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GADOVIST

SCHEDULING STATUS:
S2

PROPRIETARY NAME
(and dosage form):

GADOVIST
7,5 mL, 10 mL, 15 mL, 30 mL, 65 mL

Paramagnetic contrast medium solution
for magnetic resonance imaging

COMPOSITION
1 mL of the neutral paramagnetic contrast agent for magnetic resonance imaging contains gadobutrol (10-[(1SR,2RS)-2,3-dihydroxy-1-hydroxy-methylpropyl]-1,4,7,10-tetraazacyclo-dodecane-1,4,7-triacetic acid, gadolinium-complex) 604,72 mg (equivalent 1,0 mmol) as active ingredient, as well as 0,513 mg calcobutrol sodium, 1,211 mg trometamol, hydrochloric acid and water for injection as inactive ingredients.
Physico-chemical properties

Contrast medium concentration (mg/mL)                                 (mmol/mL)	604,72 1,0
Osmolarity at 37°C (mOsm/L solution)	1117
Osmolality at 37°C (mOsm/kg H2O)	1603
Viscosity at 37°C (mPa·s)	4,96
pH	7,0 –7,4

PHARMACOLOGICAL CLASSIFICATION
A. 28 Contrast media.

PHARMACOLOGICAL ACTION
Pharmacodynamic properties
Gadovist is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by gadobutrol, the neutral complex consisting of gadolinium (III) and the macrocyclic dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrol).
In T2*-weighted gradient echo sequence the induction of local magnetic field fluctuations by the large magnetic moment of gadolinium leads to a signal decrease of tissues in such sequences.
Gadobutrol leads to distinct shortening of the relaxation times even in low concentrations. At pH 7 and 40°C the relaxivity - determined from the influence on the spin-lattice relaxation time of protons in water - is about 3,58 L/mmol·sec and the spin-spin relaxation time is about 3,99 L/mmol·sec. The relaxivity displays only slight dependency on the strength of the magnetic field.
The macrocyclic ligand forms a firm complex with the paramagnetic gadolinium ion with extremely high in vivo and in vitro stability. Gadobutrol is a highly water-soluble, extremely hydrophilic compound with a distribution coefficient between n-butanol and buffer at pH 7,6 of about 0,006. The substance does not display any particular protein binding or inhibitory interaction with enzymes. Gadovist does not activate the complement system and, therefore, probably has a very low potential for inducing anaphylactoid reactions.
Pharmakokinetic properties
After intravenous administration, gadobutrol is rapidly distributed in the extracellular space and is eliminated in an unchanged form via the kidneys by glomerular filtration. The extrarenal elimination is negligible.
In animal studies it has been demonstrated that Gadovist does not penetrate the intact blood-brain barrier, and that placental transfer and transfer into milk was very low. Enterohepatic circulation has not been observed. Absorption after oral administration was found to be very small.
The pharmacokinetics of Gadovist in humans were dose proportional. Up to 0,4 mmol Gadovist/kg body weight, the plasma level declined after an early distribution phase with a half-life of about 90 minutes, identical to the renal elimination rate. At a dose of 0,1 mmol Gadovist/kg body weight, 0,59 mmol Gadovist/L plasma was measured 2 minutes after the injection and 0,3 mmol Gadovist/L plasma 60 minutes post-injection. Within two hours more than 50% of the given dose was eliminated via the urine. At a dose of 0,1 mmol Gadovist/kg body weight about 100,3 +2,6% of the dose was excreted within 72 hours after administration. Less than 0,1% was eliminated via the faeces. The average renal clearance of Gadovist was found to be about 120 mL/minute and was, therefore, comparable to that of other aqueous soluble substances like inulin. No metabolites were detected in plasma or urine.

INDICATIONS

•	Contrast enhancement in cranial and spinal magnetic resonance imaging.
•	First pass magnetic resonance imaging studies of cerebral perfusion (see “Warnings”).

CONTRA-INDICATIONS
Hypersensitivity to any of the ingredients.
Safety has not been demonstrated in pregnancy and lactation. It is recommended that breastfeeding should be discontinued for at least 24 hours after the administration of Gadovist.

