Consumer medicine information

Gadovist 1.0

Gadobutrol

BRAND INFORMATION

Brand name

Gadovist Solution for injection

Active ingredient

Gadobutrol

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Gadovist 1.0.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Gadovist 1.0. It does not contain all the available information. It does not take the place of talking to your doctor or health care professional.

All diagnostic agents have risks and benefits. Your doctor has weighed the risks of you using Gadovist 1.0 against the benefits it is expected to have for you.

If you have any concerns about using this diagnostic agent, ask your doctor or radiologist.

Keep this leaflet.

You may need to read it again.

WHAT GADOVIST 1.0 IS USED FOR

Gadovist 1.0 is used at the same time as magnetic resonance imaging (MRI) to aid in the detection of known or suspected abnormalities in the body: brain, spinal cord, blood vessels, head and neck region, chest, breast, abdomen, pelvis, kidneys, bones, muscles and heart.

Gadovist 1.0 is for use in adults, adolescents and children including full-term newborns.

MRI is a form of medical diagnostic imaging that forms pictures after detecting water molecules in normal and abnormal tissues. This is done using a complex system of magnets and radiowaves.

Gadovist 1.0 is itself a magnetic liquid that alters the way in which the MRI machine detects certain tissues within the body, often making the pictures clearer and often showing things that may not have been visible using MRI alone.

Gadovist 1.0 is only available at MRI units for use in conjunction with MRI.

Ask your doctor if you have any questions about why Gadovist 1.0 is being used in you.

Your doctor may be using it for another reason.

BEFORE YOU ARE GIVEN GADOVIST 1.0

When you must not be given it

Your radiologist will assess if it is appropriate for you to be administered Gadovist 1.0.

You must not be given Gadovist 1.0 if you have an allergy to:

  • gadobutrol, the active ingredient in Gadovist 1.0, or
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, throat, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given Gadovist 1.0 after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

The doctor will check this for you.

Before you are given it

Tell your doctor if you have allergies to any medicines, foods, preservatives or dyes.

Tell your doctor if you are allergic to diagnostic agents. Allergy like reactions may occur after use of Gadovist 1.0.

In some cases you may need special care with Gadovist 1.0 and your doctor will need to consider whether to give you Gadovist 1.0.

Recent information shows that gadolinium (as in Gadovist 1.0) may build up in the brain after multiple uses and the effect on the brain is unknown right now.

Your doctor will:

  • carefully consider whether to use repeated doses
  • use the lowest dose

Tell your doctor if you have, or have had, any medical conditions especially the following:

  • very poor kidney function or severe kidney problems
  • a liver transplant
  • any allergies e.g. seafood allergies, hay fever, hives)
  • bronchial asthma
  • severe heart and circulatory disorders
  • a low threshold for seizures.

Tell your doctor if you are pregnant, or think you may be pregnant.

Your doctor can discuss with you the risks and benefits involved.

There is no need to stop breastfeeding if you need an examination involving Gadovist 1.0.

Tell your doctor if you have a heart pacemaker or any material containing iron implanted in your body.

If you have not told your doctor about any of the above, tell him/her before you are given Gadovist 1.0.

Taking other medicines

Tell your doctor if you are taking any medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

In particular, tell your doctor if you are taking:

  • beta-blockers (medicines used to treat high blood pressure or other heart conditions).

If you experience an allergy-like reaction to Gadovist 1.0, any treatment given to you may be affected by these medicines.

Your doctor/radiologist has more information on medicines to be careful with or avoid while receiving Gadovist 1.0.

HOW GADOVIST 1.0 IS GIVEN

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

It is recommended that you do not eat for 2 hours before the use of Gadovist 1.0.

If you do not understand the instructions you have been given, ask your doctor.

How much is given

The actual dosage of Gadovist 1.0 that is right for you will be worked out by the radiologist and will depend on the region of your body to be examined and your weight.

How it is given

Gadovist 1.0 is injected via a small needle into a vein, usually in the back of your hand or in front of your elbow.

When it is given

Gadovist 1.0 will be administered immediately before your MRI examination.

If you are given too much (overdose)

As Gadovist 1.0 is administered by a doctor, overdose is unlikely. If it does happen, the doctor will treat any symptoms that follow.

If you currently have a problem with your kidneys or liver, the doctor may decide to remove Gadovist 1.0 from the body by means of a blood-cleansing procedure (dialysis).

Immediately tell your doctor or other medical staff or telephone the Poisons Information Centre (Australia: 13 11 26 or New Zealand: 0800 POISON or 0800 764 766) for advice if you think that you or anyone else may have been given too much Gadovist 1.0.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

AFTER HAVING GADOVIST 1.0

Things you must do

Follow carefully the directions given to you by your doctor and other medical staff.

Things to be careful of

Tell your doctor if you are going to have any laboratory tests.

SIDE EFFECTS

Tell your doctor as soon as possible if you do not feel well whilst receiving or after being given Gadovist 1.0.

