Magnevist 0.5 mmol/ml Solution for Injection

1ml of solution for injection contains 469 mg gadopentetic acid, dimeglumine salt (equivalent to 0.5 mmol gadopentetic acid, dimeglumine salt).

For a full list of excipients, please see section 6.1.

Solution for injection.

A clear, sterile solution, free from particles.

pH 7.0-7.9

Osmolarity 1833-2067 mosmol/kg

For diagnostic use by intravenous administration only.

Cranial and spinal magnetic resonance imaging (MRI)

In particular for the demonstration of tumours and for further differential-diagnostic clarification in suspected meningioma, (acoustic) neurinoma, invasive tumours (e.g. glioma) and metastases; for the demonstration of small and/or isointense tumours; in suspected recurrence after surgery or radiotherapy; for the differentiated demonstration of rare neoplasms such as haemangioblastomas, ependymomas and small pituitary adenomas; for improved determination of the spread of tumours not of cerebral origin.

Additionally in spinal MRI: Differentiation of intra- and extramedullary tumours; demonstration of solid tumour areas in known syrinx; determination of intramedullary tumour spread.

Whole body MRI

Including the facial skull, the neck region, the thoracic space including the heart and abdominal space, the female breast, the pelvis and the active and passive locomotive apparatus, and imaging of vessels throughout the body.

In particular, Magnevist permits diagnostic information:

For the demonstration or exclusion of tumours, inflammations and vascular lesions;

For determination of the spread and demarcation of these lesions;

For the differentiation of the internal structure of lesions;

For assessment of the circulatory situation of normal and pathologically changed tissues;

For the differentiation of tumour and scar tissue after therapy;

For the recognition of recurrent prolapse of a disk after surgery.

For the semi-quantitative eva luation of renal function combined with anatomical organ diagnosis.

General Information

The safety rules customary for magnetic resonance imaging must be observed, e.g. exclusion of cardiac pacemakers, ferromagnetic implants.

Between 0.14 Tesla and 1.5 Tesla the recommendations for the use of Magnevist apply, regardless of the field strength of the magnet.

Magnevist is to be administered only by intravenous injection according to the instructions provided in section 4.2 (“Instructions for use/handling”). Contrast enhanced MRI can be commenced immediately afterwards.

Dietary suggestions

Nausea and vomiting are known possible adverse events of all MRI contrast media. The patient should therefore refrain from eating for two hours prior to investigation to reduce the risk of aspiration.

Infants (1 month – 2 years)

In infants the required dose should be administered by hand.

Anxiety

Pronounced states of excitement, anxiety and pain may increase the risk of side effects or intensify contrast medium-related reactions. These patients may be given a sedative.

Dosage

Wherever possible, intravascular administration of contrast agent is to be given with the patient lying down.T1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations.

Cranial and spinal MRI

Adults, adolescents and children (including infants> 1 month)

In general, the administration of 0.2 ml Magnevist/kg body weight is sufficient for good enhancement and to answer the clinical question.

If a strong clinical suspicion of a lesion persists despite a normal contrast enhanced MRI, a further injection of 0.2 or, in adults, even of 0.4 ml Magnevist/kg body weight within 30 minutes with immediately following MRI may increase the diagnostic yield of the examination.

For the exclusion of metastases or recurrent tumours in adults the injection of 0.6 ml Magnevist/kg body weight often leads to higher diagnostic confidence.

Maximum single dose: 0.6 ml (for adults) or 0.4 ml (for children) Magnevist/kg body weight.

Whole body MRI

Adults, adolescents and children.

In general, the administration of 0.2 ml Magnevist/kg body weight is sufficient for good enhancement and to answer the clinical question.

In special cases, e.g. in lesions with poor vascularisation and/or a small extracellular space, the administration of 0.4 ml Magnevist/kg body weight may be necessary for an adequate contrast effect especially on use of relatively slightly T1-weighted scanning sequences.

In cases of exclusion of a lesion or tumour recurrences in adults, the injection of 0.6 ml Magnevist/kg body weight may lead to higher diagnostic confidence.

For the visualisation of vessels, depending on the region to be investigated and the examination technique, in adults the injection of up to 0.6 ml/kg body weight may be required.

Maximum single dose: 0.6 ml (for adults) or 0.4 ml (for children) Magnevist/kg body weight.

Children (under two years): Limited experience in whole body MRI.

Special Populations

Renal impairment

Magnevist is contraindicated in patients with severe renal impairment (GFR < 30 ml/min/1.73m²) and in patients in the perioperative liver transplantation period (see section 4.3). Magnevist should only be used after careful risk/benefit eva luation in patients with moderate renal impairment (GFR 30-59 ml/min/1.73m²) at a dose not exceeding 0.2ml/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.

Neonates up to 4 weeks of age and infants up to 1 year of age

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 0.2ml/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.

Elderly (aged 65 years and above)

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

Instructions for use/handing

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

The rubber stopper should never be pierced more than once.

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

Hypersensitivity to any of the ingredients.

