INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo MAGNEVIST

SCHEDULING STATUS:
S2

PROPRIETARY NAME
(and dosage form):

MAGNEVIST

MAGNEVIST 5 mL
MAGNEVIST 10 mL
MAGNEVIST 15 mL
MAGNEVIST 20 mL
MAGNEVIST 30 mL
MAGNEVIST 100 mL

Paramagnetic contrast medium for
magnetic resonance imaging (MRI)

COMPOSITION
1 mL Magnevist contains
gadopentetic acid (dihydrogen[N,N-bis[2-[bis(carboxymethyl)-amino]ethyl]-glycinate(5-)] gadolinate (2-), dimeglumine salt 469,01 mg, diethylene triamine pentaacetic acid (DTPA), (3-azapentamethylene diamine-N,N,N',N'-3-pentaacetic acid) meglumine salt, maximum 1,02 mg in aqueous solution.

Contrast medium concentration 
        (mg/mL)         469,01
        (mol/L)         0,5
Contrast medium content (g) per 
        5 mL         2,3
        10 mL         4,7
        15 mL         7,0
        20 mL         9,4
        30 mL         14,1
        100 mL         46,9
Osmolarity at 37°C (osm/L solution)         1,44
Osmolality at 37°C (osm/kg H2O)         1,96
Osmotic pressure at 37°C 
        (atm)         49,8
        (MPa)         5,06
Density (kg/L) 
        at 20°C         1,210
        at 37°C         1,195
Viscosity (mPa.s or cP) 
        at 20°C         4,9
        at 37°C         2,9
pH         6,5-8,0

PHARMACOLOGICAL CLASSIFICATION
A. 28 Contrast media.

PHARMACOLOGICAL ACTION
Magnevist is a paramagnetic contrast medium for use in magnetic resonance imaging (MRI).
The contrast enhancing effect is brought about by the di-N-methylglucamine salt of gadopentetate (Gd-DTPA), the gadolinium complex of diethylenetriamine pentaacetic acid. The spin-lattice relaxation time of the excited nuclei, which is shortened by the gadolinium ion, causes an enhancement of the signal intensity, in the case of suitable image sequence (eg with T
1-weighted spin echo), in MRI.
The paramagnetic effectiveness (relaxivity), determined by influencing the spin-lattice relaxation time of protons in water, is approximately 3,8 l mmol-1 sec-1 at pH 7 and 39 C and displays only a slight dependency on the strength of the magnetic field.
The gadolinium ion forms a stable complex with DTPA in vivo and in vitro (log k = 22-23) which is intensely hydrophilic.
In the organism, gadopentetate behaves like other biologically inert compounds (ie mannitol or inulin). The gadolinium complex has no noteworthy protein-binding nor inhibitory interaction with enzymes, ie myocardial Na+ and K+-ATPase. Magnevist does not activate the complement system.
After injection of Magnevist, the resulting opacification of areas with dysfunction of the blood brain barrier (eg glioblastoma) and of other intracranial and intraspinal lesions of non-cerebral origin, may provide diagnostic information additional to that obtainable with a plain scan.
In higher concentrations and on prolonged incubation, gadopentetate 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.
•        Pharmacokinetic information
Following intravenous administration, the compound is distributed rapidly in the extracellular space and is eliminated unchanged by glomerular filtration via the kidneys. It was observed in man that the pharmacokinetics are independent of the dose. Up to 0,25 mmol gadopentetate/kg body weight (= 0,5 mL Magnevist/kg body weight) the plasma level fell, after an early distribution phase lasting a few minutes, with a half-life of about 90 minutes, which corresponds to the rate of renal elimination. With a dose of 0,1 mmol gadopentetate/kg body weight (= 0,2 mL Magnevist/kg body weight), 0,6 mmol gadopentetate/L was found 3 minutes post injection and 0,24 mmol gadopentetate/L 60 minutes post injection. Up to 6 hours post injection an average of 83% of the dose was eliminated renally. Up to 5 days post injection approximately 91% of the dose was found in the urine. Less than 1% of the dose was excreted with the faeces. Splitting off of the paramagnetic ion or metabolites could not be detected and renal clearance of gadopentetate is approximately 120 mL/minute related to 1,73 m² and is therefore comparable to inulin or 51Cr-EDTA.
At 0,1 mmol/kg gadopentetate is completely eliminated via the kidneys even in the presence of impaired renal function (creatinine clearance >20 mL/minute); the plasma half-life increases in relation to the degree of renal insufficiency, an increase in the extra-renal elimination was not observed.
Because the serum half-life is prolonged (up to 30 hours) in the presence of greatly impaired renal function (<20 mL/minute), gadopentetate should be eliminated by means of extracorporeal haemodialysis (refer to “Side effects and special precautions”and “Known symptoms of overdosage and particulars of its treatment”).