All contrast media can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

A high level of excitement, anxiety and pain may increase the risk of side effects or make contrast agent related reactions more intense.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor to answer any questions you may have.

Tell your doctor if you notice any of the following after injection of Gadovist 1.0 and they worry you:

  • headache
  • dizziness
  • nausea.

The above list includes the more common side effects of Gadovist 1.0. They are usually mild and short-lived. If they persist or get worse, tell your doctor.

Tell your doctor immediately if you notice any of the following:

  • swelling of the face, eyelids, lips, tongue or other parts of the body
  • coughing or throat irritation
  • itching or hives
  • wheezing, shortness of breath, difficulty breathing, gasping
  • gagging, feeling of suffocation
  • abnormal heart beat (maybe faster)
  • uncontrolled shaking (convulsions)
  • unpleasant smells
  • loss of consciousness
  • low blood pressure
  • pale skin
  • flushing (redness)
  • weakness, discomfort
  • feeling cold
  • large areas of hardened skin
  • joint pain.

These may be serious side effects. You may need urgent medical attention. Serious side effects are rare.

Some of these side effects could be the first signs of an allergic reaction. You may need urgent medical attention or hospitalisation.

Allergic reactions occur more frequently in patients with an allergic disposition.

Severe reactions requiring emergency treatment can occur, causing low blood pressure, loss of consciousness or heart attack, increase in heart rate, difficulty breathing, and swelling of the face, lips or tongue leading to severe breathing difficulties and shock may occur.

Tell the doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people. Rarely, delayed reactions can occur.

PRODUCT DESCRIPTION

Storage

The MRI unit will store Gadovist 1.0 under the conditions advised by the manufacturer. Shelf life and storage conditions are printed on the pack.

What it looks like

Gadovist 1.0 is a clear, colourless to slightly yellow 1.0 mmol/mL solution for injection and is supplied in glass vials and glass or plastic pre-filled syringes of various sizes.

Ingredients

Active ingredients:

  • gadobutrol (604.72 mg/mL)

Inactive ingredients:

  • calcobutrol sodium
  • trometamol
  • hydrochloric acid
  • water for injections

Supplier

Made in Germany for:

Bayer Australia Limited
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073

Bayer New Zealand Limited
3 Argus Place, Hillcrest,
North Shore
Auckland 0627

Australian registration number

Gadovist 1.0 AUST R numbers:

Glass vial and pre-filled syringes:
7.5 mL vial – AUST R 67048
15 mL vial – AUST R 67047
30 mL vial – AUST R 72494
5 mL syringe – AUST R 72493
7.5 mL syringe – AUST R 67046
10 mL syringe – AUST R 72518
15 mL syringe – AUST R 67045
20 mL syringe – AUST R 72517

Plastic pre-filled syringes:
5 mL syringe – AUST R 72493
7.5 mL syringe – AUST R 67046
10 mL syringe – AUST R 72518
15 mL syringe – AUST R 67045
20 mL syringe – AUST R 72517

Not all presentations may be marketed in Australia or New Zealand.

Date of preparation

October 2017

You can find the latest Consumer Medicine Information on the TGA website (www.ebs.tga.gov.au) for Australia or on the MEDSAFE website (www.medsafe.govt.nz) for New Zealand.

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd

All rights reserved.

BRAND INFORMATION

Brand name

Gadovist Solution for injection

Active ingredient

Gadobutrol

Schedule

Unscheduled

 

1 Name of Medicine

Gadobutrol.

6.7 Physicochemical Properties

Gadovist 1.0 (gadobutrol) solution for injection is the complex consisting of gadolinium (III) and the macrocyclic dihydroxy-hydroxymethylpropyl-tetraazacyclododecane-triacetic acid (butrol), and is an injectable neutral contrast medium for magnetic resonance imaging (MRI). Gadobutrol is to be administered by intravenous injection.

Chemical structure.

Gadovist 1.0 injection is a 1.0 mmol/mL solution of 10-(2,3-dihydroxy-1- hydroxymethylpropyl)- 1,4,7,10- tetraazacyclododecane- 1,4,7-triacetic acid, Gd-complex, with a molecular weight of 604.7 and has the following structural formula.

Physicochemical properties.

See Table 11.
Gadovist 1.0 solution has a pH of 6.6 to 8.0.

2 Qualitative and Quantitative Composition

Gadovist 1.0 is available as a 1.0 mmol/mL solution for injection and each mL of Gadovist 1.0 contains 604.72 mg (1.0 mmol) gadobutrol.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Gadovist 1.0 solution for injection is a clear, colourless to pale yellow solution and contains no antimicrobial preservative.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Gadovist 1.0 is a paramagnetic contrast agent for magnetic resonance imaging. The contrast enhancing effect is mediated by gadobutrol, a neutral (nonionic) complex consisting of gadolinium (III) and the macrocyclic ligand dihydroxy-hydroxymethylpropyl- tetraazacyclododecane- triacetic acid (butrol).
When T1-weighted scanning sequences are used in proton magnetic resonance imaging, the gadolinium ion induced shortening of the spin lattice relaxation time of excited atomic nuclei leads to an increase of the signal intensity and, hence, to an increase of the image contrast of certain tissues. In T2*-weighted gradient echo sequence, however, the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.

