MAGNEVIST INJECTION

PATIENT LEAFLET: INFORMATION FOR THE USER

2. Before you are given Magnevist
Do not use Magnevist if: you suffer from severe kidney problems, 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. 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) the patient is a newborn baby up to 4 weeks of age. Take special care with Magnevist Your doctor will need to take special care when giving you Magnevist if: you are, or suspect you are allergic (hypersensitive) to any of the ingredients of Magnevist (see Section 6: Further Information) 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 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 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 your kidneys do not work properly. Magnevist should only be given after careful consideration if you have kidney problems you have recently had, or soon expect to have, a liver transplant 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.

Magnevist

Gadopentetate dimeglumine Read all of this leaflet carefully before you are given this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, please ask the doctor giving you Magnevist (the radiologist) or the hospital/MRI-centre staff. 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.

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: 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 0.2ml Magnevist per kilogram body weight is used. In special cases this may be increased in adults to 0.4ml or even 0.6ml per kilogram body weight, and, to 0.4ml 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 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.

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SUMMARY OF PRODUCT CHARACTERISTICS

Magnevist
1. TRADE NAME OF MEDICINAL PRODUCT
Magnevist

Gadopentetate dimeglumine

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 than once. 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 yield. 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: 0.6ml 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 T1-weighted scanning sequences. For the exclusion of a lesion or tumour recurrences the injection of 0.6ml Magnevist per kg body weight may increase the diagnostic yield.

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 ml/min/1.73 m2) and in patients in the perioperative liver transplantation period (see section 4.3). Magnevist should only be used after careful risk/benefit evaluation in patients with moderate renal impairment (GFR 30 59 ml/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 years): 0.2ml 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 contrainidicated 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, 0.2ml 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 T1-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 Use of Magnevist is contraindicated in patients with severe renal impairment (GFR <30 ml/ min/1.73m2), 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 use 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: previous reaction to contrast media, history of bronchial asthma, 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 ratio. 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. 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). 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 with severe renal impairment, 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 ml/ 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. 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). 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. 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 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. 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: Nephrogenic systemic fibrosis. 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 convention: uncommon: 1/1,000 to < 1/100; rare: 1/10,000 to <1/1,000. The adverse drug reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under not known. Table 1: Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Magnevist.
System organ class Blood and lymphatic system disorders Immune system disorders Uncommon Rare Not known Serum iron increased* Hypersensitivity /anaphylactoid reaction (e.g. anaphylactoid shock*, Anaphylactoid reaction *, Hypersensitivity reactions *, Shock *, Hypotension *, Conjunctivitis, Loss of consciousness *, Throat tightness*, Sneezing, Urticaria, Pruritus, Rash, Erythema, Dyspnoea*, Respiratory arrest *, Bronchospasm *, Wheezing, Laryngospasm *, Laryngeal oedema *, Pharyngeal oedema *, Cyanosis *, Rhinitis, Angioedema *, Oedema face*, Reflex tachycardia) Disorientation Agitation Confusion Coma* Convulsion* Somnolence* Paraesthesia Speech Burning disorder sensation Parosmia Tremor Visual disturbance Eye pain Lacrimation Hearing impaired Ear pain Tachycardia* Cardiac arrest* Arrhythmia Heart rate decreased/ bradycardia* ThromboSyncope* phlebitis Vasovagal Flushing reaction Vasodilatation Blood pressure increased

