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PATIENT LEAFLET: INFORMATION FOR THE USER

Magnevist®

Gadopentetate dimeglumim

Read all of this leaflet carefully before you are given this medicine.

R Keep this leaflet. You may need to read it again.

R If you have any further questions, please ask the doctor giving you Magnevist (the radiologist) or the hospita^MRI-centre staff.

R If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor, radiologist or the hospital/MRI-centre staff.

In this leaflet:

1.    What Magnevist is and what it is used for

2.    Before you are given Magnevist

3.    How you will be given Magnevist

4.    Possible side effects

5.    How to store Magnevist

6.    Further information

1. What Magnevist is and what it is used for

Magnevist is used together with a technique called Magnetic Resonance Imaging (MRI) to create artificial contrast or enhancement, this can help make the MRI scan of the brain, spine, vessels, or other area of your body that your doctor wants to investigate look clearer.

MRI is a modern scanning technique which produces very high quality pictures of various parts of your body without using X-rays. The use of MRI can provide a quick, early and accurate diagnosis. The scanner uses a strong magnetic field and radio waves to measure the magnetic properties of body tissues. Using a computer, this information is converted into a black and white picture which can help your doctor see and investigate the differences between normal and abnormal tissue.

Sometimes MRI is used in areas where it cannot produce a clear black and white picture. This is when Magnevist is used. Magnevist produces a clearer image and allows the doctor to see the area of interest better. Sometimes several scans will be taken before Magnevist is injected and then further scans taken after the injection.

This medicine is provided as a solution for intravenous injection only. It is for diagnostic use only.

2. Before you are given Magnevist

Do not use Magnevist if:

R you are, or suspect you are allergic

(hypersensitive) to any of the ingredients of Magnevist (see Section 6: Further Information)

R you suffer from severe kidney problems and/ or sudden loss of kidney function, or if you are a patient who is about to have or has recently had a liver transplant, as use of Magnevist in patients with these conditions has been associated with a disease called Nephrogenic Systemic Fibrosis (NSF). NSF is a disease involving thickening of the skin and connective tissues. NSF may result in severe joint immobility, muscle weakness or may affect the normal working of internal organs which may potentially be life threatening.

R you have a heart pacemaker or if there are any implants or clips containing iron inside your body. (This is not because of an interaction with Magnevist but because if you have any of these, you should not be placed in a strong magnetic field)

R the patient is a newborn baby up to 4 weeks of

Take special care with Magnevist

Your doctor will need to take special care when

giving you Magnevist if:

R you have a history of allergy (e.g. hay fever, hives), asthma, or have had a reaction to another type of contrast media. This is because you may be more likely to have an allergic reaction

R you suffer from heart or blood circulation problems. This is because in the rare event that you have an allergic reaction, it is more likely to be serious or fatal

R you have epilepsy or have ever had fits, seizures or a mass in or around your brain. Fits or seizures have occurred rarely in patients with similar conditions. Tell the radiographer or MRI-centre staff so that they will be prepared to deal with any problems that occur

R your kidneys do not work properly and/or if you suffer from a sudden loss of kidney function. Magnevist should only be given after careful consideration if you have kidney problems

R you have recently had, or soon expect to have, a liver transplant

R the patient is an infant under 1 year of age. As kidney function is immature in infants up to 1 year of age, Magnevist will only be used in infants after careful consideration by the doctor. Before you receive Magnevist, you must tell the radiographer or MRI-centre staff if any of these apply to you. You will also need to have a blood test to check how well your kidneys are working. Allergy-like reactions may occur after the use of Magnevist. Severe reactions are possible. Most of these reactions occur within 30 minutes after administration. Therefore, you will be observed for at least 30 minutes after the injection.

Delayed reactions may occur (hours or even days later) (see section 4 "Possible side effects").

If you have any blood tests after your MRI scan, tell your doctor you have been given Magnevist. This is because some tests for iron levels in the blood may be affected for up to 24 hours after Magnevist has been given.

