Gadovist

  • Name:

    Gadovist

  • Company:
    info
  • Active Ingredients:

    Gadobutrol

  • Legal Category:

    Product subject to restricted prescription (C)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 09/01/18

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Summary of Product Characteristics last updated on medicines.ie: 7/9/2020

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Bayer Limited

Bayer Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 7 September 2020 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Updated on 10 January 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to restricted prescription (C)

Updated on 10 January 2018 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

In section 4.1 - Addition of "Gadovist should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI)."

In Section 4.2 - Addition of "The lowest dose that provides sufficient enhancement for diagnostic purposes should be used. The dose should be calculated based on the patient's body weight, and should not exceed the recommended dose per kilogram of body weight detailed in this section."

Date of revision has been updated to November 2017.

Updated on 9 January 2018 PIL

Reasons for updating

  • Change to information for healthcare professionals

Updated on 9 January 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 24 May 2017 PIL

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 13 May 2016 SmPC

Reasons for updating

  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

In section 5.1 Pharmacodynamic properties:
Pharmacodynamic effects:

-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. -was removed.

In section 10. DATE OF REVISION OF THE TEXT:
October 2015 May 2016 -was removed and added respectively.

Updated on 4 March 2016 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 9 December 2015 PIL

Reasons for updating

  • Change to packaging
  • Change to dosage and administration

Updated on 2 November 2015 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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.

 

Updated on 11 August 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.6 - Special precautions for disposal and other handling

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

Section 4.1 has been changed from:

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

to:

'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....'

Section 4.8 has been changed from:

'

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.........'

to:

'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....'

to:

'...

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 (CLtot) 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.'

to:

'.....

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.'

 


Updated on 6 August 2015 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to date of revision
  • Change to dosage and administration
  • Changes to therapeutic indications

Updated on 11 November 2014 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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

Updated on 10 November 2014 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 8 November 2013 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

In the adverse event table in sectuion 4.8, the spelling of paresthesia has been updated to paraesthesia
Also in section 4.8, the spelling of hematoma has been updated to haematoma

The date of revision of the text has been updated from July to September 2013

Updated on 6 November 2013 PIL

Reasons for updating

  • Change to date of revision

Updated on 12 August 2013 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 6.3 - Shelf life
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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

 

Updated on 7 August 2013 PIL

Reasons for updating

  • Change to storage instructions
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 12 July 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

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).

……………………………

 

Frequency

System Organ Class

Common

Uncommon

Rare

Not known

Immune system disorders

 

Hypersensitivity /anaphylactoid reaction*# (e.g. anaphylactoid shock§*, circulatory collapse§*, respiratory arrest§*, pulmonary oedema§*, bronchospasm§, cyanosis§, oropharyngeal swelling§*,

laryngeal oedema§, hypotension*, blood pressure increased§, chest pain§, urticaria,

face oedema, angioedema§, conjunctivitis§, eyelid oedema, flushing, hyperhidrosis§, cough§, sneezing§, burning sensation§, pallor§)

Hypersensitivity

/anaphylactoid

reaction (e.g.

anaphylactoid shock§*,

circulatory collapse§*,

respiratory arrest§*,

bronchospasm§,

cyanosis§,

oropharyngeal

swelling§*,

laryngeal oedema§, hypotension*, blood

pressure increased§,

chest pain§, urticaria,

face oedema§,

angioedema§,

conjunctivitis§, eyelid

oedema§, flushing,

hyperhidrosis§, cough§,

sneezing§, burning

sensation§, pallor)

 

……………………………

Nervous system disorders

Headache

 

Dizziness,

Dysgeusia

Paresthesia

Loss of consciousness*,

Convulsion,

Parosmia

 

 

 

§ 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

 

Updated on 2 July 2013 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to storage instructions
  • Change to side-effects
  • Change to how the medicine works
  • Change to further information section
  • Change to dosage and administration
  • Change to improve clarity and readability

Updated on 31 October 2012 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to restricted prescription (C)

Free text change information supplied by the pharmaceutical company

4.1 Therapeutic indications

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

 

 

 

Updated on 27 September 2012 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 10 - Date of revision of the text

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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

Updated on 27 September 2012 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to date of revision

Updated on 5 September 2012 PIL

Reasons for updating

  • Change to further information section
  • Change to date of revision

Updated on 30 August 2012 PIL

Reasons for updating

  • Change to date of revision
  • Changes to therapeutic indications

Updated on 20 July 2012 SmPC

Reasons for updating

  • Change to paediatric information
  • Change to section 10 - Date of revision of the text

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Change to paediatric information
- section 4.1 - change from indicated for use in children 7 years and older, to indicated for use in children 2 years and older. 
- section 4.2, also updated in the paediatric population subsection, with regards to the above change in indication.
- section 5.2, updated in subsection Characteristics in special patient populations - Paediatric populations - to reflect further information with regards to the indication change above.

Updated on 25 June 2012 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to drug interactions
  • Change to how the medicine works
  • Change to date of revision
  • Change to dosage and administration

Updated on 7 December 2011 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

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SPC update following approval of CCDS#16 ( NL/H/xxxx/WS/011)

Updated on 5 December 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to side-effects
  • Change to further information section
  • Change to date of revision
  • Change to name of manufacturer

Updated on 27 January 2011 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 3 - Pharmaceutical form
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.1 - List of excipients
  • Change to section 6.3 - Shelf life
  • Change to section 6.4 - Special precautions for storage
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 9 - Date of renewal of authorisation
  • Change to section 10 - Date of revision of the text

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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

 

 

 

Adverse reactions from clinical trial data (experience in more than 2900 patients)

Additional adverse reactions from postmarketing spontaneous reporting

System Organ Class

Uncommon

Rare

Rare

Immune system disorders

 

Anaphylactoid reaction

Anaphylactoid shock

 

 

 

 

Nervous system disorders

Headache,

Dizziness,

Dysgeusia, Paresthesia,

Parosmia

 

Loss of consciousness, Convulsion

Eye disorders

 

 

 

Conjunctivitis, Eyelid oedema

Cardiac disorders

 

 

Cardiac arrest, Tachycardia

Vascular disorders

Vasodilatation

Hypotension

Circulatory collapse, Flushing

 

 

 

Respiratory, thoracic and mediastinal disorders

 

Dyspnoea

Respiratory arrest, Bronchospasm, Cyanosis, Oropharyngeal swelling, Cough, Sneezing

Gastrointestinal disorders

Nausea

Vomiting

 

Skin and subcutaneous tissue disorders

 

Urticaria,

Rash

Face edema, Hyperhidrosis, Pruritus, Erythema

 

 

 

 

General disorders and administration site conditions

Injection site pain,

Injection site reaction

 

Nephrogenic Systemic Fibrosis (NSF), Feeling hot, Malaise,

 

 

 

 

 

 

 

 

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

 

 

The peel-off tracking label on the 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.

 

 

 

 

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

Updated on 26 January 2011 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change to instructions about overdose
  • Change to storage instructions
  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to further information section
  • Change to dosage and administration
  • Change to date of revision

Updated on 25 January 2010 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text

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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

Updated on 13 January 2010 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change to further information section
  • Change to date of revision
  • Change to dosage and administration

Updated on 29 April 2009 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

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Incorporation of changes following an incoming mutual recognition variation.

Updated on 29 April 2009 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to side-effects
  • Change to further information section

Updated on 23 October 2007 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text
  • Change to improve clarity and readability

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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.".