Consumer medicine information

Gadovist 1.0

Gadobutrol

BRAND INFORMATION

Brand name

Gadovist

Active ingredient

Gadobutrol

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

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

SUMMARY CMI

GADOVIST® 1.0

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I given GADOVIST 1.0?

GADOVIST 1.0 contains the active ingredient gadobutrol. GADOVIST 1.0 is a contrast agent used during a magnetic resonance imaging (MRI) examination.

For more information, see Section 1. Why am I given GADOVIST 1.0? in the full CMI.

2. What should I know before I am given GADOVIST 1.0?

Do not use if you have ever had an allergic reaction to GADOVIST 1.0 or any of the ingredients listed at the end of the CMI.

Talk to your doctor, radiographer or nurse if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given GADOVIST 1.0? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with GADOVIST 1.0 and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given GADOVIST 1.0?

GADOVIST 1.0 is injected into your vein by a doctor, radiographer or nurse immediately before or during your MRI examination. It is recommended that you do not eat for 2 hours before you are given GADOVIST 1.0.

More instructions can be found in Section 4. How am I given GADOVIST 1.0? in the full CMI.

5. What should I know while receiving GADOVIST 1.0?

Things you should doTell your doctor, radiographer or nurse if you have:
  • experience any of the severe symptoms of loss of consciousness or heart attack, increase in heart rate, difficulty breathing, low blood pressure and swelling of the face, lips or tongue leading to severe breathing difficulties and shock
  • have very poor kidney function or severe kidney problems
  • had a liver transplant, impaired liver function or liver cirrhosis
  • have severe heart and circulatory disorders
  • have low threshold for seizures.
Looking after your medicineThe MRI unit will store GADOVIST 1.0 as required by the manufacturer.

For more information, see Section 5. What should I know while receiving GADOVIST 1.0? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If they do occur, they are usually minor and temporary. Do not be alarmed by this list. You may not experience any of them.

Serious side effects can include severe allergic reactions, nephrogenic systemic fibrosis (NSF) and heart attack. Common side effects can include headache, nausea and dizziness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: Gadolinium-based contrast agents can increase the risk of nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severely impaired kidney function either with or without liver impairment, cirrhosis or liver transplant. For more information, speak with your doctor, radiographer or nurse.



FULL CMI

GADOVIST® 1.0 (GAD-oh-vist)

Active ingredient: gadobutrol

Consumer Medicine Information (CMI)

This leaflet provides important information about using GADOVIST 1.0. You should also speak to your doctor, radiographer, nurse or pharmacist if you would like further information or if you have any concerns or questions about using GADOVIST 1.0.

Where to find information in this leaflet:

1. Why am I given GADOVIST 1.0?
2. What should I know before I am given GADOVIST 1.0?
3. What if I am taking other medicines?
4. How am I given GADOVIST 1.0?
5. What should I know while receiving GADOVIST 1.0?
6. Are there any side effects?
7. Product details

1. Why am I given GADOVIST 1.0?

GADOVIST 1.0 contains the active ingredient gadobutrol.

GADOVIST 1.0 is a contrast agent used during a magnetic resonance imaging (MRI) examination. It aids 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 a liquid that alters the way in which the MRI machine detects certain tissues within the body, often making the pictures clearer and showing things that may not have been visible using MRI alone.

2. What should I know before I am given GADOVIST 1.0?

Warnings

Do not use GADOVIST 1.0 if:

  • you are allergic to gadobutrol, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor, radiographer or nurse if you have:

  • any other allergies (e.g. seafood, hay fever, hives, anaphylaxis)
  • very poor kidney function or severe kidney problems
  • had a liver transplant, impaired liver function or liver cirrhosis
  • bronchial asthma
  • severe heart and circulatory disorders
  • low threshold for seizures
  • a heart pacemaker or any material in your body containing iron
  • are taking beta-blockers used for high blood pressure or heart conditions
  • take any medicines for any other condition.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

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

Use in children

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

It is recommended that you do not eat for 2 hours before you are given GADOVIST 1.0.

