of warmth

Rare: (may affect up to 1 in 1,000 people)

• fainting
• convulsion
• altered sense of smell
• rapid heartbeat
• palpitations
• dry mouth
• feeling of general discomfort ( malaise )
• cold sensation

Other side effects reported after Gadovist approval with unknown frequency (frequency cannot be estimated from available data):

• heart stops beating ( cardiac arrest )
• a severe lung disease ( acute respiratory distress syndrome )
• fluid in the lungs ( pulmonary edema )
• cases of nephrogenic systemic fibrosis - NSF (which causes hardening of the skin and may also affect soft tissues and internal organs) have been reported.

After administration of Gadovist, changes in kidney function have been observed in blood tests (e.g., increased serum creatinine).

Reporting of side effects

If you experience any side effects, including those not listed in this leaflet, talk to your doctor or radiologist. You can also report side effects directly via the national reporting system at: http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Gadovist

Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the label and carton following "Exp". The expiry date refers to the last day of that month. This medicinal product does not require any special storage conditions.
Chemical, physical and microbiological stability of the product after opening has been demonstrated for 24 hours at 20–25°C.
From a microbiological standpoint, the product should be used immediately after opening.
This medicinal product is a clear, colourless to pale yellow solution. Do not use this medicinal product if there is any obvious change in colour, if particles are present, or if the container appears damaged.
Medicinal products must not be disposed of via wastewater or household waste. Healthcare professionals will dispose of this medicinal product when it is no longer needed. This will help protect the environment.

6. Package contents and other information

What Gadovist contains

• The active substance is gadobutrol.

1 ml of injectable solution contains 604.72 mg of gadobutrol (equivalent to 1.0 mmol of gadobutrol,
containing 157.25 mg of gadolinium).
1 vial of 2 ml contains 1209.44 mg of gadobutrol.
1 vial of 7.5 ml contains 4,535.4 mg of gadobutrol.
1 vial of 15 ml contains 9,070.8 mg of gadobutrol.
1 vial of 30 ml contains 18,141.6 mg of gadobutrol.
1 bottle of 65 ml contains 39,306.8 mg of gadobutrol.

• The other components are sodium calcobutrol (see end of section 2), trometamol, hydrochloric acid 1 N, and water for injections.

Description of the appearance of Gadovist and package contents
Gadovist is a clear, colourless to pale yellow injectable solution. The packages contain:

• 1 or 3 vials containing 2 ml of injectable solution
• 1 or 10 vials containing 7.5, 15 or 30 ml of injectable solution
• 1 or 10 bottles containing 65 ml of injectable solution (in a 100 ml infusion bottle)

Hospital pack:

• 3 vials of 2 ml of injectable solution
  • 10 vials of 7.5, 15 or 30 ml of injectable solution
  • 10 bottles of 65 ml of injectable solution

Not all pack sizes may be marketed.

Marketing Authorisation Holder:
Bayer S.p.A.
Viale Certosa, 130
20156 Milan
Italy

Manufacturer:
Bayer AG
Müllerstrasse 178
13353 Berlin
Germany

This medicinal product is authorised in the European Economic Area countries under the following names:

This leaflet was last updated on

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The following information is intended exclusively for healthcare professionals:

• Renal impairment

Prior to administration of Gadovist, it is recommended that all patients be screened for renal dysfunction using laboratory tests.
Cases of nephrogenic systemic fibrosis (NSF) have been reported following the use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR <30 mL/min/1.73 m²). Patients undergoing liver transplantation are at particular risk, as the incidence of acute renal failure is high in this patient population. Since NSF may occur with Gadovist, the medicinal product should be used in patients with severe renal impairment and in patients during the perioperative period of liver transplantation only after careful assessment of the risk-benefit ratio and if essential diagnostic information cannot be obtained by non-contrast MRI.

If use of Gadovist is necessary, the dose should not exceed 0.1 mmol/kg body weight. No more than one dose should be administered per examination. Due to the lack of data on repeated administrations, injections of Gadovist should not be repeated without an interval of at least 7 days between doses.

Since renal clearance of Gadovist may be reduced in elderly patients, screening for renal function is particularly important in patients aged 65 years and older.