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

Special Warnings

• Hypersensitivity

As with other intravenous contrast agents, Magnevist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions characterized by cardiovascular, respiratory or cutaneous manifestations and ranging to severe reactions including shock. Most of these reactions occur within at least half an hour of administration. However in rare cases delayed reactions (hours later or up to several days) may occur (see Undesirable effects).

As with other contrast enhanced diagnostic procedures, post-procedure observation of the patient is recommended.

Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.

The risk of hypersensitivity reactions is higher in the case of - previous reaction to contrast media,

-history of bronchial asthma

-history of allergic disorders

Therefore, before any contrast medium is injected, the patient should be questioned for a history of allergy (e.g. seafood allergy, hay fever, hives), sensitivity to contrast media and bronchial asthma and premedication with antihistamines and/or glucocorticoids may be considered.

Patients taking beta blockers who experience such reactions may be resistant to treatment with beta agonists.

Patients with cardiovascular disease are more susceptible to serious, 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 < 30 ml/min/1.73m²). 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 development of NSF in patients with moderate renal impairment (GFR 30–59 ml/min/1.73 m²) is unknown, therefore, Magnevist should be only used after careful risk-benefit eva luation in patients with moderate renal impairment.

Haemodialysis shortly after Magnevist administration may be useful at removing Magnevist 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.

• Seizure disorders

Patients with seizure disorders or intracranial lesions may be at increased risk of seizure activity as has been reported rarely in association with Magnevist administration.

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

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.

Elderly

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

No known interaction with other medicaments.

Interference with diagnostic tests:

The result of serum iron determination employing methods measuring complexes (e.g. bathophenanthroline) within 24 hours of Magnevist examination may result in inaccurately low values due to the free DTPA contained in the contrast medium formulation.

• Pregnancy

There are no data from the use of gadopentetic acid in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Magnevist should not be used during pregnancy unless the clinical condition of the woman requires use of gadopentetic acid.

• Lactation

It is unknown whether gadopentetic acid is excreted in human milk. There is insufficient information on the excretion of gadopentetic acid in animal 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.

No known.

Adverse reactions with the use of Magnevist are usually mild to moderate and transient in nature. The most frequently reported adverse reactions are nausea, vomiting, headache, dizziness and injection site reactions (e.g. pain, coldness, warmth). Severe and life-threatening reactions as well as deaths have been reported.

Delayed contrast medium reactions are rare (see “Special Warnings”)

Frequency of adverse reactions from clinical trial data:

No individual adverse reaction reached a frequency greater than “uncommon”.

Based on experience in more than 11,000 patients the following undesirable effects have been observed and classified by investigators as drug- related.

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).

• Various kinds of injection site reactions (injection site coldness, injection site paraesthesia, injection site swelling, injection site warmth, injection site pain, injection site oedema, injection site irritation, injection site haemorrhage, injection site erythema, injection site discomfort.

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Additional adverse reactions from post-approval (spontaneous reporting) data:

* in patients with preexisting renal impairment

** Various kinds of injection site reactions (injection site necrosis, injection site thrombophlebitis, injection site phlebitis, injection site inflammation, injection site extravasation).

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.

Cases of nephrogenic systemic fibrosis (NSF) have been reported with Magnevist (see section 4.4).

The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

No signs of intoxication secondary to an 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.

Renal function should be monitored in patients with renal impairment.

On inadvertent overdosage or in greatly limited renal function, Magnevist can be removed by haemodialysis. However there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

Pharmacotherapeutic group: Paramagnetic contrast media, ATC code: V08CA01.

Magnevist is a paramagnetic contrast agent for magnetic resonance imaging.

The contrast-enhancing effect is mediated by the di-N-methylglucamine salt of gadopentetic acid, dimeglumine - the gadolinium complex of pentetic acid (diethylene triamine pentaacetic acid = DTPA).

When a suitable scanning sequence (e.g. T1-weighted spin-echo technique) is used in proton magnetic resonance imaging, the gadolinium ion-induced shortening of the spin-lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues.

Gadopentetic acid, dimeglumine is a highly paramagnetic compound which leads to distinct shortening of the relaxation times even in low concentration. The paramagnetic efficacy, the relaxivity – determined from the influence on the spin-lattice relaxation time of protons in plasma – is about 4.95 l/mmol/sec and displays only slight dependency on the strength of the magnetic field.

DTPA forms a firm complex with the paramagnetic gadolinium ion with extremely high in-vivo and in-vitro stability (log K = 22-23). The dimeglumine salt of gadopentetic acid, dimeglumine is highly water-soluble, extremely hydrophilic compound with a distribution coefficient between n-butanol and buffer at pH 7.6 of about 0.0001. The substance does not display any particular protein binding or inhibitory interaction with enzymes (e.g. myocardial Na⁺ and K⁺ ATPase). Magnevist does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions.

At higher concentrations and on prolonged incubation, gadopentetic acid, 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 hemolysis, which might explain the slight increase in serum bilirubin and iron occasionally observed in the first few hours after injection.