3. What if I am taking other medicines?

Tell your doctor, radiographer, nurse or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with GADOVIST 1.0 and affect how it works.

Tell your doctor, radiographer or nurse if you are taking beta-blockers used for high blood pressure or heart conditions.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect GADOVIST 1.0.

4. How am I given GADOVIST 1.0?

How much to be given

  • The dosage of GADOVIST 1.0 is based on your weight and area of your body that will be examined. The doctor, radiographer or nurse will calculate the right dose for you.

When GADOVIST 1.0 is given

  • GADOVIST 1.0 will be given immediately before or during your MRI examination.

How GADOVIST 1.0 is given

  • GADOVIST 1.0 is injected by a small needle into a vein, usually in your hand or arm.

If you are given too much GADOVIST 1.0

If you think that you have been given too much GADOVIST 1.0, ask the doctor, radiographer or nurse. As GADOVIST 1.0 is given by the doctor, radiographer or nurse, overdose is unlikely. If it does happen, a 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).

You should immediately:

  • phone the Poisons Information Centre (by calling Australia: 13 11 26 or New Zealand 0800 POISON or 0800 764 766), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while receiving GADOVIST 1.0?

Things you should do

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

Call your doctor, radiographer or nurse straight away if you:

  • experience any of the severe symptoms of loss of consciousness or heart attack, increase in heart rate, difficulty breathing, low blood pressure and swelling of the face, lips or tongue leading to severe breathing difficulties and shock
  • have very poor kidney function or severe kidney problems
  • had a liver transplant, impaired liver function or liver cirrhosis
  • have severe heart and circulatory disorders
  • have low threshold for seizures.

Remind any doctor, dentist or pharmacist you visit that you have been given GADOVIST 1.0.

Recent information shows that gadolinium (contained 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 and will use the lowest dose of GADOVIST 1.0.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how GADOVIST 1.0 affects you.

GADOVIST 1.0 is expected to have little to no effect on the ability to drive and use machines.

Looking after your medicine

  • 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.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about 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.

Allergic reaction

Some people may experience symptoms of an allergic reaction such as loss of consciousness or heart attack, increase in heart rate, difficulty breathing, low blood pressure and swelling of the face, lips or tongue leading to severe breathing difficulties and shock.

Allergic reactions occur more frequently in people with a history of allergies to other contrast agents, to foods (e.g. seafood) or those who suffer from anaphylaxis, hay fever or bronchial asthma.

Most of these reactions occur within 30 minutes of receiving GADOVIST 1.0. Rarely, some of these reactions may be delayed (up to several days after receiving GADOVIST 1.0).

Nephrogenic Systemic Fibrosis

If you have very poor kidney function or severe kidney disease, and you receive any gadolinium-containing contrast agent for an MRI, you may be at risk of developing a rare condition known as Nephrogenic Systemic Fibrosis (NSF). This condition can cause hardening (fibrosis) of the skin and tissues.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal disorders
  • Nausea
  • Vomiting
  • Dry mouth
Nervous system disorders
  • Headache
  • Dizziness
  • Distaste in mouth
  • Pins and needles sensation
  • Unpleasant smells
General disorders
  • Feeling hot or cold
  • Malaise (tired)
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Immune system disorders
  • Experience 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
  • Low blood pressure
Nervous system disorders
  • Loss of consciousness
  • Uncontrolled shaking (convulsions)
Cardiac disorders
  • Abnormal heartbeat (maybe faster)
  • Heart attack
Skin disorders
  • Pale skin
  • Flushing (skin redness)
  • Itchy skin
  • Rash
General disorders
  • Injection site reaction
  • Feeling cold
  • Rashes, large areas of hardened skin
  • Weakness, discomfort
  • Joint pain
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor, radiographer, nurse or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration in Australia online at www.tga.gov.au/reporting-problems or in New Zealand nzphvc.otago.ac.nz/reporting. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

This medicine is only available in an MRI unit.