Taking or using other medicines Please tell the radiologist or MRI-centre staff if you are taking or have recently taken any other medicines, including medicines obtained without prescription. This is particularly important if you are taking:

R beta blockers (drugs used to treat heart problems or blood pressure). This is because in the rare event that you have an allergic reaction, you may need to be given different medicines than normal to treat the reaction.

Using with food and drink

MRI contrast media like Magnevist can make you

feel sick or actually be sick. Therefore, you may be

asked not to eat anything for 2 hours before the

examination.

Pregnancy and breast-feeding

Ask your doctor for advice before taking any medicine.

Pregnancy

You must tell your doctor if you think you are or might become pregnant as Magnevist should not be used during pregnancy unless strictly necessary. Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Breast-feeding should be discontinued for at least 24 hours after you receive Magnevist.

3. How you will be given Magnevist

You will be asked to lie down on the MRI scanning bed and then Magnevist will be injected into a vein. The MRI staff will observe you for at least 30 minutes after the injection just in case you have any side effects.

The dose of Magnevist varies depending on your weight and how much the image of the area needs to be made clearer. Typically a single injection of

0.2 ml Magnevist per kilogram body weight is used.

In special cases this may be increased in adults to 0.4 ml or even 0.6 ml per kilogram body weight, and, to 0.4 ml per kilogram body weight maximum in children aged over 1 year (cranial and spinal MRI) or aged over 2 years (whole body MRI). The doctor will decide how much Magnevist is needed for your investigation.

In infants (under 2 years of age) the required dose should be administered by hand.

With the exception of brain and spine examinations, there is limited experience using Magnevist in patients younger than 2 years. Scanning may start immediately after Magnevist injection but may take place later depending on your examination (usually up to 45 minutes).

You should not be given Magnevist if you suffer from severe kidney problems and/or sudden loss of kidney function or if you are a patient who is about to have or has recently had a liver transplant. Magnevist should also not be used in newborn babies up to the age of 4 weeks.

If you have moderate kidney problems, you should only receive one dose of Magnevist during a scan and you should not receive a second injection for at least 7 days.

As kidney function is immature in infants up to 1 year of age, infants should only receive one dose of Magnevist during a scan and should not receive a second injection for at least 7 days.

It is not necessary to adjust your dose if you are 65 years of age or older but you will have a blood test to check how well your kidneys are working.

If you receive more Magnevist than you should

No symptoms of overdosing have so far been reported. If overdosing does happen the doctor will treat any resulting symptoms and will check whether your kidneys are working normally. Your doctor may need to use a kidney dialysis machine to remove Magnevist. There is no evidence to suggest that this will prevent the development of NSF (see section 4 Possible side effects) and should not be used as treatment for the condition.

Please turn over j

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SUMMARY OF PRODUCT CHARACTERISTICS

(haver)    Magnevist®

Gadopentetate dimeglumim

Maximum single dose: 0.6ml Magnevist per kg of body weight.

Special Populations Renal impairment

Magnevist is contraindicated in patients with severe renal impairment (GFR < 30 m^min/1.73 m^{1 2 3 4}) and/or acute kidney injury and in patients in the perioperative liver transplantation period (see section 4.3). Magnevist should only be used after careful rislk/benefit evaluation in patients with moderate renal impairment (GFR 30 - 59 m^ min/1.73 m²) at a dose not exceeding 0.2 ml per kg body weight (see section 4.4). More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Magnevist injections should not be repeated unless the interval between injections is at least 7 days. Hepatic impairment Since gadopentetate is almost exclusively eliminated in an unchanged form via the kidneys, no dosage adjustment is considered necessary in patients with moderate hepatic impairment. Data on patients with severe hepatic impairment are not available (see section 5.2).

Elderly (aged 65 years and above)

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).

Paediatric Population Cranial and spinal MRI Children (including infants under the age of 2

0.2 ml Magnevist per kg body weight is sufficient to provide diagnostically adequate contrast. In infants (under 2 years of age) the required dose should be administered by hand.