Haemodialysis immediately after administration of Gadovist may be helpful in removing Gadovist from the body. However, there is no evidence to support the use of haemodialysis in the prevention or treatment of NSF in patients not already undergoing dialysis.

• Pregnancy and lactation Gadovist must not be used during pregnancy unless the clinical condition of the woman necessitates the use of Gadovist.

The physician and the breastfeeding mother should decide whether to discontinue breastfeeding for 24 hours after administration of Gadovist.

• Hypersensitivity reactions

As with other intravenous contrast agents, Gadovist may be associated with anaphylactoid/hypersensitivity-type reactions or other idiosyncratic reactions, characterized by cardiovascular, respiratory, and cutaneous manifestations, sometimes severe up to shock. In general, patients with cardiovascular disorders are more susceptible to severe or even fatal outcomes from severe hypersensitivity reactions.

The risk of hypersensitivity reactions is increased in the following cases:

• previous reactions to contrast media
• history of bronchial asthma
• history of allergic disorders

In patients with a predisposition to allergy, the decision to use Gadovist should be made only after careful assessment of the risk-benefit ratio.

Many of these reactions occur within 30 minutes after administration; therefore, patient monitoring after the procedure is recommended.

Immediate availability of emergency treatment for hypersensitivity reactions must be ensured, and emergency measures must be readily available.

In rare cases, delayed reactions (occurring hours to several days later) have been observed.

• Seizure disorders

As with all other gadolinium-containing contrast agents, particular caution is required in patients with a low seizure threshold.

• Overdose

In case of accidental overdose, cardiovascular monitoring (including ECG) and monitoring of renal function are recommended as precautionary measures.

In case of overdose in patients with renal impairment, Gadovist can be removed by haemodialysis. After three haemodialysis sessions, approximately 98% of the product is eliminated from the body. However, there is no evidence that haemodialysis is effective in preventing nephrogenic systemic fibrosis (NSF).

• Before injection This medicinal product is for single use only. This medicine is a clear, colourless to slightly yellow solution. It should be inspected visually prior to use. Gadovist should not be used if obvious discolouration, particulate matter, or container defects are present.

• Instructions for use

Gadovist must be drawn from the vial into the syringe immediately before use.

The rubber stopper must not be punctured more than once.
Any unused contrast medium must be discarded after the examination.
If this medicinal product is to be administered using an automated injector, the suitability of the system for such use must be demonstrated by the medical device manufacturer.
Any additional instructions provided by the manufacturer of the respective equipment must also be followed.
Any unused solution must be disposed of in accordance with local regulations.

Stability after container opening
Any unused injectable solution remaining after the examination must be discarded. Chemical, physical and microbiological stability of the product after opening has been demonstrated for 24 hours at 20–25°C.
From a microbiological standpoint, the product should be used immediately. If not used immediately, the duration and storage conditions become the responsibility of the user.
The traceability label on the vials/bottles must be removed and affixed to the patient's documentation to ensure accurate recording of the gadolinium-containing contrast agent used. The administered dose must also be recorded.
If electronic documentation is used, the product name, batch number and dose must be entered into the patient’s electronic record.

Dosage
Use the lowest dose that provides sufficient diagnostic enhancement. The dose should be calculated based on the patient’s body weight and must not exceed the recommended dose per kilogram of body weight specified in this section.

• Adults

Indications for the central nervous system (CNS):
The recommended dose for adults is 0.1 mmol per kilogram of body weight (mmol/kg body weight).
This corresponds to 0.1 mL/kg body weight of the 1.0 M solution.
If there is a strong clinical suspicion of a lesion despite a non-diagnostic MRI, or if more precise information could influence patient management, an additional injection of up to 0.2 mL/kg body weight may be administered within 30 minutes of the previous dose. A dose of 0.075 mmol of gadobutrol per kg body weight (equivalent to 0.075 mL of Gadovist per kg body weight) may be used for CNS imaging.

Whole-body MRI (excluding MRA):
In general, administration of 0.1 mL of Gadovist per kg body weight is sufficient to address diagnostic questions.

Contrast enhancement in Magnetic Resonance Angiography (MRA):
Single field-of-view (FOV) imaging: 7.5 mL for patients weighing less than 75 kg, 10 mL for patients weighing 75 kg or more (corresponding to 0.1–0.15 mmol/kg body weight).
Multiple FOV imaging (>1 FOV): 15 mL for patients weighing less than 75 kg, 20 mL for patients weighing 75 kg or more (corresponding to 0.2–0.3 mmol/kg body weight).