What GADOVIST 1.0 contains

Active ingredient
(main ingredient)		Gadobutrol
Other ingredients
(inactive ingredients)		Calcobutrol sodium
Trometamol
Hydrochloric acid
Water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What GADOVIST 1.0 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.

Glass vial and pre-filled syringes:
2 mL vial – AUST R 286854
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.

Who distributes GADOVIST 1.0

Bayer Australia Limited
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073
www.bayer.com.au

Bayer New Zealand Limited
PO Box 2825
Shortland Street
Auckland 1140
New Zealand
Free phone 0800 229 376

This leaflet was prepared in December 2020.

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information or on the Medsafe website (www.medsafe.govt.nz) for New Zealand.

® Registered trademark

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Gadovist

Active ingredient

Gadobutrol

Schedule

Unscheduled

 

1 Name of Medicine

Gadobutrol.

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.

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.

4.2 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, Severe renal impairment and liver transplant patients; Boxed Warnings).

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.

4.3 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 (also 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 premature infants and 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.

4.7 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.

4.8 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 lists 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: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000.
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 reports.


Clinical safety.

The type and frequency of adverse reactions following the administration of Gadovist 1.0 in various indications was evaluated in a large international prospective non-interventional trial (GARDIAN). The safety population encompassed 23,708 patients of all age groups including children (n = 1,142; 4.8%) and elderly (n = 4,330; [18.3% between the ages of 65 and < 80] and n = 526; [2.2% of ≥ 80 years of age]). Median age was 51.9 years.
Two hundred and two patients (0.9%) reported overall 251 adverse events (AEs), and 170 (0.7%) reported 215 events categorized as adverse drug reactions (ADRs), majority (96.8%) of which were mild or moderate in intensity.
Most commonly documented ADRs were nausea (0.3%), vomiting (0.1%) and dizziness (0.1%). ADR rates were 0.9% in females and 0.6% in males. There were no differences in ADR rates according to the dose of gadobutrol. Four of the 170 patients with ADRs (0.02%) experienced a serious adverse event, with one event (anaphylactic shock) leading to fatal outcome.
In the paediatric population AEs were reported in 8 of the 1,142 (0.7%) children. In six children these AEs were classified as ADRs (0.5%).

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.

Renal impairment.

In a prospective pharmacoepidemiologic study (GRIP) to assess the magnitude of potential risk for development of NSF in renally impaired patients, 908 patients with varying degrees of renal impairment, of which 234 patients had severe renal impairment (eGFR < 30 mL/min/1.73 m2) received Gadovist 1.0 at the standard approved dose for CE-MRI. Patients were followed over the course of two years for signs and symptoms of NSF. No patient enrolled in the study developed NSF.

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.
In New Zealand: https://nzphvc.otago.ac.nz/reporting/

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).
New Zealand: The National Poisons Centre on 0800 POISON (0800 764766).

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.

The relaxivity (r1) of gadobutrol, measured in vitro in human blood/plasma at physiological conditions and at clinically relevant field strengths (1.5 and 3.0 T), is in the range of 3.47 - 4.97 L/mmol/sec.
In clinical doses, the relaxivity of gadobutrol leads to a distinct shortening of the relaxation times of protons in tissue water.
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.
The stability of the gadobutrol complex has been studied in vitro at physiological conditions (in native human serum, at pH 7.4 and 37°C) over the time period of 15 days. The amounts of released gadolinium ions from gadobutrol were below the limit of quantification of 0.1% of total gadolinium demonstrating the high complex stability of gadobutrol under the tested conditions.

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 1,234 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 population1. 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 guideline1 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.
1European 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.

5.2 Pharmacokinetic Properties

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.

Excretion.

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.

Characteristics in special patient populations.

Patients with 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 (also 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.

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.

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:

CAS number.

138071-82-6.

Physicochemical properties.

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

7 Medicine Schedule (Poisons Standard)

Australia: Not Scheduled.
New Zealand: General Sales Medicine.

Summary Table of Changes