Gadovist 1.0 mmol/ml solution for injection in prefilled syringe

3.             How Gadovist will be given

The usual dose

The actual dose that is right for you will depend on your body weight and on the region being examined by MRI:

In adults a single injection of 0.1 millilitre Gadovist per kg body weight is recommended (this means for a person weighing 70 kg the dose would be 7 millilitre), however a further injection of up to 0.2 millilitre per kg body weight within 30 minutes of the first injection may be given. A total amount of 0.3 millilitre Gadovist per kg body weight may be given at maximum (this means for a person weighing 70 kg the dose would be 21 millilitres) for imaging of the central nervous system (CNS) and CE-MRA. A dose of 0.075 millilitres Gadovist per kg body weight may be given at minimum (this means for a person weighing 70 kg the dose would be 5.25 millilitres) for the CNS.

6, Marketing Auhtorisation Holder

Bayer Limited, 1st Floor, The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, Ireland 

4.2    Posology and method of administration

Adults

CNS indications

A dose of 0.075 mmol gadobutrol per kg body weight (equivalent to 0.075 ml Gadovist per kg body weight) may be administered at minimum for imaging of the CNS (see section 5.1).

5.1   Pharmacodynamic properties

Clinical efficacy

In a study designed as an intra-individual, crossover comparison, gadobutrol at a reduced dose of 0.075 mmol/kg was compared to gadoterate meglumine at its standard dose of 0.1 mmol/kg for contrast enhanced MRI of the CNS in 141 patients with enhancing CNS lesions on gadoterate meglumine enhanced MRI. The primary variables included lesion contrast enhancement, lesion morphology, and lesion border delineation. Images were analysed by three independent blinded readers. Noninferiority to gadoterate meglumine for the degree of improvement over unenhanced imaging was demonstrated for all three primary variables (at least 80% of effect retained) based on the average reader. The mean number of lesions detected by gadobutrol (2.14) and gadoterate (2.06) were similar.

7.      MARKETING AUTHORISATION HOLDER

Bayer Limited, 1st Floor The Grange Offices, The Grange, Brewery Road, Stillorgan, Co. Dublin, A94 H2K7, Ireland

3.             How Gadovist will be given

In adults a single injection of 0.1 millilitre Gadovist per kg body weight is recommended (this means for a person weighing 70 kg the dose would be 7 millilitre), however a further injection of up to 0.2 millilitre per kg body weight within 30 minutes of the first injection may be given. A total amount of 0.3 millilitre Gadovist per kg body weight may be given at maximum (this means for a person weighing 70 kg the dose would be 21 millilitres) for imaging of the central nervous system (CNS) and CE-MRA. A dose of 0.075 millilitres Gadovist per kg body weight may be given at minimum (this means for a person weighing 70 kg the dose would be 5.25 millilitres) for the CNS.

The following information is intended for healthcare professionals only:

Posology

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 ml/kg BW within 30 minutes of the first injection may be performed.

A dose of 0.075 mmol gadobutrol per kg body weight (equivalent to 0.075 ml Gadovist per kg body weight) may be given at minimum for imaging of the CNS.

4.2    Posology and method of administration

Adults

CNS indications

A dose of 0.075 mmol gadobutrol per kg body weight (equivalent to 0.075 ml Gadovist per kg body weight) may be administered at minimum for imaging of the CNS (see section 5.1).

5.1    Pharmacodynamic properties

In a study designed as an intra-individual, crossover comparison, gadobutrol at a reduced dose of 0.075 mmol/kg was compared to gadoterate meglumine at its standard dose of 0.1 mmol/kg for contrast enhanced MRI of the CNS in 141 patients with enhancing CNS lesions on gadoterate meglumine enhanced MRI. The primary variables included lesion contrast enhancement, lesion morphology, and lesion border delineation. Images were analysed by three independent blinded readers. Noninferiority to gadoterate meglumine for the degree of improvement over unenhanced imaging was demonstrated for all three primary variables (at least 80% of effect retained) based on the average reader. The mean number of lesions detected by gadobutrol (2.14) and gadoterate (2.06) were similar.

Section 6.5 has been changed and now includes the following:

Plastic syringes:

One 10-ml prefilled syringe (cyclo-olefin polymer) with a plunger stopper (siliconized bromobutyl) and a tip seal (thermoplastic elastomer) contains 5 ml, 7.5 ml, 10 ml solution for injection.