Pharmacodynamic effects.

In clinical doses, gadobutrol leads to distinct shortening of the relaxation times of protons in tissue water. At pH 7, a magnetic field strength of 0.47 T and 40°C, the relaxivity (r1), determined from the influence on the spin lattice relaxation time (T1) of protons, is about 3.6 L/mmol-1sec-1 in water and 5.6 L/mmol-1sec-1 in plasma and the relaxivity (r2), determined from the influence on the spin-spin relaxation time (T2), is about 4 L/mmol-1sec-1 in water and 6.5 L/mmol-1sec-1 in plasma. The relaxivity displays only slight dependency on the strength of the magnetic field.
The macrocyclic ligand forms a stable complex with the paramagnetic gadolinium ion with extremely high in vivo and in vitro stability (thermodynamic stability constant: log K = 21-22). Gadobutrol is a highly water soluble, extremely hydrophilic compound with a distribution coefficient between n-butanol and buffer at pH 7.6 of about 0.006. The substance does not display any inhibitory interaction with enzymes.

Clinical trials.

Contrast enhanced magnetic resonance imaging, (CE-MRI) of the whole body, including head and neck region, thoracic space, breast, abdomen, pelvis, retroperitoneal space, extremities and musculoskeletal system and cardiac MRI.

The use of Gadovist 1.0 in CE-MRI of the whole body is supported by company sponsored studies and a systematic review of the literature.

CE-MRI of the liver and kidneys.

Results from three clinical studies involving 1234 patients (2 pivotal and one open label study), demonstrated noninferiority of Gadovist 1.0 compared to Magnevist (dimeglumine gadopentetate), for diagnosing malignant lesions in liver and kidneys in CE-MRI at a dose of 0.1 mmol/kg BW. The primary efficacy variables were accuracy and increase in diagnostic accuracy from pre- to combined pre- and postcontrast MRI scans. Efficacy was measured from clinical studies and blinded readings. Other assessments from the 2 pivotal studies to support the comparable efficacy of Gadovist 1.0 to Magnevist in CE-MRI were lesion extent, lesion subclassification, technical efficacy and therapeutic impact. The standard of reference for each study was assessment by an independent truth panel or against a predefined and independent standard of truth, (SOT).
Results from the two pivotal studies are summarised in Table 3.

CE-MRI of the breast.

Patients with recently diagnosed breast cancer were enrolled in two clinical trials designed to evaluate the efficacy of Gadovist for the assessment of malignant breast disease prior to surgery. Patients underwent precontrast breast MRI prior to administration of Gadovist 1.0 at a dose of 0.1 mmol/kg, followed by postcontrast breast MRI. For both studies, precontrast (UMRM) and pre-plus-post contrast breast images (CMRM) were independently evaluated by three readers for the presence or absence of malignancy. The standard of truth (SoT) consisted of histopathologically confirmed malignant disease or alternatively X-ray mammography (XRM) plus ultrasound for nonmalignant disease.
For each study, the coprimary endpoints were the demonstration of superior sensitivity for the detection of malignancy on a subject level of CMRM image sets compared to UMRM image sets and demonstration of the correct exclusion of malignancy (specificity) based on disease free breasts of greater than 80% by CMRM for the same 2 of 3 independent readers.
The two identical clinical trials, GEMMA-1 and GEMMA-2, evaluated a total of 787 subjects. Efficacy results presented for GEMMA-1 are based upon post-hoc analyses of the original clinical data. In GEMMA-1, 390 subjects were assessed, all were female and the average age was 55.7 years. For GEMMA-2, 397 subjects were assessed, 396 were female, 1 was male and the average age was 57.1 years.
In both trials, Gadovist 1.0 enhanced breast MRI demonstrated superior detection of malignancy compared to unenhanced MRI. The addition of XRM to the CMRM did not substantially improve the detection of malignancy by CMRM (see Table 4).
As all subjects had a confirmed malignancy, specificity was calculated on a breast level. Most subjects had a malignancy in one breast and no disease in the other (contralateral) breast. The specificity of Gadovist 1.0 enhanced breast MRI, based on breasts with no malignancy, was greater than the performance threshold of 80% for all blinded readers in GEMMA-1 and for 2 of 3 blinded readers in GEMMA-2 (see Table 5).
For both studies, the coprimary endpoints were met simultaneously for 2 of the 3 readers for sensitivity and specificity.

CE-MRI of the body.