Psychiatric disorders Nervous system disorders Dizziness Headache Dysgeusia

Eye disorders

Ear and labyrinth disorders Cardiac disorders

Vascular disorders

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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: itching difficulty breathing mild swelling of the face, lips, tongue or throat coughing or sneezing 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 common ones: Uncommon (may affect 1 to 10 users in 1,000) feeling sick being sick changes in the way things taste dizziness headache feeling hot or cold pain 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) hypersensitivity (allergy or allergy-like) reactions, e.g. anaphylactoid shock (severe allergy-like reaction) shock (circulatory collapse) low blood pressure conjunctivitis loss of consciousness throat tightness sneezing hives, nettle-type rash pruritus (severe itching) rash redness of the skin difficulty in breathing or stopped breathing (respiratory arrest) wheezing swelling in the voice box or throat; spasm in the muscles around the voice box blueness of lips runny nose (rhinitis) swelling of the face, throat, mouth, lips and/ or tongue abnormally fast heartbeat reddening or warming of the face or skin; burning sensations; numbness and tingling; fever fast or irregular heart beat; chest pain; disorientation fits or seizures, general weakness; tiredness or generally feeling unwell shaking (tremor) inflammation of a vein caused by or associated with a blood clot widening of blood vessels pain or discomfort in the throat, throat irritation, coughing stomach pain or discomfort; diarrhoea dry mouth; pains or numbness and tingling in the mouth toothache; thirst pain in the arms, hands, legs and feet

swelling of the arms, hands, legs and feet Other side effects (frequency unknown) Nephrogenic Systemic Fibrosis (which causes hardening of the skin and may affect also soft tissue and internal organs) changes in body temperature, chills, sweating high blood pressure; slow heartbeat; sudden stopping of the heart (cardiac arrest) temporary rapid decrease in blood pressure resulting in pallor, which may also result in loss of consciousness (vasovagal reaction) confusion; agitation; problems with speech or hearing sleepiness; fainting; coma pain in the eyes or ears; watery eyes; problems with eyesight or sense of smell difficulty breathing; increase or decrease in breathing rate; watery mouth 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 fluid in the lungs back or joint pain; 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 inflammatory-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.

6. Further Information
What Magnevist contains The active substance is gadopentetate dimeglumine. 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 pack Magnevist is a solution for injection available in 5ml, 10ml, 15ml, 20ml, 30ml vials, 10ml, 15ml, 20ml ampoules and also in packs of five of 10ml, 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 May 2012 To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)
Please be ready to give the following information: Product name MAGNEVIST vials MAGNEVIST prefilled syringes Reference number 00010/0542 00010/0543

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.

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System organ class Respiratory, thoracic and mediastinal disorders Uncommon Rare Throat irritation Pharyngolaryngeal pain/ pharynx discomfort Cough Not known Respiratory distress Respiratory rate increased or Respiratory rate decreased Pulmonary oedema* Salivation

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties Pharmacotherapeutic group: paramagnetic contrast media ATC Code: V08CA01 Mechanism of action Magnevist is a paramagnetic contrast agent for magnetic resonance imaging. When T1-weighted scanning sequences are used in magnetic resonance imaging, the gadopentetateinduced shortening of the spin-lattice relaxation time (T1) of excited water protons leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues. Pharmacodynamic effects Gadopentetate is a highly paramagnetic compound which leads to distinct shortening of the relaxation times even at low concentrations. The paramagnetic efficacy at a magnetic field strength of 1.5 T and 37C, the relaxivity (r1) determined from the influence on the T1 relaxation time of the water protons in plasma and the relaxivity (r2) determined from the influence on the T2 relaxation time - is about 4.1 0.2 l/ (mmolsec) and 4.6 0.8 l/(mmolsec), respectively. The relaxivities display only slight dependency on the strength of the magnetic field. Diethylene triamine pentaacetic acid (DTPA) forms a complex with the paramagnetic gadolinium ion with high in-vivo and in-vitro stability (thermodynamic stability constant: log KGdL = 22-23). Gadopentetate dimeglumine is a highly water-soluble, hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.0001. When tested in vitro with the enzymes acetylcholinesterase and lysozyme at clinically relevant concentrations gadopentetate dimeglumine did not display significant inhibitory interaction. Magnevist does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions. In higher concentrations and on prolonged incubation, gadopentetate dimeglumine has a slight in-vitro effect on erythrocyte morphology. After intravenous administration of Magnevist in man, the reversible process could lead to weak intravascular haemolysis, which might explain the slight increase of serum bilirubin and iron occasionally observed in the first few hours after injection. Physico-chemical properties of Magnevist 0.5 mmol/ml are listed below: Magnevist 0.5 mmol/ml (0.5 mol/l) Contrast medium concentration (mg/ml) Contrast medium content (g) per 5ml 10ml 15ml 20ml 30ml Osmolarity at 37C (mosmol/l solution) Osmolality at 37C (mosmol/kg H20) Osmotic pressure at 37C (atm) (MPa) Density (g/ml or kg/l) at 20C