• Paediatric population

For children of all ages (including full-term neonates), the recommended dose is 0.1 mmol of gadobutrol per kg body weight (corresponding to 0.1 mL of Gadovist per kg body weight) for all indications (see section 1).
Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist should be used in these patients only after careful consideration and at a dose not exceeding 0.1 mmol/kg body weight. More than one dose must not be administered during a single examination. Due to lack of data on repeated administrations, Gadovist injections should not be repeated unless the interval between doses is at least 7 days.

Administration
The required dose is administered intravenously as a bolus injection. MRI with contrast may begin immediately after (or shortly after, depending on the pulse sequences and examination protocol) the injection.
Optimal signal enhancement occurs during the first arterial pass of the contrast agent for Magnetic Resonance Angiography, and within approximately 15 minutes after Gadovist injection for CNS indications (timing depends on lesion/tissue type).
T1-weighted sequences are particularly suitable for contrast-enhanced examinations.
Further information on the use of Gadovist is provided in section 3 of the Summary of Product Characteristics.

Patient Information Leaflet: Information for the patient

Gadovist 1.0 mmol/ml injectable solution, pre-filled syringe/cartridge

Gadobutrol
Please read this leaflet carefully before receiving this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, consult your doctor, the person administering Gadovist (the radiologist), or hospital/clinic MRI staff. If you experience any side effects, including those not listed in this leaflet, inform your doctor or radiologist. See section 4.

Contents of this leaflet:

1. What Gadovist is and what it is used for
2. What you need to know before receiving Gadovist
3. How you will receive Gadovist
4. Possible side effects
5. How to store Gadovist
6. Package contents and other information

1. What Gadovist is and what it is used for

Gadovist is a contrast agent for Magnetic Resonance Imaging (MRI) used in the diagnosis of the brain,
spinal cord, and blood vessels.
Gadovist may also help the doctor to highlight the nature of a known or suspected abnormality (benign or malignant)
in the liver and kidneys.
Gadovist may also be used for magnetic resonance imaging of abnormalities in other parts of the body.
Gadovist enhances the visualization of abnormal structures or lesions and helps to differentiate
between healthy and diseased tissue. It is indicated for adults and children of all ages (including full-term newborns).
How Gadovist works
MRI is an imaging diagnostic technique that exploits the behavior of water molecules in normal and abnormal
tissues. This technique is based on a complex system of magnets and radio waves. Computers record the activity and convert it into images.
Gadovist is administered by intravenous injection. This medicinal product is for diagnostic use only and
will be administered only by healthcare professionals experienced in clinical MRI practice.

2. What you should know before receiving Gadovist

Do NOT use Gadovist if

• you are allergic to gadobutrol or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor before you are given Gadovist if

• you suffer or have suffered from an allergy (e.g. hay fever, hives) or asthma
• you have previously had reactions to any contrast agent
• you have severely impaired kidney function
• you suffer from brain disorders with seizures (epileptic seizures) or other diseases of the nervous system
• you have a pacemaker or if there are implants or clips containing iron in your body

Your doctor will decide whether or not you can undergo the planned examination.

• Allergic-type reactions or other types of reactions causing heart problems, breathing difficulties, and skin reactions may occur after the use of Gadovist. Severe reactions are possible. Many of these reactions occur within half an hour after administration of Gadovist; therefore, you will be monitored after the procedure. Delayed reactions (after hours or days) have been observed (see section 4).

Kidneys/liver
Inform your doctor if

• your kidneys are not functioning properly
• you have recently had, or are expected to have a liver transplant in the near future.

Your doctor may decide to perform a blood test to assess whether your kidneys are functioning properly before deciding to use Gadovist, especially if you are 65 years of age or older.
Newborns and infants
Since kidney function is not yet mature in children up to 4 weeks of age and in infants up to 1 year of age, Gadovist will be used in these patients only after careful medical evaluation.
Other medicines and Gadovist
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Pregnancy and breastfeeding
Ask your doctor for advice before taking any medicine

• Pregnancy Gadobutrol may cross the placenta. It is not known whether this affects the baby. Inform your doctor if you think you may be pregnant or if you are planning a pregnancy. Gadovist must not be used during pregnancy unless strictly necessary.
• Breastfeeding Inform your doctor if you are breastfeeding or intend to start breastfeeding. Your doctor will decide whether you should continue or interrupt breastfeeding for a period of 24 hours after administration of Gadovist.