A multicentre, randomised, single blind, parallel group comparison, phase 3 study (13297), investigated the efficacy and safety of Gadovist 1.0 compared to Magnevist following a single injection in Asian patients referred for contrast enhanced MRI of the body (including breast, heart, abdomen, kidney, pelvis, or extremities). One hundred and seventy eight (178) patients received Gadovist and 185 patients received Magnevist.
The primary objective was to demonstrate noninferiority of unenhanced plus Gadovist 1.0 enhanced MRI compared to unenhanced plus Magnevist enhanced MRI at a dose of 0.1 mmol/kg body weight based on the evaluation of three primary efficacy variables: contrast enhancement, border delineation and internal morphology of lesions, which in combination were linked to the detection and visualisation of lesions in the body regions.
The total scores (mean ± SD) of these three visualisation parameters for combined (unenhanced plus enhanced) images were 9.39 ± 1.06 for Gadovist 1.0, and 9.34 ± 1.23 for Magnevist in the per protocol set (PPS) population (see Table 6). Statistical analysis demonstrated that Gadovist 1.0 was noninferior to Magnevist in lesion visualisation.
Results of a subgroup analysis by body region are presented in Table 7. The lower limits of the 95% CIs of the difference (Gadovist 1.0 minus Magnevist) in the total score were -0.783 or above for all body regions.

Contrast enhanced magnetic resonance angiography (CE-MRA).

Two pivotal studies including 362 patients have been performed in which the diagnostic efficacy of gadobutrol enhanced MRA with that of i.a. DSA (intra-arterial digital subtraction angiography) was compared clinically and by blinded reader re-evaluation. In one study, the aorta and supra-aortal, thoracic, and abdominal branch vessels (1 FOV), and in the other study pelvic and peripheral arteries (3 FOVs) were evaluated. Table 8 summarises the dose information and the agreement rates between gadobutrol 1.0 mmol/mL enhanced MRA and i.a. DSA regarding differentiation between nonrelevantly and relevantly diseased vessel segments.
Lower agreement rates have been observed predominantly in vessel segments with small diameter such as vertebral arteries and arteries of the calf due to limited spatial resolution. The coronary arteries have not been included in any study and contrast enhanced MRA with gadobutrol 1.0 mmol/mL can thus not be recommended for this indication.

Use in children less than 18 years.

The paediatric development program followed European guidelines for the development of medicinal products in the paediatric population2. Under these guidelines if paediatric pharmacokinetic (PK) data is shown to be similar to adult PK data then adult clinical efficacy and safety may be extrapolated to the paediatric population.
Two single pharmacokinetic (PK) phase I/III studies in paediatric populations have been performed to investigate PK, safety and efficacy at the standard intravenous dose of 0.1 mmol/kg body weight. The first study (310788) was conducted in 138 children between 2 to 17 years of age. The second study (91741) was conducted in 44 children from birth to less than 2 years of age (including full-term newborns). Efficacy and safety were assessed as secondary endpoints.
Results of the studies demonstrated that body weight was the main covariate that affects clearance (CL) and volume of distribution (V).
The 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 normalised plasma clearance (CL) and volume of distribution (V), as well as elimination half-life and excretion rate.
Approximately 99% (median) of the dose was recovered in urine within 6 hours (this information was derived from the 2 to < 18 year old age group).
In study 91741, the basic technical adequacy of the images was ‘excellent’ in the vast majority of subjects (i.e. clearly visualised regions) in both unenhanced MRI (40/44 subjects, 90.91%) and combined MRI (41/44 subjects, 93.18%). For the majority of subjects (24/44, 54.55%), the combined image set allowed an additional diagnostic gain i.e. the initial diagnosis was changed to an improved diagnosis. In one subject, the diagnosis changed to a new diagnosis. In 19/44 subjects (43.18%), the diagnosis remained unchanged.
Out of a 3 point scale, the confidence in diagnosis assessed as confident and very confident was higher in the combined MRI (43/44 subjects, 97.73%) compared to unenhanced MRI (38/44 subjects, 86.37%).
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.
Safety findings in the paediatric population were consistent with experience from studies in adult populations and confirmed the known safety profile of Gadovist 1.0.
A summary of post hoc estimated and derived PK parameters for children and adults is presented in Tables 9 and 10.
These studies demonstrated the PK profile for Gadovist 1.0 in the paediatric population was comparable to the PK profile in adults. Therefore in children of all ages (including full term newborns), no dose adjustment is needed. The approved standard dose for adults (0.1 mmol/kg BW) for all indications is the same in the paediatric population. As per the European guideline2 the demonstration of similar PK results in the paediatric and adult populations support extrapolation of adult indications and safety profile for gadobutrol into the paediatric population.

5.2 Pharmacokinetic Properties

General introduction.

Gadobutrol behaves in the organism like other highly hydrophilic biologically inert, renally excreted compounds (e.g. mannitol or inulin).

Absorption and distribution.

