GADOVIST 1 mmol/ml INJECTABLE SOLUTION IN VIAL

2. What you need to know before you use Gadovist

Do not use Gadovist if you

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

Warnings and precautions

Consult your doctor before using Gadovist if you

• have or have had an allergy (e.g., hay fever, hives) or asthma
• have had a previous reaction to any contrast medium
• have severely impaired kidney function
• have cerebral disorders with seizures (fits) or have other nervous system diseases
• have a pacemaker or any implant or clip that contains iron in your body.

Your doctor will decide whether it is possible to perform the planned examination.

• Allergic reactions or other types of reactions that involve heart problems, difficulty breathing, or skin reactions may occur after using Gadovist. Severe reactions are possible. Most of these reactions occur within 30 minutes after administration of Gadovist. Therefore, you will be observed after treatment. Delayed reactions (after hours or days) have been observed (see section 4).

Kidneys/Liver

Tell your doctor if

• your kidneys are not working properly
• you have recently had or are about to have a liver transplant.

Your doctor may decide to perform a blood test to check the proper functioning of your kidneys before deciding on the use of Gadovist, especially if you are 65 years or older.

Newborns and Infants

Due to the immaturity of the renal function of newborns up to 4 weeks and infants up to 1 year of age, Gadovist should only be used in these patients after careful evaluation by the doctor.

Other medicines and Gadovist

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor or pharmacist before using this medicine.

• Pregnancy

Gadobutrol may cross the placenta. It is not known whether it affects the fetus. You should inform your doctor if you think you are pregnant or might be, as Gadovist should not be used during pregnancy unless it is considered absolutely necessary.

• Breastfeeding

Tell your doctor if you are breastfeeding or about to start. Your doctor will assess whether you should continue or interrupt breastfeeding 24 hours after administration of Gadovist.

Gadovist contains sodium

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

3. How to use Gadovist

Gadovist is injected by a healthcare professional through a small needle into a vein. Your MRI examination can start immediately.

After injection, you will be observed for at least 30 minutes.

Usual dosage

The usual dose that is right for you will depend on your body weight and the region examined by MRI:

In adults, a single injection of 0.1 milliliters of Gadovist per kilogram of body weight is recommended (this means that for a person weighing 70 kg, the dose would be 7 milliliters). However, an additional injection of up to 0.2 milliliters per kilogram of body weight may be administered within 30 minutes after the first injection. A total of 0.3 milliliters of Gadovist per kilogram of body weight may be administered as a maximum (this means that for a 70 kg person, the dose would be 21 milliliters) for the acquisition of images of the central nervous system (CNS) and magnetic resonance angiography (MRA) with contrast. A minimum dose of 0.075 milliliters of Gadovist per kilogram of body weight (this means that for a 70 kg person, the dose would be 5.25 milliliters) may be administered for the CNS.

At the end of the leaflet, additional information on the administration and handling of Gadovist is included.

Dosage in special populations

The use of Gadovist is not recommended in patients with severe kidney problems or in patients who have recently had or are about to have a liver transplant. However, if use is required, during an examination, only one dose of Gadovist should be administered, and a second injection should not be administered until at least 7 days have passed.

Use in newborns, infants, children, and adolescents

The recommended dose in children of all ages (including full-term newborns) is a single injection of 0.1 milliliters of Gadovist per kilogram of body weight for all indications (see section 1).

Due to the immaturity of the renal function of newborns up to 4 weeks and infants up to 1 year of age, Gadovist should only be used in these patients after careful evaluation by the doctor. Newborns and infants should only receive one dose of Gadovist during an examination and should not receive a second injection until at least 7 days have passed.

Elderly patients

If you are 65 years or older, it is not necessary to adjust the dose, but you may have a blood test to check the proper functioning of your kidneys.

If you use more Gadovist than you should

Overdose is unlikely to occur. If it happens, your doctor will treat all symptoms and may use dialysis to remove Gadovist from your body. There is no evidence to suggest that hemodialysis is suitable for preventing the development of nephrogenic systemic fibrosis (NSF; see section 4), so it should not be used to treat this disease. In some cases, your heart will be monitored.