Magnevist is contraindicated in neonates up to 4 weeks of age (see section 4.3).

Due to immature renal function in infants up to 1 year of age Magnevist should only be used in these patients after careful consideration at a dose not exceeding 0.2 ml per kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Magnevist injections should not be repeated unless the interval between injections is at least 7 days.

If a strong clinical suspicion of a lesion persists despite a normal scan in patients over 1 year of age, a further injection of 0.2ml Magnevist per kg body weight within 30 minutes may increase the diagnostic yield.

Whole body MRI

Children (over the age of 2 years):

In general, 0.2 ml Magnevist per kg body weight is sufficient to provide diagnostically adequate contrast.

In special cases, e.g. in lesions with poor vascularisation and/or a small extracellular space,

0.4 ml Magnevist per kg body weight may be necessary for an adequate contrast especially with relatively less heavily ^-weighted scanning sequences.

Neonates and Infants under the age of 2 years: Magnevist is contraindicated in neonates up to 4 weeks of age (see section 4.3).

Experience in children under the age of 2 years is limited. However, this limited experience has shown that 0.2ml Magnevist per kg body weight may be used in this particular age group. In infants (under 2 years of age) the required dose should be administered by hand.

Due to immature renal function in infants up to 1 year of age Magnevist should only be used in these patients after careful consideration at a dose not exceeding 0.2 ml per kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Magnevist injections should not be repeated unless the interval between injections is at least 7 days.

4.3    Contraindications

Hypersensitivity or allergy to the active substance or to any of the excipients listed in section 6.1 (see also Section 4.4).

Use of Magnevist is contraindicated in patients with severe renal impairment (GFR <30 m^min/ 1.73m²) and/or acute kidney injury, in patients in the perioperative liver transplantation period and in neonates up to 4 weeks of age (see section 4.4).

4.4    Special warnings and special precautions for

R Hypersensitivity and hypersensitivity reactions Particularly careful risk-benefit assessment is required in patients with known hypersensitivity to Magnevist.

As with other intravenous contrast agents, Magnevist can be associated with anaphylactoid/ hypersensitivity or other idiosyncratic reactions (characterised by cardiovascular, respiratory or cutaneous manifestations) ranging to severe reactions including shock.

The risk of hypersensitivity reactions is higher in case of:

R previous reaction to contrast media,

R history of bronchial asthma,

R history of allergic disorders In patients with an allergic disposition (especially with a history of the above-mentioned conditions) the decision to use Magnevist must be made after particularly careful evaluation of the risk-benefit

Most of these reactions occur within half an hour of administration. Therefore, post-procedure observation of the patient is recommended. Medication for the treatment of hypersensitivity reactions as well as readiness for institution of emergency measures are necessary.

Delayed reactions (hours later or up to several days) have been rarely observed (see section 4.8 Undesirable effects).

Patients who experience hypersensitivity reactions while taking beta blockers may be resistant to treatment effects of beta agonists.

Patients with cardiovascular disease are more susceptible to serious or even fatal outcomes of severe hypersensitivity reactions.

R Patients with impaired renal function Prior to administration of Magnevist, all patients should be screened for renal dysfunction by obtaining laboratory tests.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of Magnevist and some other gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR <30ml/min/1.73 m²) and/or acute kidney injury. Magnevist is contraindicated in these patients (see section 4.3). Patients undergoing liver transplantation are at particular risk since the incidence of acute renal failure is high in this group. Therefore Magnevist must not be used in patients in the perioperative liver transplantation period and in neonates (see section 4.3).

The risk for the development of NSF in patients with moderate renal impairment (GFR 30-59 m^ min/1.73 m²) is unknown, therefore Magnevist should only be used after careful risk-benefit evaluation in patients with moderate renal impairment.