Gadobutrol is rapidly distributed in the extracellular space. Protein binding is negligible. After a dose of 0.1 mmol gadobutrol/kg body weight, 0.59 mmol gadobutrol/L plasma was measured 2 minutes postinjection and 0.3 mmol gadobutrol/L plasma 60 minutes postinjection.
Current evidence suggests that gadolinium accumulates in the brain after repeated administration of gadolinium-containing contrast agents (GBCAs) although the exact mechanism of gadolinium passage in the brain has not been established.

Metabolism.

Gadobutrol is not metabolised.

Elimination.

Gadobutrol is eliminated from plasma with a mean terminal half-life of 1.81 hours (range 1.33-2.13 hours).
Gadobutrol is excreted in an unchanged form via the kidneys. The extrarenal elimination is negligible. Renal clearance of gadobutrol is 1.1 to 1.7 mL/min/kg in healthy subjects and, thus, comparable to the renal clearance of inulin, pointing to the fact that gadobutrol is eliminated by glomerular filtration. More than 50% of the given dose was excreted via the urine within two hours after intravenous administration. Gadobutrol was completely excreted within 24 hours. Less than 0.1% was eliminated via the faeces.

Linearity/ nonlinearity.

The pharmacokinetics of gadobutrol in humans was dose proportional (e.g. Cmax, AUC) and dose dependent (e.g. Vss, t1/2) respectively.

Renal impairment.

In patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance.
The mean terminal half-life was prolonged to 5.8 hours in mild (to moderately) impaired patients (80 > CLCR > 30 mL/min) and further prolonged to 17.6 hours in severely impaired patients not on dialysis (CLCR < 30 mL/min).
The mean serum clearance was reduced to 0.49 mL/min/kg in mild (to moderately) impaired patients (80 > CLCR > 30 mL/min) and to 0.16 mL/min/kg in severely impaired patients not on dialysis (CLCR < 30 mL/min).
Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within 5 days (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration ).
Gadobutrol is cleared by haemodialysis with approximately 70% of a given dose eliminated during the first haemodialysis session and 98% eliminated after the third session, regardless of the dose given.

Elderly population.

Due to physiological changes in renal function with age, in elderly healthy volunteers (aged 65 years and above) systemic exposure was increased by approximately 33% (men) and 54% (women) and terminal half-life by approximately 33% (men) and 58% (women). The plasma clearance is reduced by approximately 25% (men) and 35% (women), respectively. The recovery of the administered dose in urine was complete after 24 hours in all volunteers and there was no difference between elderly and nonelderly healthy volunteers.

Investigation in animals.

In rabbits the placental transfer was insignificant, 0.01% of the administered dose being detected in the fetuses.
In lactating rats less than 0.1% of the total administered dose was excreted into the breast milk.
In rats, absorption after oral administration was found to be very small and amounted to about 5% based on the fraction of the dose excreted in urine.
Enterohepatic circulation has not been observed.

5.3 Preclinical Safety Data

Nonclinical safety data.

Non-clinical data reveal no special hazard for humans based on conventional studies of systemic toxicity, genotoxicity, and contact-sensitizing potential.
Experimental local tolerance studies in animals following a single paravenous, subcutaneous, or intramuscular application indicated that slight local intolerance reactions could occur at the administration site after inadvertent paravenous administration.
In nonclinical cardiovascular safety pharmacology studies, depending on the dose of gadobutrol administered, transient increases in blood pressure and myocardial contractility were observed. As these effects were minimal and transient, and due to anaesthesia of the animals, they are not considered relevant to humans. In humans, no increase in blood pressure was observed in clinical studies.

Genotoxicity.

Bacteria, mammalian cells and animal studies investigating the genotoxicity (gene mutation and chromosomal aberration) of gadobutrol in vitro and in vivo did not show genotoxic potential.

Carcinogenicity.

The carcinogenic potential of gadobutrol has not been investigated in long-term animal studies.

Studies in neonatal/juvenile animals.

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 full-term newborns and infants.
2. European Medicines Agency, CHMP, London, 28 June 2006, Doc. Ref. EMEA/CHMP/EWP/147013/2004. Guideline on the Role of Pharmacokinetics in the Development of Medicinal Products in the Paediatric Population.

4 Clinical Particulars

4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.
Gadovist 1.0 is indicated in adults and children including full term newborns for:
Contrast enhancement in cranial and spinal magnetic resonance imaging (MRI).
Contrast enhancement in whole body MRI including head and neck region, thoracic space, breast, abdomen (pancreas, liver and spleen), pelvis (prostate, bladder and uterus), retroperitoneal space (kidney), extremities and musculoskeletal system.
Use in first pass MRI studies of cerebral perfusion (see Section 4.4 Special Warnings and Precautions for Use).
Contrast enhancement in magnetic resonance angiography (CE-MRA) (see Section 5.1 Clinical trials).
Contrast enhancement in cardiac MRI including assessment of rest and pharmacological stress perfusion and delayed enhancement.

4.3 Contraindications

Gadovist 1.0 should not be administered to patients with known hypersensitivity to any of the ingredients.