The physico-chemical properties of the 0.5 mmol/ml solution of Magnevist are listed below:

Gadopentetic acid, dimeglumine behaves in the organism like other highly hydrophilic biologically inert compounds (e.g. mannitol or inulin).

The pharmacokinetics observed in man were dose-independent.

• Distribution

After intravenous administration, the compound quickly diffuses in the extracellular space. Up to 0.25 mmol gadopentetic acid, dimeglumine/kg body weight (Δ 0.5 ml Magnevist/kg), the plasma level fell after an early distribution phase lasting a few minutes with a half-life of about 90 minutes, identical to the renal elimination rate. At a dose of 0.1 mmol gadopentetic acid, dimeglumine/kg (Δ 0.2 ml Magnevist/kg body weight), 0.6 mmol gadopentetic acid, dimeglumine/l plasma were measured 3 minutes after the injection and 0.24 mmol gadopentetic acid, dimeglumine/l plasma 60 minutes post injection.

Seven days after intravenous administration of radioactively labelled gadopentetic acid, dimeglumine, distinctly less than 1 % of the dose administered was found in the rest of the body of both the rat and the dog. The relatively highest concentrations of the compound were found in the kidneys in the form of the intact gadolinium complex.

The compound penetrates and passes neither an intact blood-brain nor the blood-testis barrier. The slight amount which overcomes the placental barrier is quickly eliminated by the foetus.

• Metabolism

No cleavage of the paramagnetic ion or metabolic break-down was demonstrable.

• Elimination

Gadopentetic acid, dimeglumine is eliminated in unchanged form via the kidneys by glomerular filtration. The portion eliminated extrarenally is extremely small.

An average of 83% of the dose was eliminated via the kidneys by 6 hours p.i. About 91% of the dose was recovered in the urine within the first 24 hours. By the 5^th day after the injection the dose eliminated with the faeces was less than 1%.

The renal clearance of gadopentetic acid, dimeglumine referred to 1.73m² was about 120 ml/min and is therefore comparable to that of inulin or ⁵¹Cr-EDTA.

• Characteristics in patients

Gadopentetic acid, dimeglumine is completely eliminated via the kidneys even in the presence of impaired renal function (creatinine clearance > 20 ml/min); the plasma half-life increases in relation to the degree of renal insufficiency, an increase in the extrarenal elimination was not observed.

Because the serum half-life is prolonged (up to 30 hours) in the presence of greatly impaired renal function (creatinine clearance < 20 ml/min), gadopentetic acid, dimeglumine could be eliminated by means of extracorporeal hemodialysis.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, systemic toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

• Systemic toxicity

Experimental systemic tolerance studies following repeated daily intravenous administration produced no findings which object to a single diagnostic administration of Magnevist to humans.

On the basis of the results of the acute toxicity studies, a risk of acute intoxication is highly unlikely on use of Magnevist in adults.

• Genotoxicity, tumorigenicity

Studies into genotoxic effects (gene, chromosomal and genome mutation tests) of gadopentetic acid, dimeglumine in vivo and in vitro gave no indication of a mutagenic potential.

In a tumorigenicity study with Magnevist in rats no compound-related tumours could be observed. Due to this fact, the absence of genotoxic effects and taking into account the pharmacokinetics and the absence of indications of toxic effects on fast-growing tissues as well as the fact that Magnevist was only administered once, there is no evident risk of a tumorigenic effect on humans.

• Reproduction toxicity

Reproduction-toxicological studies in animals gave no indication of a teratogenic or other embryotoxic potential following an administration of Magnevist during pregnancy.

• Local tolerance and contact-sensitizing potential

Experimental local tolerance studies with Magnevist following single as well as repeated intravenous administration and single intraarterial administration gave no indication that adverse local effects are to be expected in blood vessels of humans. Experimental local tolerance studies following a single paravenous, subcutaneous as well as intramuscular administration indicated that slight local intolerance reactions could occur at the injection site after inadvertent paravenous administration.

Studies into contact-sensitizing effect gave no indication of a sensitizing potential of Magnevist.

Meglumine

Pentetic acid

Water for injection

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Unopened: 4 years.

Once opened: Chemical and physical in-use stability has been demonstrated for 24 hours at temperature not above 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours, below 25°C, unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions.

Do not store above 30°C. Because of the sensitivity to light, store the vials in the outer carton.

6 ml vial containing 5 ml Magnevist

10 ml vial containing 10 ml Magnevist

15 ml vial containing 15 ml Magnevist

20 ml vial containing 20 ml Magnevist

Injection Vial: glass type 1 Ph.Eur. colourless

Stopper: stopper type 1, chlorobutyl-elastomer, black

Bordered Cap: aluminium, totally removable coloured plastic (polypropylene) cap.

Not all pack sizes may be marketed.

Magnevist should not be drawn into the syringe until immediately before use.

For single use only.

Discard any unused medium within 24 hours of opening.

The peel-off tracking label on the vials should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded.

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

PA 1410/6/1

Date of first authorisation: 8/10/1992

Date of last renewal: 8/10/2007

August 2010