WARNINGS
Anaphylactoid reactions may occur. Supportive medication (adrenaline) and equipment (eg endotracheal tube and oxygen ventilator) should be close at hand when investigation is performed. In patients with an allergic disposition, the decision to use Gadovist must be made after particularly careful evaluation of the risk-benefit ratio.
Safety and efficacy have not been demonstrated in children.
Safety in renal impairment has not been demonstrated. The elimination of gadobutrol is delayed in patients with impaired renal function. In particularly severe cases, it is advisable to remove Gadovist from the body by haemodialysis: for removal of the agent from the body, at least 3 dialysis sessions within 5 days of the injection should be performed.
Cerebral perfusion studies
Information to support the clinical usefulness of magnetic resonance imaging studies of cerebral perfusion is limited. Clinical studies were conducted only in patients with a unilateral carotid artery stenosis and/or unilateral cerebral infarct who were assessed as being in a clinically stable condition.

DOSAGE AND DIRECTIONS FOR USE
General information
The dose required should only be administered intravenously. Contrast-enhanced magnetic resonance imaging can usually commence shortly after the injection, depending on the pulse sequences used and the protocol for the examination. Optimal opacification is generally observed within a period of about 15 minutes after injection of Gadovist (time depending on type of lesion/tissue). Enhancement generally lasts up to 45 minutes after injection of Gadovist.
Gadovist should not be drawn into the syringe and the prefilled syringe should not be prepared until immediately before use. Any contrast agent solution not used in one examination must be discarded.
In addition, the following applies to use of the infusion bottle containing 65 mL: The contrast medium must be administered by means of a powered injector. The tube from the injector to the patient (patient’s tube) must be changed after every examination. Any contrast medium solution left over in the bottle, the connecting tubes and all disposable parts of the injector system must be discarded within 8 hours. Any additional instructions from the respective equipment manufacturer must also be strictly adhered to.
T1-weighted scanning sequences are usually used for contrast-enhanced examinations.
For perfusion studies, T2*-weighted gradient echo sequences are recommended.
General safety rules customary for magnetic resonance imaging must be observed.
Intravenous administration of Gadovist should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least 30 minutes, since experience with contrast media shows that the majority of all severe incidents occur within this time.
Dosage
In renal impairment the dose should be limited to 0,1 mL Gadovist/kg body weight.
The following dosage guidelines apply to adults. No clinical experience is yet available in patients under 18 years of age.
Cranial and spinal magnetic resonance imaging
0,1 mL Gadovist per kg body weight (equivalent of 0,1 mmol/kg body weight) given intravenously at a rate of 2 mL per second.
When more accurate information on the number, size or extent of lesions might influence management or therapy of the patient, a further injection of 0,1 or of even 0,2 mL Gadovist/kg body weight at a rate of 2 mL per second within 30 minutes of the first injection may increase the diagnostic yield of the examination.
Cerebral perfusion studies
For T2*-weighted gradient echo sequences 0,3 mL Gadovist/kg body weight (0,3 mmol/kg), given intravenously at a rate of 5 mL/second using a powered injector, is recommended.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Nausea and vomiting and also allergic-type dermal and mucosal reactions have occasionally been observed after the administration of Gadovist.
Short-lasting mild to moderate feelings of coldness, warmth or pain at the injection site may occur.
Transient headaches have occasionally been reported.
Convulsions, vasodilatation, dizziness, chills and syncope have been reported.
Transient sensations of taste or smell may occur during or immediately after bolus injection.
On paravascular injection Gadovist may cause tissue pain lasting several minutes. No other tissue reactions have been observed.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
No signs of intoxication from an overdose have so far been observed during clinical use. On the basis of the results of the acute toxicity studies, a risk of acute intoxication is highly unlikely with Gadovist.
On inadvertent overdosage or if renal function is severely restricted, Gadovist can be removed from the body by extracorporeal dialysis.

IDENTIFICATION
Solution - clear, free of particles.

PRESENTATION
Clear glass vials of 7,5 mL, 15 mL and 30 mL.
Clear glass pre-filled syringes of 7,5 mL, 10 mL and 15 mL.
Clear glass bottles of 65 mL.

STORAGE INSTRUCTIONS
Store below 30°C. Protect from light. Keep out of reach of children.

7,5, 10, 15 and 30 mL -	Any contrast agent solution not used in one examination must be discarded.
65 mL -	Any remaining contents of the 65 mL bottles must be discarded 8 hours after opening under aseptic conditions.

REGISTRATION NUMBERS

Gadovist 7,5 mL	:	34/28/0383
Gadovist 10 mL	:	34/28/0384
Gadovist 15 mL	:	34/28/0385
Gadovist 30 mL	:	34/28/0386
Gadovist 65 mL	:	34/28/0387

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
10 April 2002

SCHERING (PTY) LTD
(Reg No: 1964/009072/07)
Subsidiary of
Schering AG        Germany

Updated on this site: January 2005
Source: Pharmaceutical Industry
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