Haemodialysis shortly after Magnevist administration may be useful at removing Magnevist from the body. Approximately 70% of the administered dose is removed with each dialysis session, such that after 3 dialysis sessions of 3 hours each, about 97% of the total administered dose is eliminated from the body. There is no evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis. R Neonates and infants Magnevist is contraindicated in neonates up to 4 weeks of age (see section 4.3). Due to immature renal function in infants up to 1 year of age, Magnevist should only be used in these patients after careful consideration (see section 4.2).

R Elderly

As the renal clearance of gadopentetate may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

R Seizure disorders

Patients with seizure disorders or intracranial lesions may be at increased risk of seizure activity, as this has been reported rarely in association with Magnevist administration (see section 4.8).

For patients predisposed to seizures, precautionary measures should be taken, e.g. close monitoring; all equipment and drugs necessary to counter any convulsions which may occur must be made ready for use beforehand.

4.5    Interactions with other medicaments and other forms of interaction

No interaction studies with other medicinal products have been conducted.

The results of serum iron determinations using complexometric methods (e.g. bathophenanthroline) may result in falsely low values for up to 24 hours after the administration of Magnevist because of the free DTPA contained in the contrast-medium solution.

4.6    Pregnancy and lactation

R Pregnancy

There are no data from the use of gadopentetate in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3). Magnevist should not be used during pregnancy unless the clinical condition of the woman requires use of gadopentetate.

R Lactation

Small amounts of gadopentetate dimeglumine (up to 0.04% of the administered dose) are excreted in human milk. A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued for at least 24 hours after the administration of Magnevist.

4.7    Effects on ability to drive and use machines

None stated.

4.8    Undesirable effects

The overall safety profile of Magnevist is based on data from post-marketing surveillance and from more than 11,000 patients in clinical trials.

The most frequently observed adverse drug reactions (> 0.4%) in patients receiving Magnevist in clinical trials are various injection site reactions, headache and nausea.

Most of the adverse drug reactions in clinical trials were of mild to moderate intensity.

Overall, the most serious adverse drug reactions in patients receiving Magnevist are:

R Nephrogenic systemic fibrosis.

R Anaphylactoid reactions/anaphylactoid shock Delayed hypersensitivity/anaphylactoid reactions (hours later up to several days) have been rarely observed (see section 4.4).

The adverse drug reactions observed with Magnevist are represented in the table below. They are classified according to System Organ Class (MedDRA). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials are classified according to their frequencies. Frequency groupings are defined according to the following

consciousness* * tightness*,

Urticaria, Pruritus, Rash, Erythema, Dyspnoea* Respiratory

Bronchospasm* *, Wheezing, Laryngospasm* * Laryngeal oedema^* *, Pharyngeal oedema* * Cyanosis^* *, Rhinitis^*, Angioedema^* *, Oedema face*, Reflex

tachycardia*)

Disorientation

Convulsion*

Paraesthesia

Burning

Tremor

Eye

Ear and labyrinth disorders

Tachycardia*

Arrhythmia

decreased/

bradycardia*

Vascular    Thrombo-    Syncope*

^{disorders    phlebitis}    Vasovagal

Flushing    reaction

Vasodilatation Blood

pressure

increased

4. Possible side effects

Like all medicines, Magnevist can cause side effects, although not everybody gets them.

Side effects you may get after being given a contrast medium like Magnevist are usually mild to moderate and do not last long.

However, as with similar contrast media, severe and life-threatening reactions, as well as deaths, have been reported. If you require further information, please contact your doctor.

The most frequently observed side effects in patients receiving Magnevist that may affect 4 or more in 1,000 users are various injection site reactions, headache and nausea (feeling sick).

The most serious side effects in patients receiving Magnevist are Nephrogenic Systemic Fibrosis (NSF) and anaphylactoid reactions (allergy-like reactions). NSF is a severe reaction, mainly involving a thickening of the skin and connective tissues, and may result in severe joint immobility, muscle weakness or may affect the normal working of internal organs which may potentially be life-threatening.

In rare cases, allergy-like reactions may occur, including severe reactions such as shock, that may need immediate medical intervention.

