Magnevist®

Each 1ml of Magnevist solution contains 469.01mg of gadopentetic acid, dimeglumine salt. This represents 0.5 moles of Magnevist/l (0.5mmol/ml).

Solution for injection.

As a paramagnetic contrast medium in cranial, spinal and whole body magnetic resonance imaging (MRI).

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 ferro-magnetic objects including vascular clips etc) must be observed.

Instructions for use/handling

Magnevist is to be administered only by intravenous injection.

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.

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

Cranial and spinal MRI

Adults:

In general, the administration of 0.2ml Magnevist/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/kg body weight within 30 minutes may increase the diagnostic yield.

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

Children (including neonates and infants under the age of 2 years):

0.2ml Magnevist/kg body weight is sufficient to provide diagnostically adequate contrast.

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/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 /kg body weight within 30 minutes may increase the diagnostic yield.

Whole body MRI

Adults:

In general, 0.2ml Magnevist/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/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/kg body weight may lead to a higher diagnostic confidence.

Children (over the age of 2 years):

In general, 0.2ml Magnevist/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/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/kg body weight may be used in this particular age group.

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/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.

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/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.

Elderly (aged 65 years and above)

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

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).

• Hypersensitivity and hypersensitivity reactions

Particularly careful risk-benefit assessment is required in patients with known hypersensitivity to Magnevist or any of its ingredients.

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.

Most of these reactions occur within half an hour of administration. However, in rare cases delayed reactions (hours later or up to several days) may occur (see section 4.8 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 readiness for institution of emergency measures are necessary.

The decision to use Magnevist must be made after particularly careful evaluation of the risk-benefit ratio in patients with either a:

- previous reaction to contrast media,

- history of bronchial asthma,

- history of allergic disorders,

since experience shows that these patients suffer more frequently than others from hypersensitivity reactions.

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.

• 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.

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.

• 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. 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. In infants the required dose should be administered by hand.

• Elderly

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

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

• Pregnancy

There are no data from the use of gadopentetic acid 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 gadopentetic acid.

• Lactation

Small amounts of gadopentetic acid 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.

None stated.

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 Section 4.4, 'Special Warnings and Precautions for Use').

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)

** in patients with pre-existing renal impairment

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

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

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.

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.

If intoxication occurs due to overdosage or in cases of substantially impaired renal function, Magnevist can be removed by haemodialysis. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).

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 concentrations. 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 a 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.

In 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 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:

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

After intravenous administration, the compound quickly diffuses in the extracellular space and is eliminated in unchanged form via the kidneys by glomerular filtration. The portion eliminated extrarenally is extremely small. 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.

The pharmacokinetics observed in man were dose-independent. Up to 0.25mmol gadopentetic acid, dimeglumine/kg body weight (= 0.5ml 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 0.1mmol/kg (= 0.2ml Magnevist/kg body weight), 0.6mmol/l plasma were measured 3 minutes after the injection and 0.24mmol/l plasma 60 minutes p.i.; 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 24 hours of the injection. By the 5th day, the portion of the dose eliminated with the faeces was less than 1%. No cleavage of the paramagnetic ion or metabolic break-down was demonstrable. The renal clearance of gadopentetic acid, dimeglumine referred to 1.73m² was about 120ml/min and is therefore comparable to that of inulin or ⁵¹ Cr-EDTA.

Gadopentetic acid, dimeglumine is completely eliminated via the kidneys even in the presence of impaired renal function (creatinine clearance > 20ml/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 < 20ml/min), gadopentetic acid, dimeglumine should be eliminated by means of extracorporeal haemodialysis.

Characteristics in elderly populations

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.

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.

Meglumine

Pentetic acid (DTPA)

Water for injections

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

5 years.

Protect from light.

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.

The peel-off tracking label on the vials/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.

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berks RG14 1JA

Trading as Bayer plc, Bayer Schering Pharma

Vials: PL 00010/0542

Pre-filled syringes: PL 00010/0543

Vials: Date of first authorisation: 01 May 2008

Pre-filled syringes: Date of first authorisation 01 May 2008

Vials: 28 February 2011

Pre-filled syringes: 28 February 2011

POM