Viscosity (mPa.s) pH

at 37C at 20C at 37C

1.195 4.9 2.9 7.0 - 7.9

Gastrointestinal disorders

Vomiting Nausea

Abdominal pain Stomach discomfort Diarrhoea Toothache Dry mouth Oral soft tissue pain and paraesthesia

Hepatobiliary disorders

Skin and subcutaneous tissue disorders Musculoskeletal, connective tissue and bone disorders Renal and urinary disorders

Blood bilirubin increased Hepatic enzyme increased Nephrogenic Systemic Fibrosis (NSF)*, *** Pain in extremity Back pain Arthralgia

General disorders and administration site conditions

Pain Feeling hot Feeling cold Injection site reactions (e.g. Injection site coldness, paraesthesia, swelling, warmth, pain, oedema, irritation, haemorrhage, erythema, discomfort, necrosis, thrombophlebitis, phlebitis, inflammation, extravasation)

Chest pain Pyrexia Oedema peripheral Malaise Fatigue Thirst Asthenia

Acute renal failure*, ** Increased serum creatinine** Urinary incontinence Urinary urgency Chills Sweating Body temperature increased or Body temperature decreased

469.01 vial 2.3 4.7 7.0 9.4 14.1 syringe 4.7 7.0 9.4 1440.0 1960.0 49.8 5.06 1.210

*

Life-threatening and/or fatal cases have been reported ** In patients with pre-existing renal impairment *** In patients with acute or chronic severe renal impairment Reactions identified only during postmarketing surveillance (frequency not known) Cases of nephrogenic systemic fibrosis (NSF) have been reported with Magnevist (see section 4.4). In patients with dialysis-dependent renal failure who received Magnevist, delayed and transient inflammatory-like reactions such as fever, chills and C-reactive protein increase have been commonly observed. These patients had the MRI examination with Magnevist on the day before haemodialysis. 4.9 Overdose No signs of intoxication secondary to an inadvertent overdose have so far been observed or reported on clinical use. Accidental overdose may cause the following effects due to the hyperosmolality of Magnevist: increase of pulmonary artery pressure, osmotic diuresis, hypervolaemia and dehydration. In case of inadvertent overdose, renal function should be monitored in patients with renal impairment. Magnevist can be removed by haemodialysis (see section 4.4). However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