If you notice:

R itching

R difficulty breathing

R mild swelling of the face, lips, tongue or throat R coughing or sneezing R runny nose or hives (nettle-type rash)

Tell your doctor, the radiologist or MRI staff immediately as these may be the first signs that a severe allergic reaction is happening. Your investigation will need to be stopped, and you may need further treatment.

Delayed reactions (hours to several days after administration) can occur rarely, if you are concerned you should contact your doctor.

Below the reported side effects of Magnevist are listed by frequency, starting with the more

Uncommon (may affect 1 to 10 users in 1,000)

R feeling sick R being sick

R changes in the way things taste R dizziness R headache R feeling hot or cold R pain

R sensations or reactions at the injection site such as: warm or cold feelings, paraesthesia ("pins and needles"), swelling, pain, accumulation of

fluid at the injection site, irritation, bleeding, reddish painful skin, discomfort, death of skin tissue (necrosis), inflammation of a vein caused by or associated with a blood clot (thrombophlebitis), inflammation, inflammation of a vein (phlebitis), bleeding into the tissue at the injection site, bruising, change in skin colour.

Rare (may affect 1 to 10 users in 10,000)

R hypersensitivity (allergy or allergy-like) reactions, e.g.

P anaphylactoid shock (severe allergy-like reaction)

P shock (circulatory collapse)

P low blood pressure P conjunctivitis P loss of consciousness P throat tightness P sneezing

P hives, nettle-type rash P pruritus (severe itching)

P redness of the skin

P difficulty in breathing or stopped breathing (respiratory arrest)

P wheezing

P swelling in the voice box or throat; spasm in the muscles around the voice box P blueness of lips P runny nose (rhinitis)

P swelling of the face, throat, mouth, lips and/ or tongue

P abnormally fast heartbeat R reddening or warming of the face or skin; burning sensations; numbness and tingling;

R fast or irregular heart beat; chest pain;

R disorientation

R fits or seizures, general weakness; tiredness or generally feeling unwell R shaking (tremor)

R inflammation of a vein caused by or associated with a blood clot R widening of blood vessels R pain or discomfort in the throat, throat irritation, coughing

R stomach pain or discomfort; diarrhoea R dry mouth; pains or numbness and tingling in the mouth R toothache; thirst

R pain in the arms, hands, legs and feet

R swelling of the arms, hands, legs and feet Other side effects (frequency unknown)

R Nephrogenic Systemic Fibrosis (which causes hardening of the skin and may affect also soft tissue and internal organs)

R changes in body temperature, chills, sweating R high blood pressure; slow heartbeat; sudden stopping of the heart (cardiac arrest)

R temporary rapid decrease in blood pressure resulting in pallor, which may also result in loss of consciousness (vasovagal reaction)

R confusion; agitation; problems with speech or hearing

R sleepiness; fainting; coma R pain in the eyes or ears; watery eyes; problems with eyesight or sense of smell R difficulty breathing; increase or decrease in breathing rate; watery mouth R an inability to control the passage of urine (incontinence) and an urgent need to pass urine; kidney failure in patients who already have kidney problems R fluid in the lungs R back or joint pain;

R increase in levels of iron, liver enzymes and bilirubin in the blood and serum creatinine. These may be detected in blood tests.

In patients with dialysis-dependent kidney failure who received Magnevist, delayed and passing inflammatoiy-like reactions such as fever, chills and C-reactive protein increase (a blood test marker for inflammatory reactions) have been commonly observed. These patients had the MRI examination with Magnevist on the day before haemodialysis.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, either while Magnevist is being given or for about a week afterwards, please tell your doctor or the radiologist or the MRI-centre staff.

Reporting of side effects

If you get any side effects talk to your doctor, radiologist or MRI centre staff. This includes any side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.ulkfyellowcard

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

5.    How to store Magnevist

Keep out of the reach and sight of children.

Do not use Magnevist after the expiry date which is stated on the label. The expiry date refers to the last day of that month.