One 20-ml prefilled syringe (cyclo-olefin polymer) with a plunger stopper (siliconized bromobutyl) and a tip seal (thermoplastic elastomer) contains 15 ml, 20 ml solution for injection.

'This medicinal product is for diagnostic use only. Gadovist is indicated in adults, adolescents and children aged 2 years and older for:.......'

'This medicinal product is for diagnostic use only. Gadovist is indicated in adults and children of all ages (including term neonates) for:.....'

Section 4.2 has been changed from:

'....

Paediatric population

For children aged 2 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 2 years due to a lack of data on efficacy and safety.....'

to:

'.....

Paediatric population

For children of all ages (including term neonates) the recommended dose is 0.1 mmol gadobutrol per kg body weight (equivalent to 0.1 ml Gadovist per kg body weight) for all indications (see section 4.1).

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

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist should only be used in these patients after careful consideration at a dose not exceeding 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.....'

Section 4.4 has been changed to include:

'....

Neonates and infants

Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Gadovist should only be used in these patients after careful consideration....'

The overall safety profile of Gadovist is based on data from more than 5,700 patients in clinical trials and from post-marketing surveillance...................................................

Paediatric population

Based on a single dose phase I/III study in 140 paediatric patients (see section 5.1) the frequency, type and severity of adverse reactions in children aged 2 years and older are expected to be comparable to the adverse event profile known in adults.........'

'The overall safety profile of Gadovist is based on data from more than 6,300 patients in clinical trials and from post-marketing surveillance......................

Paediatric population

Based on two single dose phase I/III studies in 138 paediatricsubjects aged 2-17 years and 44 subjects aged 0-<2 years (see section 5.1) the frequency, type and severity of adverse reactions in children of all ages (including term neonates) are consistent with the adverse drug reaction profile known in adults. This has been confirmed in a phase IV study including more than 1,100 paediatric patients and postmarketing surveillance.....'

Section 5.1 has been changed from:

'.............

Paediatric population

A single dose phase I/III study in 140 paediatric 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 2 is similar to that in adults. 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 98.7 % (median) of the administered dose, confirming fast renal excretion of gadobutrol also in the paediatric population.....'

to:

'...........

Paediatric population

Two single dose phase I/III studies in 138 subjects scheduled for CE-MRI of CNS, liver and kidneys or CE-MRA and in 44 subjects aged 0-<2 years (including term neonates) scheduled to undergo routine CE-MRI of any body region have been performed. Diagnostic efficacy and an increase in diagnostic confidence was demonstrated for all parameters evaluated in the studies and there was no difference among the paediatric age groups and when compared to adults. Gadovist was well tolerated in these studies with the same safety profile of gadobutrol as in adults.....'

Section 5.2 has been changed from:

'....

Characteristics in special patient populations

 Paediatric population

A single dose phase I/III study in 140 paediatric 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 2 is similar to that in adults. 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 98.7 % (median) of the administered dose, confirming fast renal excretion of gadobutrol also in the paediatric population....'

'...

Paediatric population

Pharmacokinetics of gadobutrol in paediatric population aged < 18 years and in adults are similar (see section 4.2).

 Two single dose phase I/III studies in paediatric patients <18 years  have been performed. The pharmacokinetics were evaluated in 130 paediatric patients aged 2 -< 18 years and in 43 paediatric patients <2 years of age (including term neonates).

It was shown that the pharmacokinetic (PK) profile of gadobutrol in children of all ages  is similar to that in adults resulting in similar values for area under the curve (AUC), body weight normalized plasma clearance (CL_tot) and volume of distribution (Vss), as well as elimination half-life and excretion rate

Approximately 99% (median value) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to <18 year old age group)....'

Section 5.3 has been changed to add:

'....

Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in children of all ages including term neonates and infants....'

Section 6.5 has been changed to add:

'....

Hospital pack:

5 prefilled syringes with 5, 7.5, 10, 15, 20 ml solution for injection...'

Setion 6.6 has been changed from:

'.........

The peel-off tracking label on the pre-filled 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.'

'.....

The peel-off tracking label on the pre-filled 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. If electronic patient records are used, the name of the product, the batch number and the dose should be entered into the patient record.'

4.2     Posology and method of administration

…

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 (see section 4.4).

…

4.8       Undesirable effects

…

Fluctuations of renal function parameters including increases of serum creatinine have been observed after administration of Gadovist.

…

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via details provided below HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

10.     DATE OF REVISION OF THE TEXT

September 2013November 2014

4.8     Undesirable effects

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via details provided below. the national reporting system listed in Appendix V.

Ireland

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

6.3     Shelf life

3 years (prefilled syringe)

Shelf life after first opening of the container:

Any solution for injection not used in one examination must be discarded. Chemical, and physical and microbiological in-use stability has been demonstrated for 24 hours at 20-25 °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.

10.     DATE OF REVISION OF THE TEXT

Julyne 2013

Red text = deleted text

Blue text = inserted text

Section 2 Qualitative and Quantitative Composition

……………………………

Excipient with known effect: 1 ml contains 0.00056 mmol (equivalent to 0.013 mg) of sodium (see section 4.4).

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

Section 4.2      Posology and method of administration

……………………………

The following sentence has been underlined: “Method of administration”

……………………………

•           DosagePosology

……………………………

The following changed from bold, underlined to italics “Adults”; “Special Populations”

……………………………

Impaired renal function Renal impairment

……………………………

Section 4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Section 4.4 Special warnings and precautions for use

……………………………

The following has been underlined “Hypersensitivity reactions”

……………………………

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.

As with other intravenous contrast agents, Gadovist can be associated with anaphylactoid/hypersensitivity or other idiosyncratic reactions, characterized by cardiovascular, respiratory or cutaneous manifestations, and ranging to severe reactions including shock. In general, patients with cardiovascular disease are more susceptible to serious or even fatal outcomes of severe hypersensitivity reactions.

The risk of hypersensitivity reactions may be higher in case of:

- previous reaction to contrast media

- history of bronchial asthma

- history of allergic disorders

In patients with an allergic disposition the decision to use Gadovist must be made after particularly careful evaluation of the risk-benefit ratio.

Most of these reactions occur within half an hour of administration. Therefore, 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 (see section 4.2).

Delayed reactions (after hours up to several days) have been rarely observed (see section 4.8).

……………………………

The following text has been underlined “Impaired renal function”; “Seizure disorders”; ”Excipients”

……………………………

Section 4.6 Fertility, pPregnancy and lactation

……………………………

LactationBreast-feeding

……………………………

Fertility

Animal studies do not indicate impairment of fertility.

Section 4.8 Undesirable effects

The overall safety profile of Gadovist is based on data from more than 4,5005,700 patients in clinical trials, and from post-marketing surveillance.

The most frequently observed adverse drug reactions (-0.5  %) in patients receiving Gadovist are headache, nausea, injection site reactions, dysgeusia and dizzinessfeeling hot.

The most serious adverse drug reactions in patients receiving Gadovist are cardiac arrest, respiratory arrest and severe anaphylactoid reactions shock(including respiratory arrest and anaphylactic shock).

……………………………

……………………………

§ Hypersensitivity / anaphylactoid reactions identified only during post-marketing surveillance (frequency not known)

* There have been reports of life-threatening and/or fatal cases have been reported outcomes from this ADR

# None of the individual symptoms ADRs listed under hypersensitivity/anaphylactoid reactions identified in clinical trials reached a frequency greater than rare (except for urticarial)

§ Hypersensitivity / anaphylactoid reactions identified only during post-marketing surveillance (frequency not known)

……………………………

Paediatric population

Based on a single dose phase  I/III study in 140  paediatric patients (see section  5.1) the frequency, type and severity of adverse reactions in children aged 2  years and older are expected to be comparable to the adverse event profile known in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Section 5.1 Pharmacodynamic properties

Underline the following terms “Mechanism of action”; “Pharmacodynamic effects”; “Clinical efficacy”

……………………………

Mechanism of action

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).

Pharmacodynamic effects

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) measured in plasma - is about 5.6 l mmol^-1 sec^-1 and the spin-spin relaxation time (T2) is about 6.5 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.

Clinical efficacy

In a pivotal phase III liver study average sensitivity in combined pre and postcontrast MRI for Gadovist-treated patients was 79 % and specificity was 81 % for lesion detection and classification of suspected malignant liver lesions (patientbased analysis).

……………………………

In a study designed as an intra-individual, crossover comparison, Gadovist was compared to gadoterate meglumine (both at 0.1 mmol/kg) in the visualization of cerebral neoplastic enhancing lesions in 132 patients.

The primary efficacy endpoint was the overall preference for either Gadovist or gadoterate meglumine by the median blinded reader. Superiority of Gadovist was demonstrated by a p-value of 0.0004. In detail, a preference of Gadovist was given for 42 patients (32 %) compared to an overall preference for gadoterate meglumine for 16 patients (12 %). For 74 patients (56 %) no preference for one or the other contrast agent was given.

For the secondary variables lesion-to-brain ratio was found to be statistically significantly higher for Gadovist (p < 0.0003). Percent of enhancement was higher with Gadovist compared to gadoterate meglumine, with a statistical significant difference for the blinded reader (p < 0.0003).

Contrast-to-noise ratio, showed a higher mean value following Gadovist (129) compared to gadoterate meglumine (98). The difference was not statistically significant.

Paediatric population

A single dose phase I/III study in 140  paediatric 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.

Section 5.2 Pharmacokinetic properties

Distribution

After intravenous administration, gadobutrol is rapidly distributed in the extra cellular space. Plasma protein binding is negligible. The pharmacokinetics of gadobutrol in humans are dose proportional. After doses up to 0.4 mmol gadobutrol/kg body weight, the plasma level declines in a biphasic manner. 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.

Biotransformation

No metabolites are detected in plasma or urine.

Elimination

The pharmacokinetics of gadobutrol in humans are dose proportional. After doses 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 – 2.1 hours), corresponding 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 % of the given dose is eliminated via the urine with a mean terminal half-life of 1.8°hours (1.3 – 2.1°hours), corresponding to the renal elimination rate. 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.

Characteristics in special patient populations

Paediatric population

……………………………

Elderly population (aged 65  years and above)

……………………………

Section 5.3 Preclinical safety data

……………………………

Radioactivelyity labelled gadobutrol administered intravenously to lactating rats was transferred to the neonates via milk at less than 0.1 % of the administered dose.

……………………………

Section 6.1 List of excipients

Calcobutrol sodium

Trometamol

Hydrochloric acid 1N (pH-adjustment)

Water for injections

Section 6.3 Shelf life

Shelf life of the medicinal product as packaged for sale:

3  years (prefilled syringe)

Section 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening of the medicinal product, see section  6.3.

Section 6.6 Special precautions for disposal and other handling

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

……………………………

Section 10 Date of revision of the text

September 2012           June 2013

Gadovist can also be used for MR Imaging of pathologies of the whole body.

It facilitates visualisation of abnormal structures or lesions and helps in the differentiation between healthy and pathological tissue.

4.2 Posology and method of administration
Adults
CNS Indications

Whole Body MRI (except MRA)

In general, the administration of 0.1 ml Gadovist per kg body weight is sufficient to answer the clinical question.

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 1.0 M solution.

10 Date of revision of text
September 2012

In section 4.1 therapeutic indication added as follows:
Gadovist can also be used for MR Imaging of pathologies of the whole body. It facilitates visualisation of abnormal structures or lesions and helps in the differentiation between healthy and pathological tissue.

In section 4.2 method of administration was updated in accordance with the change in section 4.1 as follows:
Whole Body MRI (except MRA)
In general, the administration of 0.1 ml Gadovist per kg body weight is sufficient to answer the clinical question.
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 1.0 M solution.

In section 10 Date of revision of text was changed from June 2012 to August 2012

Sections Updated:  The following additional text was added.

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution for injection contains 604.72 mg gadobutrol (equivalent to 1.0 mmol gadobutrol containing 157.25 mg gadolinium).

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 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

Physico-chemical properties:

Osmolality at 37°C: 1603 mOsm/kg H₂O

Viscosity at 37°C: 4.96 mPa·s

4.2     Posology and method of administration

Gadovist should only be administered by healthcare professionals experienced in the field of clinical MRI practice.

This product is intended for single use only

Adults

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).

Elderly (aged 65 years and above)

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

4.4         Special warnings and precautions for use

The possibility that Gadovist may cause torsade de pointes arrhythmias in an individual patient cannot be excluded (see section 5.3).

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 < 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.

As there is a possibility that NSF may occur with Gadovist, it should therefore only be used in 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’.

4.6     Pregnancy and lactation

PregnancyThere 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.

LactationGadolinium 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.

4.8       Undesirable effects

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

In case of 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).

5.1     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).

5.3     Preclinical safety data

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.

6.1     List of excipients

Hydrochloric acid 1N

6.3  Shelf life

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.

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.

6.6     Special precautions for disposal and other handling

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of last renewal: 24 January 2010

10.     DATE OF REVISION OF THE TEXT

January 2011

4.1     Therapeutic indications

Additional Text:

·    . Gadovist is indicated in adults, adolescents, and children aged 7 years and older for:

4.2         Posology and method of administration

Additional Text:

Paediatric patients

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 Therapeutic indications).

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.

5.1         Pharmacodynamic properties

Additional Text:

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

Additional Text:

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.

10.         DATE OF REVISION OF THE TEXT

Update:

November 2009

Incorporation of changes following an incoming mutual recognition variation.

Section 4.1 Therapeutic indications

1. The text "This medicinal product is for diagnostic use only." was removed.
2. The text "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." was changed to "Contrast enhanced MRI of liver and kidneys.".

Section 4.2 Posology and method of administration

1. The text "Gadovist should only be administered by physicians experienced in the field of clinical MRI practice." was removed.
2. In the section entitled "Dosage". The text "Adults" was removed.
3. The text "Paediatric patients; Gadovist is not recommended for use in population below age 18 due to a lack of data on efficacy and safety." was removed and replaced with "Specific data on the use of gadobutrol in patients younger than 18 years are not available. In these patients the product should only be used after the physicians careful consideration of the benefit against the potential risk.".

Section 4.3 Contraindications

1. The text "Hypersensitivity to the active substance or to any of the excipients." was changed to "Hypersensitivity to any of the ingredients.".

Section 4.4 Special warnings and precautions for use

1. In the section entitled "Gadovist should be used with special care in patients" the text "taking a medicinal product" was changed to "taking a drug".
2. At the End of the sixth paragraph the text "Haemodialysis shortly after Gadovist administration in patients currently receiving haemodialysis may be useful at removing Gadovist from the body, but its potential to prevent NSF is unknown and should not be used as a preventative measure in other patient groups." was removed.

Section 4.5 Interaction with other medicinal products and other forms of interaction

1. The text "No interaction studies have been performed." was changed to "As for all other gadolinium containing contrast media no interactions with other medicaments has been observed. Formal drug interaction studies have not been carried out."

Section 4.7 Effects on ability to drive and use machines

1. The text "Not relevant." was changed to "Not applicable."

Section 4.8 Undesirable effects

1. The text "Adverse reactions are "rare ( 1/10,000 to <1/1,000)" to "uncommon ( 1/1,000 to <1/100)". Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness." was changed to "Adverse reactions are "rare (<1/1,000)" to "uncommon (³1/1,000, <1/100)"."

2. The second row of the table was changed from this:

To this:

Section 5.1 Pharmacodynamic properties

1. The phrase "Paramagnetic contrast media" was changed to "Gadovist is a paramagnetic contrast agent for magnetic resonance imaging."

Section 6.5 Nature and contents of container

1. The entire section was changed to:

"5 ml in prefilled syringe of 10 ml; carton of 1 or 5

7.5 ml in prefilled syringe of 10 ml; carton of 1 or 5

10 ml in prefilled syringe of 10 ml; carton of 1 or 5

15 ml in prefilled syringe of 17 ml; carton of 1 or 5

20 ml in prefilled syringe of 20 ml; carton 1 or 5

Barrel:                          glass type I, colourless siliconized with silicone oil emulsion

Plunger stopper:            chlorobutyl elastomer, siliconized with silicone oil

Tip cap:                        chlorobutyl elastomer

Not all pack sizes may be marketed."

Section 6.6 Special precautions for disposal and other handling

1. The text "This medicinal product should be visually inspected before use." was changed to "This medicinal product is clear, colourless to pale yellow solution. It should be visually inspected before use.".

Section 7. Marketing Authorisation Holder

1. The marketing authorization holder address was changed from "HE Clissmann, 72 Heather Road, Dublin 18" to "Bayer Limited, The Atrium, Blackthorn Road, Dublin 18".

Section 8. Marketing Authorisation Number(s)

1. The PA number was changed from "PA 12/90/2" to "PA 1410/18/2".

Section 10. Date of Revision of the Text

1. The date was changed from "May 2007" to "August 2007".

Update of all sections of the text including main changes:

1. Section 4.4  Special warnings and precautions for use

The following NSF warning has been inserted:

“There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-containing contrast agents in patients with severe renal impairment (GFR <30ml/min/1.73m²). As there is a possibility that NSF may occur with Gadovist, it should only be used in these patients after careful consideration.”

2. Section 10 Date of Revision of the Text

The date has been changed from “July 2006” to “May 2007”

Section 4.1:    Introduction of a new indication - 'Contrast enhanced MRI of liver and kidneys'.

 

Section 4.2:    New dosing instructions regarding the new indication introduced in section 4.1.

 

Section 5.1:    Clinical study results to support the introduction of the new indication.