INDICATIONS
Cranial and spinal magnetic resonance imaging.
Magnevist magnetic resonance imaging (MRI) allows additional diagnostic information such as the demonstration of tumours, inflammation and vascular lesions and determination of the extent or differentiation of such lesions as well as the appearance of immediately adjacent areas (female breast, thoracic, abdominal and pelvic space).

CONTRA-INDICATIONS
Relative contra-indications include: acute renal failure and pregnancy (refer to “Side effects and special precautions”).

DOSAGE AND DIRECTIONS FOR USE
The patient is to fast for 2 hours before the examination.
The usual safety rules customary for MRI (eg exclusion of cardiac pacemakers and ferromagnetic implants) must be observed.
The required dose is administered as a single intravenous - if desired, bolus - injection. Contrast-enhanced MRI can be commenced immediately afterwards. Optimal opacification is generally observed within a period of about 45 minutes after injection of Magnevist.
T
1-weighted scanning sequences are particularly suitable for contrast-enhanced examinations.
Between 0,14 Tesla and 1,5 Tesla the recommendations for the use of Magnevist apply, regardless of the field strength of the magnet.
Wherever possible, intravascular administrations of contrast media are to be given with the patient lying down; after the end of the injection, the patient should be kept under supervision for at least half an hour.
Magnevist should not be drawn into the syringe and pre-filled syringes should not be taken from the pack or prepared for the injection until immediately before use. Contrast medium solution not used in one examination session must be discarded.
After the vial has been opened or the pre-filled syringe has been prepared for use, Magnevist remains stable for an examination day. The time indicated does not refer to physicochemical stability but to the possibility of microbiological contamination.
The following applies to the use of the 100 mL bottle:
The contrast medium must be administered by means of an automatic injector, the use of which is prohibited in newborns and babies (refer to “Known symptoms of overdosage and particulars of its treatment”).
The tube from the injector to the patient (patient’s tube) must be changed after every examination because it is contaminated with blood. Any contrast medium solution left over in the bottle, the connecting tubes and all disposable parts of the injector system must be discarded at the end of the examination day. Any additional instructions from the respective equipment manufacturer must also be adhered to.
Cranial and spinal magnetic resonance imaging
The following dosage guidelines apply to adults and children (including new-borns and babies):
In general, the administration of 0,1 mmol Magnevist/kg body weight (corresponding to 0,2 mL/kg body weight) is sufficient for good opacification and diagnosis.
If a strong clinical suspicion of a lesion persists despite a normal contrast-enhanced MRI, diagnostic yield of the examination may be increased by a further injection of 0,2 mL Magnevist/kg body weight, or in adults of up to 0,4 mL Magnevist/kg body weight, within 30 minutes with MRI being performed immediately thereafter.
For the exclusion of metastases or recurrent tumours in adults, the injection of 0,3 mmol Magnevist/kg body weight (corresponding to 0,6 mL Magnevist/kg body weight) often leads to higher diagnostic confidence.
Whole body magnetic resonance imaging (MRI)
The following dosage guidelines apply to adults and children. Experience in the indication “Whole body MRI”in children under the age of two years is limited.
In general, the administration of 0,1 mmol Magnevist/kg body weight (corresponding to 0,2 mL/kg body weight) is sufficient for good opacification and diagnosis.
In special cases, eg 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 T
1-weighted scanning sequences.
In cases of exclusion of a lesion or tumour recurrences in adults, the injection of 0,3 mmol Magnevist/kg body weight (corresponding to 0,6 mL Magnevist/kg body weight) may lead to higher diagnostic confidence.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
The decision to use Magnevist must be made after particularly careful evaluation of the risk-benefit ratio in patients with an allergic disposition (ie bronchial asthma, allergic rhinitis, eruptions, urticaria, etc), since experience shows that these patients suffer more frequently than others from hypersensitivity reactions. Anaphylactoid reactions including shock may occur. It is of decisive importance for prompt action in the event of contrast medium incidents to be familiar with the practice of emergency measures. To permit immediate counter-measures to be taken in emergencies appropriate drugs and instruments (eg endotracheal tube and ventilator) should be readily available (cf "Suggestions for the management of life-threatening acute hypersensitivity reactions or acute anaphylaxis after administration of contrast media").
Nausea and vomiting and also allergy-type dermal and mucosal reactions have occasionally been observed after the administration of Magnevist.