5.2 Pharmacokinetic properties Gadopentetate behaves in the organism like other highly hydrophilic biologically inert compounds (e.g mannitol or inulin). Absorption and distribution After intravenous administration of Magnevist, plasma levels decline rapidly bi-exponentially with a terminal half-life of about 90 minutes. Gadopentetate is rapidly distributed in the extracellular space. The total distribution volume of gadopentetate is about 0.26 l per kg. Protein binding is negligible. In studies in rats and dogs, relatively high concentrations of the intact gadolinium complex were found in the kidneys amounting to about 0.15% of administered dose seven days after intravenous administration of radioactively labelled gadopentetate. Less than 1% of the administered dose was found in the remaining parts of the body of both species. Gadopentetate neither penetrates nor passes either an intact blood-brain or blood-testis barrier. The small amount which overcomes the placental barrier is quickly eliminated by the foetus. In a clinical study in lactating women (aged 23-38 years), less than 0.04% of administered gadopentetate was excreted into human breast milk. In rats, absorption from the gastrointestinal tract after oral administration was found to be small (4%). Metabolism Gadopentetate is not metabolised. Elimination Gadopentetate is eliminated in unchanged form via the kidneys by glomerular filtration. The fraction eliminated extra-renally is less than 1% of the administered dose. An average of 83% of the dose was eliminated within 6 hours post-injection. About 91% of the dose was recovered in the urine within the first 24 hours. The renal clearance of gadopentetate was about 120ml/min/1.73m2 and is therefore comparable to substances that are exclusively excreted by glomerular filtration (e.g. inulin or 51Cr-EDTA). Characteristics in special patient populations Elderly population (aged 65 years and above) Magnevist is excreted renally and its clearance is reduced with age as expected due to the age-related physiological reduction in renal function. Magnevist urinary recovery remains similar to non-elderly subjects. Renal impairment In patients with impaired renal function; the serum half life of gadopentetate is prolonged due to the reduced glomerular filtration rate. After administration of a single intravenous dose to 10 patients with impaired renal function (4 patients with mild renal impairment [creatinine clearance 60 to < 90 ml/min] and 6 patients with moderate renal impairment [creatinine clearance 30 to < 60 ml/min]), mean half-lives were 2.6 1.2 hours and 4.2 2.0 hours for the mildly and moderately impaired patients, respectively, as compared to 1.6 0.13 hours in healthy subjects. Gadopentetate is completely renally excreted within two days in patients with slightly to

moderately impaired renal function (creatinine clearance > 30 ml/min). Paediatric population In a study with paediatric patients aged 2 months to < 2 years the pharmacokinetics (body weightnormalised clearance and distribution volume and terminal half-life) of gadopentetate were similar to adults. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, systemic toxicity, genotoxicity, carcinogenic potential and contact sensitising potential. Reproduction toxicity Reproduction-toxicological studies with Magnevist gave no indication of a teratogenic potential following the administration of Magnevist during pregnancy. With daily dosage in the pregnant rat for 10 days of 12.5 times, and in the pregnant rabbit for 13 days of at least 7.5 times the human dose per unit weight, there was slight retardation of foetal growth and ossification. Local tolerance Experimental local tolerance studies following a single paravenous, subcutaneous as well as intramuscular application indicated that slight local intolerance reactions could occur at the administration site after inadvertent paravenous administration.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients Meglumine Pentetic acid (DTPA) Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 5 years. 6.4 Special precautions for storage Keep the container (vial, ampoules, pre-filled syringe) in the outer carton in order to protect from light. This medicinal product does not require any special temperature storage conditions. 6.5 Nature and contents of container Colourless glass injection vials with chlorinated butyl rubber stoppers and pure aluminium lacquered flange caps. Pack size 5ml, 10ml, 15ml, 20ml and 30ml. Colourless glass ampoules: 10ml, 15ml and 20ml. Glass pre-filled syringes containing 10ml, 15ml and 20ml of Magnevist solution. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling This medicinal product should be visually inspected before use. Magnevist should not be used in case of severe discolouration, the occurrence of particulate matter or a defective container. The peel-off tracking label on the vials/ampoules/ syringes should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. Please also refer to section 4.2.

7. MARKETING AUTHORISATION HOLDER
Bayer plc Bayer House Strawberry Hill Newbury Berks RG14 1JA

80630549

8. MARKETING AUTHORISATION NUMBER(S)
Vials: PL 00010/0542 Pre-filled syringes: PL 00010/0543

9. DATE OF FIRST AUTHORISATION/ RENEWAL OF THE AUTHORISATION
Vials: Date of first authorisation: 01 May 2008 Pre-filled syringes: Date of first authorisation: 01 May 2008

Magnevist

10. DATE OF (PARTIAL) REVISION OF THE TEXT
Vials: 22 May 2012 Pre-filled syringes: 22 May 2012 LEGAL CATEGORY POM
80630549

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