Gadovist contains sodium
This medicine contains less than 23 mg of sodium per dose (based on the average amount administered to a 70 kg person), i.e. essentially 'sodium-free'.

3. How Gadovist is administered

Gadovist is injected intravenously by a healthcare professional using a small needle. The MRI examination may begin immediately.
After the injection, you will be monitored for at least 30 minutes.
Standard dose
The actual dose suitable for you depends on your body weight and the body region to be examined by MRI:
in adults, a single injection of 0.1 millilitres of Gadovist per kg of body weight is recommended (this means, for a 70 kg person, the dose would be 7 millilitres); however, an additional injection of up to 0.2 millilitres per kg of body weight may be given within 30 minutes of the first injection. A total dose of up to 0.3 millilitres of Gadovist per kg of body weight is permitted as the maximum dose (this means, for a 70 kg person, the dose would be 21 millilitres) for imaging of the central nervous system (CNS) and CE-MRA. A dose of 0.075 millilitres of Gadovist per kg of body weight is permitted as the minimum dose (this means, for a 70 kg person, the dose would be 5.25 millilitres) for CNS imaging.
Further information on the administration and handling of Gadovist is provided at the end of the

Package leaflet

Dosage in special patient populations
The use of Gadovist is not recommended in patients with severe kidney problems and in patients who have recently undergone or are about to undergo liver transplantation. However, if use is required, only one dose of Gadovist should be administered during the examination, and a second administration must not be given within at least 7 days.
Newborns, infants, children and adolescents

• In children of all ages (including full-term newborns), a single dose of 0.1 millilitre of Gadovist per kg of body weight is recommended for all types of diagnostic examinations (see section 1).
• Since kidney function is not yet mature in children up to 4 weeks of age and in infants up to 1 year of age, Gadovist should be used in these patients only after careful medical evaluation. Newborns and infants should receive only one dose of Gadovist during the examination and must not receive a second injection within at least 7 days.

Elderly
No dose adjustment is necessary if you are 65 years of age or older, but you may undergo a blood test to assess whether your kidneys are functioning properly.
If you receive more Gadovist than you should
Overdose is unlikely. If it does occur, your doctor will treat any symptoms and may use haemodialysis to remove Gadovist from the body. There is no evidence that this can prevent the development of Nephrogenic Systemic Fibrosis (NSF; see section 4). Therefore, haemodialysis should not be used as a treatment for this condition. In some cases, your heart may be monitored.
If you have any questions about the use of this medicine, consult your doctor or radiologist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them. Most of these reactions occur within half an hour after administration of Gadovist. In rare cases, delayed allergic-type or other adverse reactions have been observed, occurring several hours to several days after administration of Gadovist. If this happens to you, inform your doctor or radiologist immediately.

The most serious side effects (which have been fatal or life-threatening in some cases) are:

• heart stops beating ( cardiac arrest ), a severe lung disease ( acute respiratory distress syndrome ) / fluid in the lungs ( pulmonary edema ), and a severe allergic-like reaction ( anaphylactoid ) (including respiratory arrest and shock).

In addition, the following side effects have in some cases been associated with fatal or life-threatening outcomes:

• Shortness of breath ( dyspnea ), loss of consciousness, severe allergic-like reaction, severe drop in blood pressure that may lead to collapse, respiratory arrest, fluid in the lungs, swelling of the mouth and throat, and low blood pressure.

In rare cases:

• allergic-type reactions (hypersensitivity and anaphylaxis), including severe reactions (shock), may occur, requiring immediate medical intervention.

If you notice:

• swelling of the face, lips, tongue, or throat,
• coughing and sneezing,
• difficulty breathing,
• itching,
• runny nose,
• hives,

inform the MRI department staff immediately. These may be the first signs of an impending serious reaction. It may be necessary to stop the examination and administer additional treatments.

The most commonly observed side effects (may affect 5 or more subjects per 1,000) are:

• headache, feeling unwell ( nausea ), and dizziness.