Short-lasting sensations of local warmth or pain associated with the venous puncture or contrast medium injection have been recorded.
In less frequent cases, convulsions have been observed following administration of Magnevist, however, a causal relationship seems to be questionable.
Transient headaches, vasodilatation, dizziness, chills and syncope following administration of Magnevist have been occasionally reported; a causal relationship has not been established.
Transient sensations of taste (sweetish) may occur on bolus injection.
The hyperosmolar injection solution may cause tissue pain lasting up to 20 minutes on paravascular injection. No other tissue reactions have been observed.
In impaired renal function, the benefits must be weighed particularly carefully against the risks before deciding to perform the examination. Because heterotopic secretion takes place only slowly in the presence of impaired renal function, the retention time in the organism is prolonged in such cases. No further impairment of renal function or other adverse events attributable to administration of the contrast medium have so far been observed at a dose of 0,1 mmol/kg. In severely impaired renal function or chronic renal failure, elimination of gadopentetate can be effected by means of extracorporeal haemodialysis.
In new-borns and babies the required dose should be administered by hand (refer to “Known symptoms of overdosage and particulars of its treatment”).
Elevated serum iron and serum bilirubin values have been observed after administration of Magnevist. However, they were seldom sustained for more than 48 hours and always fell to the initial values without any symptoms. Moreover, the increases remained within the normal range in the majority of cases observed.
The result of the serum iron determination using complexometric methods (eg bathophenanthroline) may be too low for up to 24 hours after the examination with Magnevist because of the free DTPA contained in the contrast medium solution.
Pregnancy and lactation
It has not been demonstrated that Magnevist is safe to use during pregnancy. Consequently, the need for examination merits particularly careful consideration in pregnant women.
It is known from animal experiments that minimal amounts of Magnevist (less than 0,2% of the dose administered) enter the breast milk.
Suggestions for the management of life-threatening acute hypersensitivity reactions or acute anaphylaxis after administration of contrast media
Give adrenaline subcutaneously or intravenously if the patient is in shock.
The doses of adrenaline solution are 1 mL of 1:1000 concentration (1 mg) subcutaneously, and 0,1-0,4 mL of 1:1000 concentration diluted in 10 mL physiological saline intravenously SLOWLY.
If the patient does not respond to subcutaneous administration the dose may be repeated 5-10 minutes later.
Maintain an open airway. An emergency tracheostomy may be necessary. Positive pressure oxygen administration may be required.
In the event of urticaria or angio-oedema, administer adrenaline subcutaneously followed by an antihistamine intravenously (eg diphenhydramine hydrochloride 20 mg).
For prolonged or severe reactions give hydrocortisone sodium succinate 250 mg or methylprednisolone sodium succinate 100 mg, intravenously over 30 seconds after adrenaline and the antihistamine.
Aminophylline injection 250-500 mg should be given slowly intravenously in the presence of bronchospasm.
Intravenous fluids may be required to correct hypovolaemia.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms
No signs of intoxication secondary to an overdose have so far been observed or reported in clinical use. 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. This statement is true for new-borns and babies only if the dosage of Magnevist specified for this group of patients is injected by hand and no automatic injector is used based on the limited data available in this age group.
Treatment
On inadvertent overdosage or in patients with restricted renal function, Magnevist can be removed from the body by extracorporeal dialysis.

IDENTIFICATION
Clear, sterile, pyrogen-free aqueous solution.

PRESENTATION
Clear glass vials of 5, 10, 15, 20 and 30 mL.
Clear glass pre-filled syringes of 10, 15 and 20 mL.
Clear glass bottles of 100 mL for use with an automatic injector.

STORAGE INSTRUCTIONS
Store below 25°C. Protect from light. Keep out of reach of children.

REGISTRATION NUMBERS
Magnevist 5 mL:         28/28/0639
Magnevist 10 mL:         28/28/0640
Magnevist 15 mL:         28/28/0641
Magnevist 20 mL:         W/28/199
Magnevist 30 mL:         36/28/0026
Magnevist 100 mL:         36/28/0027

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 1964/009072/07)
106 Sixteenth Road
Randjespark
Midrand        1685
P O Box 5278
Halfway House        1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
15 November 2002

Schering (Pty) Ltd
(Reg No: 1964/009072/07)
Subsidiary of
Schering AG Germany

Updated on this site: April 2003
Current: January 2005
Source: Pharmaceutical Industry

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