4.4 Special Warnings and Precautions for Use

Warning nephrogenic systemic fibrosis.

Gadolinium based contrast agents increase the risk of nephrogenic systemic fibrosis (NSF) in patients with:
acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73 m2); or
acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period.
See Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use.

General.

Pronounced states of excitement, anxiety and pain may increase the risk of adverse reactions or intensify contrast medium related reactions.

Hypersensitivity.

As with other intravenous contrast agents, Gadovist 1.0 can be associated with anaphylactoid/ hypersensitivity or other idiosyncratic reactions, characterised by cardiovascular, respiratory or cutaneous manifestations, and ranging to severe reactions including shock.
The risk of hypersensitivity reactions is 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 1.0 must be made after particularly careful evaluation of the risk/ benefit ratio.
Most of these reactions occur within half an hour of administration. Therefore postprocedure observation of the patient is recommended.
Medications for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures are necessary.
Patients taking beta-blockers who experience such reactions may be resistant to treatment with beta-agonists.
Delayed reactions (after hours up to several days) have been rarely observed (see Section 4.8 Adverse Effects (Undesirable Effects)).

Severe renal impairment and liver transplant patients.

No impairment of renal function has so far been observed.
Prior to administration of Gadovist 1.0 all patients should be screened for renal dysfunction by obtaining a history and/or laboratory tests.
In patients with severely impaired renal function the benefits must be weighed carefully against the risks, since contrast medium elimination is delayed in such cases.
Because gadobutrol is renally excreted sufficient period of time for elimination of the contrast agent from the body prior to any readministration in patients with renal impairment should be ensured. Usually, complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function at least 80% of the administered dose was recovered in the urine within 5 days (see Section 5.2 Pharmacokinetic Properties).
Gadovist 1.0 can be removed from the body by haemodialysis. After 3 dialysis sessions approximately 98% of the agent is removed from the body. For patients already receiving haemodialysis at the time of Gadovist 1.0 administration, prompt initiation of haemodialysis following the administration of Gadovist 1.0 should be considered, in order to enhance the contrast agent's elimination.
There have been reports of nephrogenic systemic fibrosis (NSF) associated with the use of gadolinium containing contrast agents including Gadovist 1.0 in patients with:
acute or chronic severe renal impairment (a glomerular filtration rate < 30 mL/min/1.73 m2); or
acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period.
NSF is a debilitating and sometimes fatal disease affecting the skin, muscle, and internal organs.
Therefore, Gadovist 1.0 should only be used in these patients after careful risk/ benefit assessment.
When administering a gadolinium based contrast agent (GBCA), do not exceed the dose recommended in the product labelling. Allow sufficient time for elimination of the GBCA prior to any readministration.

Severe cardiovascular disease.

In patients with severe cardiovascular disease, Gadovist 1.0 should only be administered after careful risk/ benefit assessment because to date only limited data are available.

Seizure disorders.

As with other gadolinium chelate containing contrast media, special precaution is necessary in patients with a low threshold for seizures.

Cerebral perfusion studies.

Information to support the clinical usefulness of MRI studies of cerebral perfusion is limited. Clinical studies were conducted only in patients with a unilateral carotid artery stenosis and/or unilateral cerebral infarct who were assessed as being in a clinically stable condition.

Accumulation of gadolinium in the brain.

The current evidence suggests that gadolinium accumulates in the brain after multiple administrations of GBCAs. Increased signal intensity on non-contrast T1 weighted images of the brain has been observed after multiple administrations of GBCAs in patients with normal renal function. Gadolinium has been detected in brain tissue after multiple exposures to GBCAs, particularly in the dentate nucleus and globus pallidus. The evidence suggests that gadolinium accumulation is higher after repeat administration of linear than after repeat administration of macrocyclic agents.
The clinical significance of gadolinium accumulation in the brain is presently unknown. In order to minimize potential risks associated with gadolinium accumulation in the brain, it is recommended to use the lowest effective dose and perform a careful benefit risk assessment before administering repeated doses.

Use in the elderly.

In clinical studies, no overall differences in safety or effectiveness were observed between elderly (aged 65 years and above) and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is considered necessary.

Paediatric use.