Many of the side effects are mild to moderate in severity.

The possible side effects observed in clinical studies prior to the approval of Gadovist are listed below according to their frequency of occurrence:

Common: (may affect up to 1 in 10 people)

• headache
• feeling unwell ( nausea )

Uncommon: (may affect up to 1 in 100 people)

• Allergic-like reactions, for example:
• low blood pressure
• hives
• facial swelling
• swelling ( edema ) of the eyelid
• flushing

The frequency of the following allergic-like reactions is not known:

• a severe allergic-like reaction ( anaphylactoid shock )
• marked drop in blood pressure that may lead to collapse ( shock )
• respiratory arrest
• breathing difficulties ( bronchospasm )
• blue lips
• swelling of the mouth and throat
• swelling of the throat
• increased blood pressure
• chest pain
• swelling of the face, throat, mouth, lips and/or tongue ( angioedema )
• conjunctivitis
• increased sweating
• cough
• sneezing
• burning sensation
• pale skin (pallor)
• dizziness, altered taste sensation, numbness, and tingling
• shortness of breath ( dyspnea )
• vomiting
• skin redness ( erythema )
• itching, including generalized itching ( pruritus )
• skin rash (including generalized rash, flat red spots [ macular rash ], small, circumscribed, raised lesions [ papular rash ], and itchy rash [pruritic exanthem])
• various types of reaction at the injection site (e.g., extravasation into surrounding tissues, burning, cold sensation, warm sensation, redness, rash, pain, or bruising)
• sensation of warmth

Rare: (may affect up to 1 in 1,000 people)

• fainting
• convulsion
• altered sense of smell
• rapid heartbeat
• palpitations
• dry mouth
• feeling of general discomfort ( malaise )
• cold sensation

Other side effects reported after the approval of Gadovist with frequency not known (frequency cannot be estimated from the available data):

• heart stops beating ( cardiac arrest )
• a severe lung disease ( acute respiratory distress syndrome )
• fluid in the lungs ( pulmonary edema )
• cases of nephrogenic systemic fibrosis - NSF (which causes hardening of the skin and may also affect soft tissues and internal organs) have been reported.

After administration of Gadovist, changes in kidney function have been observed in blood tests (e.g., increased serum creatinine).

Reporting of side effects

If you experience any side effect, including those not listed in this leaflet, talk to your doctor or radiologist. You can also report side effects directly via the national reporting system at: http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Gadovist

Keep this medicinal product out of the sight and reach of children.
Do not use this medicinal product after the expiry date stated on the label and carton after Exp. The expiry
date refers to the last day of that month. This medicinal product does not require any special storage
conditions.
Chemical, physical and microbiological stability of the product after opening has been demonstrated for 24 hours at 20–
25°C.
From a microbiological standpoint, the product should be used immediately after opening.
This medicinal product is a clear, colourless to slightly yellow solution. Do not use this medicinal product if there is an obvious change in colour, if particles are present, or if the container appears damaged.
Medicines must not be disposed of via wastewater or household waste. Healthcare professionals will dispose of this medicinal product when it is no longer needed. This will help protect the environment.

6. Package contents and other information

What Gadovist contains

• The active substance is gadobutrol.

1 ml of injectable solution contains 604.72 mg of gadobutrol (equivalent to 1.0 mmol of gadobutrol,
containing 157.25 mg of gadolinium).
A 5 ml pre-filled syringe contains 3,023.6 mg of gadobutrol
A 7.5 ml pre-filled syringe contains 4,535.4 mg of gadobutrol
A 10 ml pre-filled syringe contains 6,047.2 mg of gadobutrol
A 15 ml pre-filled syringe contains 9,070.8 mg of gadobutrol
A 20 ml pre-filled syringe contains 12,094.4 mg of gadobutrol
A 15 ml cartridge contains 9,070.8 mg of gadobutrol
A 20 ml cartridge contains 12,094.4 mg of gadobutrol
A 30 ml cartridge contains 18,141.6 mg of gadobutrol

• The other components are sodium calcobutrol (see end of section 2), trometamol, hydrochloric acid 1 N and water for injectable preparations.

Description of the appearance of Gadovist and package contents
Gadovist is a clear, colourless to slightly yellow injectable solution. The packages contain:

• 1 or 5 pre-filled syringes containing 5, 7.5, or 10 ml of injectable solution (in a 10 ml glass or plastic pre-filled syringe)
• 1 or 5 pre-filled syringes containing 15 ml of injectable solution (in a 17 ml glass pre-filled syringe or 20 ml plastic pre-filled syringe)
• 1 or 5 pre-filled syringes containing 20 ml of injectable solution (in a 20 ml glass or plastic pre-filled syringe)
• 1 or 5 cartridges containing 15, 20, or 30 ml of injectable solution (in a 65 ml cartridge)

Hospital pack:

• 5 pre-filled syringes of 5, 7.5, 10, 15, or 20 ml of injectable solution
• 5 cartridges of 15, 20, or 30 ml of injectable solution

Not all pack sizes may be marketed.

Marketing Authorization Holder:
Bayer S.p.A.
Viale Certosa, 130
20156 Milan, Italy

Manufacturer:
Bayer AG
Müllerstrasse 178
13353 Berlin, Germany

This medicinal product is authorized in the European Economic Area Member States under the following names:

This leaflet was last updated on.

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The following information is intended exclusively for healthcare professionals:

• Renal impairment

Prior to administration of Gadovist, it is recommended that all patients be screened for renal dysfunction using laboratory tests.
Cases of nephrogenic systemic fibrosis (NSF) have been reported following the use of certain gadolinium-containing contrast agents in patients with severe acute or chronic renal impairment (GFR <30 mL/min/1.73 m²). Patients undergoing liver transplantation are at particular risk due to the high incidence of acute renal failure in this patient group. Since NSF may occur with Gadovist, the medicinal product should be used in patients with severe renal impairment and in patients during the perioperative period of liver transplantation only after careful assessment of the risk-benefit ratio and if essential diagnostic information cannot be obtained by non-contrast MRI.
If use of Gadovist is necessary, the dose must not exceed 0.1 mmol/kg body weight. More than one dose should not be administered during a single examination. Due to lack of data on repeated administrations, Gadovist injections should not be repeated unless at least 7 days have elapsed between doses.
Since renal clearance of Gadovist may be impaired in elderly patients, screening for renal function is particularly important in patients aged 65 years and older.
Haemodialysis shortly after administration of Gadovist may be helpful in removing Gadovist from the body. However, there is no evidence supporting the use of haemodialysis in the prevention or treatment of NSF in patients not already undergoing dialysis.

• Pregnancy and lactation
  Gadovist must not be used during pregnancy unless the clinical condition of the woman necessitates the use of Gadovist.

The physician and the breastfeeding mother should decide whether to discontinue breastfeeding for 24 hours after administration of Gadovist.

• Hypersensitivity reactions

As with other intravenous contrast agents, Gadovist may be associated with anaphylactoid/hypersensitivity-type reactions or other idiosyncratic reactions, characterized by cardiovascular, respiratory, and cutaneous manifestations, including severe reactions up to shock. In general, patients with cardiovascular disorders are more susceptible to severe or even fatal outcomes from serious hypersensitivity reactions.
The risk of hypersensitivity reactions is increased in the following cases:

• Previous reactions to contrast media
• History of bronchial asthma
• History of allergic disorders

In patients with a predisposition to allergy, the decision to use Gadovist should be made only after careful evaluation of the risk-benefit ratio.
Many of these reactions occur within the first hour after administration; therefore, patient monitoring after the procedure is recommended.
Immediate availability of medications for the treatment of hypersensitivity reactions is required, as well as readiness to implement all necessary emergency measures.
Delayed reactions (occurring hours to several days after administration) have been reported rarely.

• Seizure disorders

As with all other gadolinium-containing contrast agents, particular caution is required in patients with a low seizure threshold.

• Overdose

In case of accidental overdose, cardiovascular monitoring (including ECG) and assessment of renal function are recommended as precautionary measures.
In cases of overdose in patients with renal insufficiency, Gadovist can be removed by haemodialysis. After three dialysis sessions, approximately 98% of the product is eliminated from the body. However, there is no evidence that haemodialysis is effective in preventing nephrogenic systemic fibrosis (NSF).

• Before injection

This medicinal product is for single use only.
This medicine is a clear, colourless to pale yellow solution. It should be inspected visually before use.
Gadovist should not be used if discolouration, particulate matter, or container defects are evident.

• Instructions for use

Prefilled syringes
The prefilled syringe should be removed from its packaging and prepared for injection immediately before administration.
The protective cap should be removed from the prefilled syringe immediately before use.

Glass syringe: MANUAL INJECTION

1. Open the packaging 2. Screw the plunger into the syringe

3. Break the protective cover 4. Remove the protective cover

5. Remove the rubber cap 6. Remove air from the syringe

Plastic syringe: MANUAL INJECTION POWER INJECTOR

1. Open the packaging 1. Open the packaging

2. Remove the syringe and plunger 2. Remove the syringe from the packaging from the packaging

3. Rotate the plunger clockwise 3. Open the cap by rotating it into the syringe

4. Open the cap by rotating it 4. Connect the syringe tip or tubing system clockwise and proceed according to the manufacturer's instructions

5. Remove air from the syringe

Cartridges
Administration of contrast agents must be performed by qualified personnel using appropriate procedures and equipment.
Sterile technique must be used in all procedures involving contrast agents.
The contrast agent must be administered using a MEDRAD Spectris-type injector.
Follow the manufacturer's instructions for the device.
Any unused solution remaining after the examination must be disposed of in accordance with local regulations.

Stability after container opening
Any unused injectable solution must be discarded. Chemical, physical, and microbiological stability of the product after opening has been demonstrated for 24 hours at 20–25°C.
From a microbiological standpoint, the product should be used immediately. Otherwise, the duration and conditions of storage are the responsibility of the user.
The traceability adhesive label on the syringes/cartridges should be removed and affixed to the patient's records to ensure accurate documentation of the gadolinium-containing contrast agent used. The administered dose must also be recorded.
If electronic documentation is used, the product name, batch number, and dose must be entered into the patient's electronic record.

Dosage
Use the lowest dose that provides sufficient diagnostic enhancement. The dose should be calculated based on the patient's body weight and must not exceed the recommended dose per kilogram of body weight specified in this section.

• Adults

Indications for the central nervous system:
The recommended dose for adults is 0.1 mmol per kilogram of body weight (mmol/kg).
This corresponds to 0.1 mL/kg body weight of the 1.0 M solution.
If there is strong clinical suspicion of a lesion despite non-significant MRI findings, or if more precise information could influence patient management, an additional injection of up to 0.2 mL/kg body weight may be administered within 30 minutes of the previous dose. A dose of 0.075 mmol of gadobutrol per kg body weight (equivalent to 0.075 mL of Gadovist per kg body weight) may be used for CNS imaging.

Whole-body MRI (excluding MRA):
In general, administration of 0.1 mL of Gadovist per kg body weight is sufficient to address diagnostic questions.

Contrast enhancement in Magnetic Resonance Angiography (MRA):
Single field-of-view (FOV) imaging: 7.5 mL for patients weighing less than 75 kg, 10 mL for patients weighing 75 kg or more (corresponding to 0.1–0.15 mmol/kg body weight).
FOV >1 imaging: 15 mL for patients weighing less than 75 kg, 20 mL for patients weighing 75 kg or more (corresponding to 0.2–0.3 mmol/kg body weight).

• Paediatric population

For children of all ages (including term neonates), the recommended dose is 0.1 mmol of gadobutrol per kg body weight (corresponding to 0.1 mL of Gadovist per kg body weight) for all indications (see section 1).
Due to immature renal function in children up to 4 weeks of age and infants up to 1 year of age, Gadovist should be used in these patients only after careful consideration and at a dose not exceeding 0.1 mmol/kg body weight. More than one dose should not be administered during a single examination. Due to lack of data on repeated administrations, Gadovist injections should not be repeated unless at least 7 days have elapsed between doses.

Administration
The required dose is administered intravenously as a bolus injection. MRI with contrast agent may begin immediately after (or shortly after, depending on pulse sequences and examination protocol) injection.
Optimal signal enhancement occurs during the first arterial pass of the contrast agent for Magnetic Resonance Angiography and within approximately 15 minutes after Gadovist injection for CNS indications (timing depends on lesion/tissue type).
T1-weighted sequences are particularly suitable for contrast-enhanced examinations.
Further information on the use of Gadovist is provided in section 3 of the package leaflet.