Keep the container (vial, ampoules, pre-filled syringe) in the outer carton in order to protect from light. Magnevist does not require any special temperature storage conditions.

Magnevist should be visually inspected before use. Magnevist is supplied as a clear, colourless to pale yellow solution. Magnevist should not be used if there is severe discolouration, if there are particles or if the container is damaged.

6.    Further Information

What Magnevist contains

The active substance is gadopentetate

1 ml Magnevist contains 0.5 mmol of gadopentetate dimeglumine (equivalent to 469.01 mg of the gadopentetate dimeglumine).

The other ingredients are meglumine, pentetic acid and water for injections.

What Magnevist looks like and contents of the

Magnevist is a solution for injection available in 5ml, 10ml, 15ml, 20ml, 30ml vials, 10ml, 15ml,

20 ml ampoules and also in packs of five of 10 ml, 15ml, or 20ml pre-filled syringes.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Bayer plc Bayer House Strawberry Hill Newbury Berkshire RG14 1JA

Manufacturer:    Bayer Pharma AG

Berlin Germany

This leaflet was last revised in July 2015

1

TRADE NAME OF MEDICINAL PRODUCT

Magnevist®

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 0.5 mmol gadopentetate dimeglumine (equivalent to 469.01 mg gadopentetate dimeglumine).

For full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Solution for injection.

4

CLINICAL PARTICULARS

4.1    Therapeutic indications

This medicinal product is for diagnostic use only as a paramagnetic contrast medium in cranial, spinal and whole body magnetic resonance imaging (MRI).

4.2    Posology and method of administration

Method of administration Magnevist is to be administered only by intravenous injection.

Nausea and vomiting are known possible adverse reactions of all extracellular MRI contrast media.

The patient should therefore refrain from eating for 2 hours prior to investigation to avoid aspiration. The usual precautions for MRI (e.g. exclusion of cardiac pacemakers and other ferromagnetic objects including vascular clips etc) must be observed.

Instructions for use/handling

Prefilled syringe:

The prefilled syringe must be taken from the pack and prepared for the injection immediately before the examination.

The tip cap should be removed from the prefilled syringe immediately before use.

After the pre-filled syringe has been prepared for use, Magnevist remains stable for an examination day. The time indicated does not refer to the physicochemical stability, but to the possibility of microbial contamination.

Vials:

Magnevist should only be drawn up into the syringe immediately before use.

The rubber stopper should never be pierced more

Any contrast medium not used in one examination must be discarded.

Contrast-enhanced MRI can start immediately after administration of the medium. T₁-weighted scanning sequences are particularly suitable for contrast-enhanced examinations with Magnevist. Ideally the patient should be recumbent during administration, and should be kept under supervision for at least 30 minutes after the injection.

Posology

The recommended doses are given in ml of Magnevist per kg body weight.

Adults:

Cranial and spinal MRI

In general, the administration of 0.2ml Magnevist per kg body weight (equivalent to 0.1mmol gadopentetate dimeglumine per kg body weight) is sufficient to provide diagnostically adequate contrast.

If a strong clinical suspicion of a lesion persists despite a normal scan, a further injection of 0.2ml or even 0.4ml, Magnevist per kg body weight within 30 minutes may increase the diagnostic

For the exclusion of metastases or recurrent tumours injection of 0.6ml Magnevist per kg body weight may increase the diagnostic yield.

Maximum single dose: 0.6 ml Magnevist per kg of body weight.

Whole body MRI

In general, the administration of 0.2ml Magnevist per kg body weight is sufficient to provide diagnostically adequate contrast.

In special cases, e.g. in lesions with poor vascularisation and/or a small extracellular space, 0.4ml Magnevist per kg body weight may be necessary for an adequate contrast especially with relatively less heavily ^-weighted scanning

For the exclusion of a lesion or tumour recurrences the injection of 0.6ml Magnevist per kg body weight may increase the diagnostic yield.