The safety and efficacy data from controlled clinical trials are limited in infants under 2 years of age. The clinical experience has demonstrated that 0.1 mL/kg body weight corresponding to 0.1 mmol/kg body weight may be used in this age group. The safety and efficacy of doses > 0.1 mmol/kg body weight, and sequential and/or repeat procedures in children have not been studied.
No studies have been conducted in paediatric patients with renal dysfunction and in premature infants; no patients younger than 6 days of age have been enrolled in the clinical trials. The clinical implications concerning the potential risk for neurotoxicity and nephrotoxicity in newborns term infants ≤ 3 days of age is unknown.
The recommended dose should not be exceeded and a sufficient period of time for elimination of the agent from the body (at least 7 days) should be allowed prior to re-administration.
Gadovist 1.0 should only be used after careful individual benefit-risk assessment in the paediatric population.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interactions studies with other medicinal products have been conducted.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A repeat dose study of reproduction toxicity in rats resulting in systemic exposures (plasma AUC) exceeding the human exposure at the maximum recommended dose by a factor of about 5 did not indicate any impairment of fertility.
(Category B3)
There are no clinical studies describing the use of gadobutrol in pregnant women. In pregnant animals dosed with radioactively labelled gadobutrol, radioactivity was detected in rabbit fetuses but not in rat fetuses. No teratogenic activity was found in rats, rabbits or cynomolgus monkeys at repeated intravenous doses of 5, 5 and 2.5 mmol/kg/day, respectively. However, repeated intravenous dosing in reproductive toxicology studies caused a retardation of embryonal development in rats and rabbits and an increase in embryolethality in rats, rabbits and monkeys at dose levels being 8 to 16 times (based on body surface area) or 25 to 50 times (based on body weight) above the diagnostic dose in humans. It is not known whether these effects can also be induced by a single administration.
The potential risk for humans is unknown.
Gadovist 1.0 should not be used during pregnancy unless clearly necessary.
It is unknown whether gadobutrol is excreted in human milk. There is evidence from a study in rats that gadobutrol is excreted into milk in very small amounts (less than 0.1% of the dose intravenously administered) and absorption via the gastrointestinal tract is poor (about 5% of the dose orally administered to adult rats was excreted in the urine).
153Gd-labelled gadobutrol was administered intravenously to lactating rats at a dose of 0.5 mmol/kg. About 3 hours after dosing, 0.01% of total dose was transferred into milk found in the stomach of the fetuses. Radioactivity was still detected in milk twenty four hours after dosing.
In the blood of suckling neonates, the labelled gadobutrol was detected at about 1% of the maternal blood level 3 hours after dosing. In a peri- and postnatal study, F1 female offspring of rats dosed at 4.5 mmol/kg/day showed a slight delay in the development of CNS function in the conditioned avoidance reaction test.
At clinical doses, no effects on the infant are anticipated and Gadovist 1.0 can be used during breastfeeding.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The overall safety profile of gadobutrol is based on data from more than 6,300 patients in clinical trials, and from postmarketing surveillance.
The most frequently observed adverse drug reactions (≥ 0.5%) in patients receiving gadobutrol are headache, nausea and dizziness.
The most serious adverse drug reactions in patients receiving gadobutrol are cardiac arrest and severe anaphylactoid reactions.
Delayed allergic reactions (hours later up to several days) have been rarely observed.
Most of the undesirable effects were of mild to moderate intensity.

Tabulated list of adverse reactions.

The adverse drug reactions (ADRs) observed with gadobutrol are represented in Table 1. They are classified according to system organ class (MedDRA version 14.1). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
ADRs are classified according to their frequencies. Frequency groupings are defined according to the following convention: common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000.
ADRs identified during clinical trials and also during postmarketing surveillance are listed in Table 1.
ADRs identified only during postmarketing surveillance, and for which a frequency could not be estimated are listed separately in Table 2.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Additional adverse reactions from postmarketing spontaneous reporting.


Additional information on special populations.


Paediatric patients.

Based on two single dose phase I/III studies in 138 subjects aged 2-17 years and 44 subjects aged 0-< 2 years, the frequency, type and severity of adverse drug reactions in children of all ages including full term newborns 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.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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:
In Australia: http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

General information.

This medicinal product is for intravenous administration only. The dose required is administered as a bolus dose. The lowest effective dose should be used. Contrast enhanced MRI can usually commence shortly after the injection depending on the pulse sequences used and the protocol for the examination. Optimal signal enhancement is observed during arterial first pass for CE-MRA and within a period of about 15 minutes after injection of Gadovist 1.0 for other indications (depending on the type of lesion and tissue).
Gadovist 1.0 should not be drawn into the syringe and the prefilled syringe should not be prepared until immediately before use. Gadovist 1.0 is for use in a single patient only. Any contrast agent solution not used in one examination must be discarded.
T1-weighted scanning sequences are usually used for contrast enhanced examinations. The usual safety rules for magnetic resonance imaging must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants.
Intravenous administration of contrast media should, if possible, be done with the patient lying down. The patient should refrain from eating for two hours prior to investigation in order to minimise risk of vomiting and possible aspiration.

Dosage.

Adults.

Dosage depends on indication. A single intravenous injection of 0.1 mmol Gadovist 1.0 per kg body weight (equivalent to 0.1 mL Gadovist 1.0 per kg body weight) is generally sufficient. A total amount of 0.3 mmol Gadovist 1.0 per kg body weight (equivalent to 0.3 mL Gadovist 1.0 per kg body weight) may be administered at maximum.

Cranial and spinal MRI.

