1. Name Of The Medicinal Product
2. Qualitative And Quantitative Composition
1 ml of solution for injection contains 604.72 mg of gadobutrol (equivalent to 1.0 mmol gadobutrol containing 157.25 mg gadolinium).
1 vial with 7.5 ml contains 4535.4 mg gadobutrol,
1 vial with 15 ml contains 9070.8 mg gadobutrol,
1 vial with 30 ml contains 18141.6 mg gadobutrol,
1 bottle with 65 ml contains 39306.8 mg gadobutrol.
1 prefilled syringe with 5.0 ml contains 3023.6 mg gadobutrol,
1 prefilled syringe with 7.5 ml contains 4535.4 mg gadobutrol,
1 prefilled syringe with 10 ml contains 6047.2 mg gadobutrol,
1 prefilled syringe with 15 ml contains 9070.8 mg gadobutrol,
1 prefilled syringe with 20 ml contains 12094.4 mg gadobutrol.
1 cartridge with 15 ml contains 9070.8 mg gadobutrol,
1 cartridge with 20 ml contains 12094.4 mg gadobutrol,
1 cartridge with 30 ml contains 18141.6 mg gadobutrol.
1 ml contains 0.00056 mmol (equivalent to 0.013 mg) of sodium (see section 4.4).
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for injection and solution for injection in pre-filled syringe/cartridge.
Clear, colourless to pale yellow liquid.
Physico-chemical properties:
Osmolality at 37°C: 1603 mOsm/kg H2O
Viscosity at 37°C: 4.96 mPa
4. Clinical Particulars
4.1 Therapeutic Indications
This medicinal product is for diagnostic use only. Gadovist is indicated in adults, adolescents and children aged 7 years and older for:
• Contrast enhancement in cranial and spinal magnetic resonance imaging (MRI).
• Contrast enhanced MRI of liver or kidneys in patients with high suspicion or evidence of having focal lesions to classify these lesions as benign or malignant.
• Contrast enhancement in magnetic resonance angiography (CE-MRA).
4.2 Posology And Method Of Administration
Gadovist should only be administered by healthcare professionals experienced in the field of clinical MRI practice.
• General information
The dose required is administered intravenously as a bolus injection. Contrast-enhanced MRI can commence immediately afterwards (shortly after the injection depending on the pulse sequences used and the protocol for the examination). Optimal opacification is observed during arterial first pass for CE-MRA and within a period of about 15 minutes after injection of Gadovist for CNS indications (time depending on type of lesion/tissue). Tissue enhancement generally lasts up to 45 minutes after injection of Gadovist.
T1 -weighted scanning sequences are particularly suitable for contrast-enhanced examinations.
Intravascular administration of contrast media should, if possible, be done with the patient lying down. After the administration, the patient should be kept under observation for at least half an hour, since experience shows that the majority of undesirable effects occur within this time.
Instructions for use:
This product is intended for single use only.
This medicinal product should be visually inspected before use.
Gadovist should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container. Contrast medium not used in one examination must be discarded.
Vials
Gadovist should not be drawn up into the syringe from the vial until immediately before use.
The rubber stopper should never be pierced more than once.
If this medicinal product is intended to be used with an automatic application system, its suitability for the intended use has to be demonstrated by the manufacturer of the medicinal device. Any additional instructions from the respective equipment manufacturer must also be strictly adhered to.
Pre-filled syringes
The prefilled syringe must be taken from the pack and prepared for the injection immediately before the administration.
The tip cap should be removed from the prefilled syringe immediately before use.
Cartridges
Administration of contrast media should be performed by qualified personnel with the appropriate procedures and equipment.
Sterile technique must be used in all injections involving contrast media.
The contrast medium must be administered by means of a MEDRAD Spectris® type injector. Instructions of the device manufacturer must be followed.
• Dosage
• Adults
CNS indications:
The recommended dose for adults is 0.1 mmol per kilogram body weight (mmol/kg BW). This is equivalent to 0.1 ml/kg BW of the 1.0 M solution.
If a strong clinical suspicion of a lesion persists despite an unremarkable MRI or when more accurate information might influence therapy of the patient, a further injection of up to 0.2 mmol/kg BW within 30 minutes of the first injection may be performed.
CE-MRI of liver and kidneys:
The recommended dose for adults is 0.1 mmol per kilogram body weight (mmol/kg BW). This is equivalent to 0.1 ml/kg BW of the 1.0M solution.
CE-MRA:
Imaging of 1 field of view (FOV): 7.5 ml for body weight below 75 kg; 10 ml for body weight of 75 kg and higher (corresponding to 0.1-0.15 mmol/kg BW).
Imaging of >1 field of view (FOV): 15 ml for body weight below 75 kg; 20 ml for body weight of 75 kg and higher (corresponding to 0.2-0.3 mmol/kg BW).
Special Populations
Impaired renal function
Gadovist should only be used in patients with severe renal impairment (GFR < 30 ml/min/1.73m2) in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI (see section 4.4). If it is necessary to use Gadovist, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Gadovist injections should not be repeated unless the interval between injections is at least 7 days.
Paediatric population
For children aged 7 years and older and for adolescents the recommended dose is 0.1 mmol Gadovist per kg body weight (equivalent to 0.1 ml Gadovist per kg body weight) for all indications (see section 4.1).
Gadovist is not recommended for use in children below age 7 years due to a lack of sufficient data on gadobutrol elimination in the age group 2 to 6 years.
Gadovist is not recommended for use in children below age 2 years due to a lack of data on efficacy and safety.
Elderly (aged 65 years and above)
No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see section 4.4).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
While injecting Gadovist into veins with a small lumen there is the possibility of adverse effects such as reddening and swelling.
The usual safety requirements for magnetic resonance imaging, especially the exclusion of ferromagnetic materials, also apply when using Gadovist.
• Hypersensitivity reactions
Hypersensitivity reactions, including anaphylactoid reactions ranging to shock, have been observed after administration of Gadovist. To be able to react immediately to an emergency, medicinal products and equipment (e.g. endotracheal tube and respirator) should be within hand-reach.
Hypersensitivity reactions are not predictable, however in patients with an allergic disposition hypersensitivity may occur more often than in patients without such a disposition. In rare cases delayed anaphylactoid reactions (after hours to days) have been observed.
• Severe cardiovascular disease
In patients with severe cardiovascular disease Gadovist should only be administered after careful risk benefit assessment because only limited data are available so far.
Gadovist should be used with special care in patients
- with known congenital long QT syndrome or a family history of congenital long QT syndrome
- with known previous arrhythmias after taking medicinal products that prolong cardiac repolarisation
- who are currently taking a medicinal product that is known to prolong cardiac repolarisation e.g. a Class III antiarrhythmic (e.g. amiodarone, sotalol).
The possibility that Gadovist may cause torsade de pointes arrhythmias in an individual patient cannot be excluded (see section 5.3).
• Hypokalemia
Gadovist should not be used in patients with uncorrected hypokalemia.
• Impaired renal function
Prior to administration of Gadovist, it is recommended that all patients are screened for renal dysfunction by obtaining laboratory tests.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with acute or chronic severe renal impairment (GFR <30ml/min/1.73m2). Patients undergoing liver transplantation period are at particular risk since the incidence of acute renal failure is high in this group.
As there is a possibility that NSF may occur with Gadovist, it should therefore only be used in these patients with severe renal impairment and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI).
Haemodialysis shortly after Gadovist administration may be useful at removing Gadovist 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.
• Elderly
As the renal clearance of gadobutrol may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.
• Seizure disorders
Like with other gadolinium containing contrast agents special precaution is necessary in patients with a low threshold for seizures.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose (based on the average amount given to a 70 kg person), i.e. essentially 'sodium-free'.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed.
4.6 Pregnancy And Lactation
Pregnancy
There are no data from the use of gadobutrol in pregnant women. Animal studies have shown reproductive toxicity at repeated high doses (see section 5.3).
Gadovist should not be used during pregnancy unless the clinical condition of the woman requires use of gadobutrol.
Lactation
Gadolinium containing contrast agents are excreted into breast milk in very small amounts (see section 5.3). At clinical doses, no effects on the infant are anticipated due to the small amount excreted in milk and poor absorption from the gut. Continuing or discontinuing of breast feeding for a period of 24 hours after administration of Gadovist, should be at the discretion of the doctor and lactating mother.
4.7 Effects On Ability To Drive And Use Machines
Not relevant.
4.8 Undesirable Effects
Adverse reactions are "rare (
The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Additional safety information:
Short-lasting mild to moderate feelings of coldness, warmth or pain at the injection site have been uncommonly observed in association with the venous puncture or contrast medium injection.
On paravascular injection Gadovist may cause tissue pain lasting up to several minutes.
Hypersensitivity reactions (e.g. urticaria, rash, vasodilation) have been uncommonly reported and were mostly of mild to moderate intensity. In rare cases anaphylactoid reactions ranging to shock may occur. Delayed anaphylactoid reactions (after hours to days) have been observed rarely (see section 4.4).
Patients with an allergic disposition suffer more frequently than others from hypersensitivity reactions.
Isolated cases of renal impairment or renal impairment aggravation have been reported.
Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with Gadovist (see section 4.4).
4.9 Overdose
The maximum daily single dose tested in humans is 1.5 mmol gadobutrol/kg body weight.
No signs of intoxication from an overdose have so far been observed during clinical use.
Due to potential effects of Gadovist on cardiac repolarisation in cases of overdose, disturbances of cardiac rhythm may be possible. Cardiovascular monitoring (including ECG) and control of renal function is recommended as a measure of precaution.
In case of an overdose in patients with renal insufficiency, Gadovist can be removed by haemodialysis. After 3 haemodialysis sessions approx. 98% of the agent are removed from the body. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Paramagnetic contrast media
ATC - Code: V08C A09
The contrast-enhancing effect is mediated by gadobutrol, the nonionic complex consisting of gadolinium(III) and the macrocyclic ligand dihydroxy- hydroxymethylpropyl- tetraazacyclododecane-triacetic acid (butrol).
In clinical doses, gadobutrol leads to shortening of the relaxation times of protons in tissue water. At 0.47 T (20 MHz), pH 7 and 40°C the paramagnetic effect (relaxivity), as determined from the effect on spin-lattice relaxation time (T1) - is about 3.6 l mmol-1 sec-1 and the spin-spin relaxation time (T2) is about 4 l mmol-1 sec-1. Within the range 0.47 to 2.0 Tesla, the relaxivity displays only slight dependency on the strength of the magnetic field.
Gadobutrol does not cross an intact blood-brain barrier and therefore does not accumulate in healthy brain tissue or in lesions featuring an intact blood-brain barrier. With high local tissue concentrations of gadobutrol the T2 effect results in a lessening of signal intensity.
In a pivotal phase III liver study average sensitivity in combined pre and post-contrast MRI for Gadovist-treated patients was 79% and specificity was 81% for lesion detection and classification of suspected malignant liver lesions (patient-based analysis).
In a pivotal phase III kidney study average sensitivity was 91% (patient-based analysis) and 85% (lesion-based analysis) for classification of malignant and benign renal lesions. Average specificity in a patient-based analysis was 52% and in a lesion based analysis 82%.
The increase of sensitivity from pre-contrast to combined pre and post-contrast MRI for Gadovist-treated patients was 33% in the liver study (patient-based analysis) and 18% in the kidney study (patient based analysis as well as lesion-based analysis). The increase in specificity from pre-contrast to combined pre and post-contrast MRI was 9% in the liver study (patient based analysis) while there was no increase in specificity in the kidney study (patient-based analysis as well as lesion-based analysis).
All results are average results obtained in blinded reader studies.
A single dose phase I/III study in 140 pediatric patients (aged 2 to 17 years) scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA has been performed. Diagnostic efficacy and an increase in diagnostic confidence was demonstrated for all parameters evaluated in the study and there was no difference among the age groups. Gadovist was well tolerated in this study with the same safety profile of gadobutrol as in adults.
5.2 Pharmacokinetic Properties
After intravenous administration, gadobutrol is rapidly distributed in the extracellular space.
Plasma protein binding is negligible.
The pharmacokinetics of gadobutrol in humans are dose proportional. Up to 0.4 mmol gadobutrol/kg body weight, the plasma level declines after an early distribution phase with a mean terminal half-life of 1.8 hours (1.3 to 2.1 hours), identical to the renal elimination rate. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 0.59 mmol gadobutrol/l plasma was measured 2 minutes after the injection and 0.3 mmol gadobutrol/l plasma 60 minutes post injection. Within two hours more than 50 % and within 12 hours more than 90% (or 92%) of the given dose is eliminated via the urine. At a dose of 0.1 mmol gadobutrol/kg BW, an average of 100.3 ± 2.6 % of the dose was excreted within 72 h after administration. In healthy persons renal clearance of gadobutrol is 1.1 to 1.7 ml min-1 kg-1 and thus comparable to the renal clearance of inulin, pointing to the fact that gadobutrol is eliminated primarily by glomerular filtration. Less than 0.1 % of the dose is eliminated via the faeces. No metabolites are detected in plasma or urine.
A single dose phase I/III study in 140 pediatric patients (aged 2 to 17 years) scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA has been performed.
It was shown that the overall pharmacokinetic (PK) profile of gadobutrol in children over 6 is similar to that in adults. For children below 7 no sufficient data on gadobutrol elimination are available at present.
PK parameters such as total clearance (CLtot), area under the curve (AUC) and volume of distribution (V) increased with increasing body weight. Neither age nor gender was found to have an additional independent effect on PK. The amount of gadobutrol excreted into urine within 6 hours p.i. was 77% (median) of the administered dose, confirming fast renal excretion of gadobutrol also in the pediatric population.
5.3 Preclinical Safety Data
Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Repeated treatment in reproductive toxicology studies caused a retardation of embryonal development in rats and an increase in embryolethality in monkeys and in rabbits at maternally toxic dose levels (8 to 17 times the diagnostic dose) only. It is not known whether these effects can also be induced by a single administration.
Radioactively labelled gadobutrol administered intravenously to lactating rats was transferred to the neonates via milk at less than 0.01% of the administered dose.
Cardiovascular effects seen in animals (dogs) at exposure levels similar (0.25 mmol/kg) and higher (1.25 mmol/kg), respectively, to maximum clinical exposure levels were a dose dependent transient increase in blood pressure (5% and 10%, above saline control) and myocardial contractility (5% and 16%, above saline control).
Cardiovascular safety pharmacology studies as well as clinical phase I studies gave indication for a potential of Gadovist to block cardiac potassium channels and an effect on cardiac repolarisation when administered in doses 3 to 8 fold higher than normally administered to patients. Therefore, the possibility that Gadovist may cause torsade de pointes arrhythmias in an individual patient cannot be excluded.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Calcobutrol sodium
Trometamol
Hydrochloric acid 1N
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
Shelf life of the medicinal product as packaged for sale:
3 years (vials)
3 years (prefilled syringe)
3 years (cartridge)
Shelf life after first opening of the container:
Any solution for injection not used in one examination must be discarded. Chemical and physical in-use stability has been demonstrated for 24 hours at 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 at 2 to 8 °C, unless opening has taken place in controlled and validated aseptic conditions.
For vials only:
The following applies to the use of the infusion bottle containing 65 ml:
After opening of the infusion bottle under aseptic conditions Gadovist remains stable for at least 8 hours at 25°C.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
For storage conditions after first opening, see section 6.3.
6.5 Nature And Contents Of Container
Vials
1 vial (type I glass) with a stopper (chlorobutyl elastomer) and a pure aluminium with internal and external lacquer flanged cap containing 7.5 ml, 15 ml or 30 ml solution for injection.
1 infusion bottle (type II glass) with a stopper (chlorobutyl elastomer) and a pure aluminium with internal and external lacquer flanged cap containing 65 ml solution for injection.
Pack sizes of:
1 and 10 vials
1 and 10 bottles
Not all pack sizes may be marketed.
Pre-filled syringes
One 10 ml pre-filled syringe (type I glass) with a plunger stopper (chlorobutyl elastomer) and a tip cap (chlorobutyl elastomer) contains 5 ml, 7.5 ml and 10 ml solution for injection.
One 17 ml pre-filled syringe (type I glass) with a plunger stopper (chlorobutyl elastomer) and a tip cap (chlorobutyl elastomer) contains 15 ml solution for injection.
One 20 ml pre-filled syringe (type I glass) with a plunger stopper (chlorobutyl elastomer) and a tip cap (chlorobutyl elastomer) contains 20 ml solution for injection.
One 65 ml cartridge (cyclo-olefine-polymer) with a plunger stopper (polyisoprene, type I, siliconised with silicone oil), a tip cap (chlorobutyl rubber), a hard core (polycarbonate), a safety cap (polypropylene) and a swivelnut (polycarbonate) contains 15, 20 or 30ml solution for injection.
Pack sizes of:
1 and 5 pre-filled syringes
1 and 5 cartridges
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Any contrast medium not used in one examination must be discarded.
Any unused product or waste material should be disposed of in accordance with local requirements.
The peel-off label on the vials/bottles/pre-filled syringes/cartridges should be stuck onto the patient record to enable accurate recording of the gadolinium contrast agent used. The dose used should also be recorded. |
7. Marketing Authorisation Holder
Bayer plc
Bayer House
Strawberry Hill
Newbury
Berkshire RG14 1JA
United Kingdom
8. Marketing Authorisation Number(S)
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9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation:
Solution for injection (vials): 01 May 2008
Solution for injection (pre-filled syringes/cartridges): 01 May 2008
Date of last renewal:
Solution for injection (vials): 14 October 2010
Solution for injection (pre-filled syringes/cartridges): 14 October 2010
10. Date Of Revision Of The Text
Solution for injection (vials): 1 July 2011
Solution for injection (pre-filled syringes/cartridges): 1 July 2011
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