In case of overdose or accidental ingestion, contact the Toxicology Information Service (telephone 91 562 04 20).

If you have any further questions about the use of this medicine, ask your doctor or radiologist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Most of these reactions occur within 30 minutes after administration of Gadovist. In rare cases, delayed allergic reactions or other types of reactions have been observed, from a few hours to several days after receiving 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:

• cardiac arrest, severe lung disease (acute respiratory distress syndrome)/ fluid in the lungs (pulmonary edema), and severe allergic reactions (anaphylactoid reactions)(including respiratory arrest and shock).

Additionally, the following life-threatening or fatal side effectshave been observed:

• shortness of breath (dyspnea), loss of consciousness, severe allergic reactions, severe drop in blood pressure that can lead to collapse, respiratory arrest, fluid in the lungs, inflammation of the mouth and throat, and low blood pressure.

In rare cases:

• allergic reactions (hypersensitivity and anaphylaxis)may occur, including severe reactions (shock) that require immediate medical intervention.

If you notice:

• swelling of the face, lips, tongue, or throat
• coughing and sneezing
• difficulty breathing
• itching
• nasal congestion
• hives (urticaria)

inform the MRI department staff immediately. These may be the first signs of a severe reaction. Your examination may be suspended, and you may need further treatment.

The most common side effects(may affect up to 1 in 10 people) are:

• headaches, feeling sick (nausea), and dizziness.

Most side effects are mild to moderate.

The following side effects have been observed in clinical trialsbefore the approval of Gadovist, according to their frequency:

Common:may affect up to 1 in 10 people

• headache
• feeling sick (nausea)

Uncommon:may affect up to 1 in 100 people

• allergic reaction, for example:

• low blood pressure
• hives (urticaria)
• swelling of the face
• swelling (edema)of the eyelids
• flushing

The frequency of the following allergic reactions is unknown:

• a severe allergic reaction (anaphylactoid shock)
• severe drop in blood pressure that can lead to collapse (shock)
• respiratory arrest
• difficulty breathing (bronchospasm)
• blue discoloration of the skin and mucous membranes (cyanosis)
• swelling of the mouth and throat
• swelling of the throat
• high blood pressure
• chest pain
• swelling of the face, throat, mouth, lips, and/or tongue (angioedema)
• conjunctivitis
• increased sweating
• coughing
• sneezing
• burning sensation
• paleness (pale skin)
• dizziness, altered taste, numbness, and tingling
• shortness of breath (dyspnea)
• vomiting
• redness of the skin (erythema)
• itching (pruritus, including generalized pruritus)
• rash (including generalized rash, flat red patches (macular rash), small raised patches (papular rash), itchy rash (pruritic rash))
• various reactions at the injection site (e.g., leakage into the surrounding tissue, burning, cold, heat, redness, rash, pain, or hematoma)
• feeling of heat

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

• fainting
• seizure (convulsions)
• altered sense of smell
• rapid heartbeat
• palpitations
• dry mouth
• general malaise
• feeling of cold

Additional side effects that have been reported after the approval of Gadovist with unknown frequency(the frequency cannot be estimated from the available data):

• cardiac arrest (cardiac arrest)
• Severe lung disease (acute respiratory distress syndrome)
• Fluid in the lungs (pulmonary edema)
• Cases of nephrogenic systemic fibrosis - NSF (which causes skin hardening and may also affect soft tissues and internal organs) have been reported.

After administration of Gadovist, changes in renal function test results (e.g., increased serum creatinine) have been observed.

Reporting of side effects

If you experience any side effects, consult your doctor or radiologist, even if they are not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines https://www.notificaram.es. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Gadovist

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The expiry date is the last day of the month shown. This medicine does not require any special storage conditions.

Chemical, physical, and microbiological stability has been demonstrated for 24 hours at 20-25°C. From a microbiological point of view, the product should be used immediately after opening.

This medicine is a clear, colorless to pale yellow solution. Do not use this medicine if you notice a severe change in color or the presence of particles or if the container appears to be defective.

Medicines should not be disposed of via wastewater or household waste. The healthcare professional will dispose of this medicine when it is no longer needed. This will help protect the environment.

6. Container Contents and Additional Information

Composition of Gadovist

The active ingredient is gadobutrol.

1 ml of injectable solution contains 604.72 mg of gadobutrol (equivalent to 1 mmol of gadobutrol containing 157.25 mg of gadolinium).

1 vial with 2 ml contains 1,209.44 mg of gadobutrol.

1 vial with 7.5 ml contains 4,535.4 mg of gadobutrol.

1 vial with 15 ml contains 9,070.8 mg of gadobutrol.

1 vial with 30 ml contains 18,141.6 mg of gadobutrol.

1 bottle with 65 ml contains 39,306.8 mg of gadobutrol.

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

Appearance of the Product and Container Contents

Gadovist is a clear, colorless to pale yellow injectable solution.

The container contents are:

• 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 bottle)

Clinical containers:

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

Only some package sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Bayer Hispania, S.L.

Av. Baix Llobregat, 3-5

08970 Sant Joan Despí (Barcelona)

Spain

Manufacturer

Bayer AG

Müllerstrasse 178

13353 Berlin

Germany

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

Date of the last revision of this leaflet:09/2024.

Other sources of information

Detailed information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) (http://www.aemps.gob.es)

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This information is intended only for healthcare professionals:

• Renal Insufficiency

Before administration of Gadovist, it is recommended to evaluate all patients for possible renal dysfunction through laboratory tests.

Cases of nephrogenic systemic fibrosis (NSF) associated with the use of some gadolinium contrast agents have been reported in patients with severe acute or chronic renal insufficiency (GFR or glomerular filtration rate < 30 ml/minute/1.73 m2). Patients undergoing liver transplantation have a special risk since the incidence of renal failure is high in this group. Since there is a possibility that NSF may occur with Gadovist, it should only be used in patients with severe renal insufficiency and in patients in the perioperative period of a liver transplant after a careful risk-benefit assessment and if diagnostic information is essential and cannot be available through contrast-free magnetic resonance imaging. If the use of Gadovist is necessary, the dose should not exceed 0.1 mmol/kg body weight. During an examination, no more than one dose should be administered. Due to the lack of information on repeated administration, the administration of Gadovist should not be repeated unless an interval of at least 7 days has passed between injections.

Since the renal elimination of Gadovist may be reduced in elderly patients, it is especially important to evaluate patients aged 65 and older for possible renal dysfunction.

Hemodialysis shortly after administration of Gadovist may be useful for the elimination of Gadovist from the body. After 3 sessions of hemodialysis, approximately 98% of the contrast agent is eliminated from the body. However, there is no evidence that hemodialysis is suitable for the prevention of nephrogenic systemic fibrosis (NSF) in patients who are not yet undergoing hemodialysis.

• Pregnancy and Lactation

Gadovist should not be used during pregnancy unless the clinical situation of the woman requires treatment with Gadovist.

The continuation or interruption of breastfeeding 24 hours after administration of Gadovist will be at the discretion of the doctor and the breastfeeding mother.

• Hypersensitivity Reactions

As with other intravenous contrast agents, Gadovist may be associated with hypersensitivity/anaphylactoid reactions or other idiosyncratic reactions characterized by cardiovascular, respiratory, or cutaneous manifestations, which can range from mild to severe reactions, including shock. In general, patients with cardiovascular diseases are more susceptible to serious or even fatal consequences from severe hypersensitivity reactions.

The risk of hypersensitivity reactions may be greater in the following cases:

• previous reaction to contrast agents
• history of bronchial asthma
• history of allergic disorders

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

Most of these reactions occur within 30 minutes after administration. Therefore, it is recommended to observe the patient after treatment.

It is necessary to have the appropriate medication for the treatment of hypersensitivity reactions, as well as to prepare for the application of emergency measures.

In rare cases, delayed reactions (after hours or several days) have been observed.

• Seizure Disorders

As with other gadolinium-based contrast agents, special caution should be taken in patients with a low convulsive threshold.

• Overdose

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

In the case of overdose in patients with renal insufficiency, Gadovist can be eliminated through hemodialysis. After 3 sessions of hemodialysis, approximately 98% of the contrast agent is eliminated from the body. However, there is no evidence that hemodialysis is suitable for the prevention of nephrogenic systemic fibrosis (NSF).

• Before Injection

This medicinal product is intended for single use.

This medicinal product is a clear, colorless to pale yellow solution. The solution should be visually inspected before use. Gadovist should not be used if it shows significant color changes, particle formation, or if the container is defective.

• Instructions for Use

Gadovist should not be placed in the syringe until immediately before use.

The rubber stopper should not be pierced more than once.

Unused contrast agent in an examination should be discarded.

If this medicinal product is intended to be used with an automated application system, the suitability of this system for the intended use must be demonstrated by the manufacturer of the system. Any additional instructions from the manufacturer must also be strictly followed.

Any unused contrast agent in an examination should be disposed of according to local regulations.

Validity Period after First Opening of the Container

Any unused solution for injection should be discarded. Chemical, physical, and microbiological stability have been demonstrated for 24 hours at 20-25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the storage times during use and the conditions prior to use are the responsibility of the user.

The detachable label of the vials/bottles should be stuck to the patient's medical record to allow for accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. In the case of electronic patient records, the product name, batch number, and administered dose should be entered.

Posology

The lowest dose that provides sufficient contrast for diagnostic purposes should be used. The dose should be calculated based on the patient's body weight and should not exceed the recommended dose per kilogram of body weight indicated in this section.

• Adults

Indications in the CNS

The recommended dose in adults is 0.1 mmol per kilogram of body weight (mmol/kg bw), equivalent to 0.1 ml/kg bw of the 1.0 M solution.

If a clinically justified suspicion of a lesion persists despite a non-diagnostic MRI or when more precise information may influence patient treatment, an additional dose of up to 0.2 ml/kg bw may be administered within 30 minutes after the first injection. A dose of 0.075 mmol of gadobutrol per kg of body weight (equivalent to 0.075 ml of Gadovist per kg of body weight) may be administered as a minimum for CNS imaging.

Whole-body MRI (except MRA)

In general, administration of 0.1 ml of Gadovist per kg of body weight is sufficient to answer the clinical question.

Contrast-Enhanced Magnetic Resonance Angiography (MRA)

Imaging of 1 field of view (FOV): 7.5 ml for body weights below 75 kg; 10 ml for body weights of 75 kg or more (equivalent to 0.1-0.15 mmol/kg bw).

Imaging of more than 1 field of view (FOV): 15 ml for body weights below 75 kg; 20 ml for body weights of 75 kg or more (equivalent to 0.2-0.3 mmol/kg bw).

• Pediatric Population

The recommended dose in children of all ages (including term neonates) is 0.1 mmol of gadobutrol per kilogram of body weight (equivalent to 0.1 ml of Gadovist per kilogram of body weight) for all indications (see section 1).

Due to the immaturity of renal function in neonates up to 4 weeks and infants up to 1 year of age, Gadovist should only be used in these patients after careful assessment at a dose not exceeding 0.1 mmol/kg body weight. During an examination, no more than one dose should be administered. Due to the lack of information on repeated administration, the administration of Gadovist should not be repeated unless an interval of at least 7 days has passed between injections.

Images

The required dose is administered intravenously as a bolus injection. Contrast-enhanced MRI can begin immediately after (shortly after injection, depending on the pulse sequences used and the study protocol).

An optimal signal enhancement is observed during the first arterial pass for contrast-enhanced MRA and during a period of approximately 15 minutes after injection of Gadovist for CNS indications (the timing depends on the type of lesion/tissue).

T1-weighted image sequences are particularly suitable for contrast-enhanced examinations.

Additional information on the use of Gadovist is provided in section 3 of the leaflet.