0.1 mmol Gadovist 1.0 per kg body weight (equivalent to 0.1 mL Gadovist 1.0 per kg body weight), given intravenously at a rate of 2 mL per second.
In some investigations use of further doses of 0.1 mmol Gadovist 1.0 per kg body weight (equivalent to 0.1 mL Gadovist 1.0 per kg body weight) or 0.2 mmol Gadovist 1.0 per kg body weight (equivalent to 0.2 mL Gadovist 1.0 per kg body weight) to a total of 0.3 mmol Gadovist 1.0 per kg body weight (equivalent to 0.3 mL Gadovist 1.0 per kg body weight) may yield additional information.

CE-MRI of the whole body.

0.1 mL/kg body weight of the 1.0 mmol/mL Gadovist 1.0 solution (equivalent to 0.1 mmol/kg body weight) is recommended and is generally sufficient to answer clinical questions.

Cerebral perfusion studies (see Section 4.4 Special Warnings and Precautions for Use).

For gradient echo sequences 0.1-0.3 mmol Gadovist 1.0 per kg body weight (equivalent to 0.1-0.3 mL Gadovist 1.0 per kg body weight). Gadovist 1.0 given intravenously at a rate of 5 mL per second using a powered injector is recommended.

Contrast enhanced magnetic resonance angiography, CE-MRA.

Imaging of one field of view: 7.5 mL for body weight less than 75 kg; 10 mL for body weight of 75 kg or more (corresponding to 0.1-0.15 mmol per kg body weight).
Imaging more than one field of view: 15 mL for body weight less than 75 kg; 20 mL for body weight of 75 kg or more (corresponding to 0.2-0.3 mmol per kg body weight).

CE myocardial perfusion imaging and delayed enhancement.

The recommended dose is 0.05 mL/kg body weight during pharmacological stress and 0.05 mL/kg body weight at rest of the 1.0 mmol/mL Gadovist 1.0 solution (equivalent to a total dose of 0.1 mL/kg body weight or 0.1 mmol/kg body weight).
For delayed enhancement only, a total dose of 0.1 mL/kg body weight is also recommended.

Paediatric population.

For children of all ages including full term newborns the recommended dose is 0.1 mmol Gadovist 1.0 per kg body weight (equivalent to 0.1 mL Gadovist 1.0 per kg body weight) for all indications (see Section 4.1 Therapeutic Indications).
Due to immature renal function in newborns and infants up to 1 year of age, Gadovist 1.0 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 due to the lack of information on repeated administration, Gadovist 1.0 injections should not be repeated unless the interval between injections is at least 7 days.

Elderly population.

In clinical studies, no overall differences in safety or effectiveness were observed between elderly (aged 65 years and above) and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. No dosage adjustment is considered necessary.

Patients with renal impairment.

Do not exceed the recommended dose (see Section 5.2 Pharmacokinetic Properties, Patients with renal impairment; Section 4.4 Special Warnings and Precautions for Use, Boxed Warning and Severe renal impairment and liver transplant patients).

Instructions for use/ handling.

After the vial has been opened or the prefilled syringe has been prepared for use, Gadovist 1.0 remains stable for 24 hours at 20 to 25°C and must be discarded thereafter.

Visual inspection.

This medicinal product should be visually inspected before use.
Gadovist 1.0 should not be used in case of severe discoloration, the occurrence of particulate matter or a defective container.

Administration.

Vials.

Gadovist 1.0 should only be drawn into the syringe immediately before use.
The rubber stopper should never be pierced more than once.
Any contrast medium solution not used in one examination must be discarded.

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

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

No signs of intoxication secondary to an overdose have so far been reported during clinical use. Single doses of gadobutrol as high as 1.5 mmol gadobutrol/kg body weight were well tolerated. In case of inadvertent overdosage, cardiovascular monitoring (including ECG) and control of renal function are recommended as a measure of precaution.
Gadovist 1.0 can be removed from the body by haemodialysis (see Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact:
Australia: The Poison Information Centre on 131126 (Australia)

7 Medicine Schedule (Poisons Standard)

Unscheduled.

6 Pharmaceutical Particulars

6.1 List of Excipients

Gadovist 1.0 is available as a 1.0 mmol/mL solution for injection and each mL of Gadovist 1.0 contains 604.72 mg (1.0 mmol) gadobutrol, calcobutrol sodium, trometamol, hydrochloric acid and water for injections. Each mL contains 0.00056 mmol (equivalent to 0.013 mg) of sodium. Based on the average amount given to a 70 kg person this medicinal product contains less than 1 mmol sodium (23 mg) per dose.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Gadovist 1.0 is a solution containing 604.72 mg/mL gadobutrol and is available in packs of:
1 x 2 mL, 3 x 2 mL, 5 x 7.5 mL (in 10 mL), 10 x 15 mL and 10 x 30 mL glass vials, and
1 and 5 x 5 mL, 5 x 7.5 mL (in 10 mL), 5 x 10 mL, 5 x 15 mL and 5 x 20 mL prefilled glass or plastic syringes.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes