Consumer medicine information

Magnevist Solution for injection

Gadopentetate dimeglumine

BRAND INFORMATION

Brand name

Magnevist Solution for injection

Active ingredient

Gadopentetate dimeglumine

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Magnevist Solution for injection.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Magnevist. It does not contain all the available information. It does not take the place of talking to your doctor.

All diagnostic agents have risks and benefits. Your doctor has weighed the risks of you using Magnevist against the benefits they expect it will 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 MAGNEVIST IS USED FOR

Magnevist is used at the same time as magnetic resonance imaging (MRI) to aid in the detection of abnormalities in the brain, spinal cord, neck, chest, abdomen, pelvis, bones and muscles in adults; and in the brain and spinal cord in children and babies.

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.

Magnevist is a liquid that alters the way in which the MRI machine detects certain tissues within the body. Magnevist often makes the pictures clearer and often shows things that may not have been visible using MRI alone.

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

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

Your doctor may be using it for another reason.

BEFORE YOU ARE GIVEN MAGNEVIST

When you must not be given it

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

  • dimeglumine gadopentetate, the active ingredient in Magnevist
  • 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, tongue or other parts of the body
  • rash, itching or hives on the skin.

You must not be given Magnevist if you have severe disturbances of kidney function.

You must not be given Magnevist 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.

If you are not sure whether you should be given Magnevist, talk to your doctor/radiologist.

Before you are given it

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

Recent information shows that gadolinium (as in Magnevist) may accumulate in the brain after multiple use. To date, no adverse health outcomes associated with retention of gadolinium in the brain have been identified or reported.

Your doctor will:

  • carefully consider the risks and benefits of repeated doses
  • use the lowest dose

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

  • severe heart and circulatory disorders
  • poor kidney function
  • any allergies e.g. seafood allergies, hay fever, hives)
  • bronchial asthma
  • disease affecting red blood cells or anaemia (decrease in red blood cells)
  • low blood pressure
  • seizures
  • liver disease.

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

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

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

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

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.

Some medicines and Magnevist may interfere with each other. These include:

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

These medicines may be affected by Magnevist or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

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

HOW MAGNEVIST IS GIVEN

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

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

The radiologist (MRI specialist doctor) will advise the use of Magnevist if he/she feels that it is likely to assist the MRI examination in finding out more about your condition.

You should also fast for the last 2 hours prior to the examination but you may drink as usual. Further directions will be given by your doctor.

How much is given

The actual dosage of Magnevist that is right for you will be worked out by the radiologist and will depend on the region of your body to be examined. Normally only a single dose of about 15 to 20 mL of Magnevist will be required.

How it is given

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

When it is given

Magnevist will be administered immediately before your MRI examination.

How to prepare the MAGNEVIST syringe for injection

Glass syringe only:

Peel the cover from the syringe tray and take the syringe and plunger rod out of the package.

Screw the plunger into the syringe tightly

Break the first part of the protective grey cap.

Remove the protective grey cap from the tip of the syringe.

Remove the black stopper from the second part of the grey cap.

Remove the air in the syringe.

Plastic syringe only:

Hand injection:

  1. Open the package
  1. Take the syringe and plunger rod out of the package
  1. Screw the plunger rod into the syringe
  1. Unscrew the cap from the syringe
  1. Remove the air in the syringe

Injection with a power injector:

  1. Open the package
  1. Take the syringe out of the package
  1. Unscrew the cap from the syringe
  1. Connect the tip of the syringe onto the tubing system and follow the device manufacturer’s instructions

If you are given too much (overdose)

As Magnevist 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 Magnevist 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 Magnevist. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

AFTER HAVING MAGNEVIST

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.

Delayed reactions may occur. In this case Magnevist could prevent you from driving safely and the ability to operate any tools or machines may be impaired.

SIDE EFFECTS

Tell your doctor/radiologist as soon as possible if you do not feel well whilst receiving or after being given Magnevist.

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.

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 and they worry you:

  • dizziness
  • headache
  • unpleasant/altered taste
  • nausea or vomiting
  • local reaction around the injection site namely, pain, coldness, warmth, or a burning sensation.

The above list includes the more common side effects of Magnevist. 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:

  • conjunctivitis, watery eyes, disturbed vision, smell, hearing or speech
  • ear or eye pain, ringing in the ears, pins and needles or a burning sensation
  • agitation, confusion, or disorientation
  • sensation of tickling, tingling, burning, pricking or numbness
  • involuntary twitching
  • uncontrolled shaking (convulsions)
  • drowsiness , dizziness or light-headedness
  • flushing, red or itchy skin; rash, or hives, swelling
  • uncomfortable or irritated throat with swelling, or pain or a sensation of tightness
  • coughing, sneezing, wheezing, hayfever
  • breathlessness, difficulty breathing, or a change in breathing rate
  • back pain or sore joints
  • chest pain or an abnormal, fast or slow heart beat
  • low or high blood pressure
  • stomach pain or discomfort
  • diarrhoea
  • toothache, dry or sore mouth
  • uncontrollable passing of urine, or feel an urgent need to pass urine
  • chills, fever, generally feeling unwell, tired or thirsty
  • discolouration and thickening of the skin (may feel “woody” and resemble an orange-peel texture), that may be painful and result in reduced joint mobility (nephrogenic systemic fibrosis).

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, 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.

STORING MAGNEVIST

Storage

Keep Magnevist in the carton in order to protect from light until it is time to use it (applies to the glass presentations only).

Keep Magnevist in a cool dry place where the temperature stays below 30°C.

The MAGNEVIST syringes, vials and bottles should not be frozen.

PRODUCT DESCRIPTION

What it looks like

Magnevist is a clear, colourless to slight yellow solution supplied in bottles and pre-filled glass and plastic syringes of various sizes.

Ingredients

Active ingredients:

  • Magnevist – contains 469 mg dimeglumine gadopentetate per mL

Inactive ingredients:

  • meglumine
  • meglumine pentetate
  • water for injections
  • pentetic acid (2 mmol/L injection syringe only)
  • sodium chloride (2 mmol/L injection syringe only)

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

Glass vials, pre-filled syringes and bottle:

10 mL vial – AUST R 10697

30 mL vial– AUST R 59542

15 mL vial - AUST R 48494

20 mL vial - AUST R 48495

10 mL pre-filled syringe – AUST R 54671

15 mL pre-filled syringe – AUST R 54670

20 mL pre-filled syringe - AUST R – 54669

2 mmol/L pre-filled syringe – AUST R 98146

100 mL bottle – AUST R 90883

Plastic pre-filled syringes:
10 mL syringe – AUST R 54671
15 mL syringe – AUST R 54670

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

Date of preparation

October 2017

See TGA website (www.ebs.tga.gov.au) for latest Australian Consumer Medicine Information.

See MEDSAFE website (www.medsafe.govt.nz) for latest New Zealand Consumer Medicine Information.

® Registered Trademark of Bayer AG, Germany

© Bayer Australia Ltd All rights reserved.

BRAND INFORMATION

Brand name

Magnevist Solution for injection

Active ingredient

Gadopentetate dimeglumine

Schedule

Unscheduled

 

Name of the medicine

Magnevist (dimeglumine gadopentetate) solution for intravenous injection is the N-methylglucamine salt of the gadolinium complex of diethylenetriamine pentaacetic acid, and is an injectable contrast medium for magnetic resonance imaging (MRI).

Description

Magnevist injection is a 0.5 mmol/mL solution of 1-deoxy-1-(methylamino)-D-glucitol dihydrogen [N,N-bis[2-[bis(carboxymethyl)amino]ethyl]glycinato-(5-)]gadolinate (2-) (2:1) with a molecular weight of 938.
Dimeglumine Gadopentetate (USAN).
Gadopentetate Dimeglumine (INN).
Molecular Formula: C28H54GdN5O20.
CAS Registry No.: 86050-77-3.
Magnevist injection is a sterile, clear, colourless to slightly yellow aqueous solution for intravenous administration.
Each mL contains 469 mg dimeglumine gadopentetate, 530 micrograms meglumine, 1.02 mg meglumine pentetate and water for injections. Magnevist injection contains no antimicrobial preservative.
Magnevist injection has a pH of 7.0-7.9. Magnevist Injection is hypertonic under conditions of use.

Pharmacology

Pharmacodynamics.

Mechanism of action.

Dimeglumine gadopentetate is a paramagnetic agent and, as such, it develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by the paramagnetic agent results in a relatively large local magnetic field, which can enhance the relaxation rates of water protons in the vicinity of the paramagnetic agent.
In MRI, visualisation of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) changes in proton density; 2) alteration of the spin lattice or longitudinal relaxation time (T1); and 3) variation of the spin-spin or transverse relaxation time (T2). When placed in a magnetic field, dimeglumine gadopentetate decreases the T1 and T2 relaxation time in tissues where it accumulates. At usual doses the effect is primarily on the T1 relaxation time. Optimal signal enhancement occurs with a dose of 0.1 mmol/kg (0.2 mL/kg).

Pharmacokinetics.

Absorption and distribution.

The pharmacokinetics of intravenously administered dimeglumine gadopentetate in normal subjects conform to a two compartment open model with mean distribution and elimination half-lives (reported as mean ± SD) of about 0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively.
Current evidence suggests that gadolinium accumulates in the brain after repeated administrations of gadolinium-based contrast agents (GBCAs) although the exact mechanism of gadolinium passage into the brain has not been established.
The extent of protein binding and blood cell partitioning of dimeglumine gadopentetate is not known.

Metabolism.

Dimeglumine gadopentetate is not metabolised.

Excretion.

Gadopentetate is exclusively eliminated in the urine with 83 ± 14% (mean ± SD) of the dose excreted within 6 hours, and 91 ± 13% (mean ± SD) by 24 hours, postinjection. There was no detectable biotransformation or decomposition of dimeglumine gadopentetate.
The urinary and plasma clearance rates (1.76 ± 0.39 mL/min/kg and 1.94 ± 0.28 mL/min/kg, respectively) of gadopentetate are essentially identical, indicating no alteration in elimination kinetics on passage through the kidneys and that the drug is essentially cleared through the kidney. The volume of distribution (266 ± 43 mL/kg) is equal to that of extracellular water, and clearance is similar to that of substances which are subject to glomerular filtration.

Characteristics in special patient populations.

Renal impairment.

In patients with impaired renal function, the serum half-life of gadopentetate is prolonged due to the reduced glomerular filtration rate. After administration of a single intravenous dose to 10 patients with impaired renal function (4 patients with mild renal impairment [creatinine clearance ≥ 60 to < 90 mL/min] and 6 patients with moderate renal impairment [creatinine clearance ≥ 30 to < 60 mL/min]), mean half-lives were 2.6 ± 1.2 hours and 4.2 ± 2.0 hours for the mildly and moderately impaired patients, respectively, as compared to 1.6 ± 0.13 hours in healthy subjects. In patients with severe renal impairment (creatinine clearance < 30 mL/min) but not on dialysis, mean half-life further increased to 10.8 ± 6.9 hours.
Gadopentetate is completely renally excreted within two days in patients with slightly to moderately impaired renal function (creatinine clearance > 30 mL/min). In patients with severe renal impairment, 73.3 ± 16.1% of the administered dose was recovered in the urine within two days.
In patients with renal impairment gadopentetate can be eliminated by means of haemodialysis. In a clinical study patients with renal impairment received a dose of 0.1 mmol/kg dimeglumine gadopentetate. The patients underwent a 3 hour dialysis session per day on three consecutive days. The plasma concentration of gadopentetate decreased by 70% with each dialysis session. After the last session, the plasma concentration was less than 5% of the original value.

Hepatic impairment.

In line with the almost exclusive renal elimination pathway, pharmacokinetics of gadopentetate were not altered in patients with hepatic impairment (as studied in patients with Child-Pugh B) as compared to healthy matched subjects. Data on patients with severe hepatic impairment (Child-Pugh C) are not available.

Elderly population (aged 65 years and above).

In accordance with the physiological changes in renal function with age, the systemic exposure and terminal half-life were increased from 3.3 mmol.h/L to 4.7 mmol.h/L and from 1.8 h to 2.2 h, respectively, in elderly healthy subjects (males aged 65 years and above) compared to non-elderly healthy subjects (males age range 18-57 years). Total clearance was reduced from 117 mL/min in nonelderly subjects to 89 mL/min in elderly subjects.

Paediatric population.

In a study with paediatric patients aged 2 months to < 2 years the pharmacokinetics (bodyweight normalised clearance and distribution volume and terminal half-life) of gadopentetate were similar to adults.

Gender.

The pharmacokinetics of gadopentetate in non-elderly healthy male and female subjects (aged 18-57 years) were similar.

Indications

For diagnostic use by intravenous administration only.
Using magnetic resonance imaging (MRI), dimeglumine gadopentetate provides contrast enhancement:
in intracranial and spinal lesions in adults and children, including neonates and infants, with an abnormal blood brain barrier, or abnormal vascularity;
in whole body imaging in adult patients, including the neck region, the thoracic and abdominal space, the female breast, the pelvis and the musculoskeletal system.

Note.

Reliable enhancement is not provided in imaging the pancreas and the male reproductive organs (prostate, testis and penis).

Contraindications

Magnevist should not be administered to patients with known sensitivity to any of the ingredients.
Use of Magnevist (dimeglumine gadopentetate) is contraindicated in patients with:
acute or chronic severe renal insufficiency (a glomerular filtration rate < 30 mL/min/1.73 m2); or
patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period.

Precautions

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 Contraindications and Precautions.
Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.

Hypersensitivity reactions.

Magnevist should not be administered to patients with known sensitivity to any of the ingredients (see Contraindications).
As with other intravenous contrast agents, Magnevist can be associated with anaphylactoid/ hypersensitivity or other idiosyncratic reactions characterised by cardiovascular, respiratory or cutaneous manifestations and ranging to severe reactions including shock (see Adverse Effects).
Most of these reactions occur within at least half an hour of administration. However, in rare cases, delayed reactions (hours later or up to several days) may occur. Postprocedure observation of the patient is recommended.
In patients with an allergic disposition (especially with a history of the above mentioned conditions), the decision to use Magnevist must be made after particularly careful evaluation of the risk/ benefit ratio in patients.
The risk of hypersensitivity reactions is higher in case of: previous reaction to contrast media; history of bronchial asthma; history of other allergic disorders.
Patients with cardiovascular disease are more susceptible to serious even fatal outcomes of severe hypersensitivity reactions.
In patients with allergic disposition, premedication with antihistamines and/or glucocorticoids may be considered.
Medication for the treatment of hypersensitivity reactions as well as preparedness for institution of emergency measures is necessary (e.g. appropriate drugs, an endotracheal tube and a ventilator should be at hand).
Patients taking beta blockers who experience such reactions may be resistant to treatment effects of beta agonists.
Management of anaphylaxis and emergency measures:
As hypersensitivity/ anaphylaxis is a medical emergency the number of symptoms and/or signs that has been documented for each case may vary considerably.
If hypersensitivity reactions occur, administration of the contrast medium must be discontinued immediately and, if necessary, specific therapy instituted via a venous access. It is therefore advisable to use a flexible indwelling cannula for intravenous contrast medium administration.
Prompt and early treatment of anaphylaxis may prevent the development of symptoms in other organ systems.

Anaemia.

Patients receiving Magnevist injection should be instructed to inform their physician if they have anaemia or any disease that affects red blood cells.
The accepted safety considerations and procedures that are required for MRI are applicable when Magnevist injection is used for contrast enhancement. In addition, deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by dimeglumine gadopentetate may possibly potentiate sickle erythrocyte alignment. Magnevist injection in patients with sickle cell anaemia and other haemoglobinopathies has not been studied.
Patients with other haemolytic anaemias have not been adequately evaluated following administration of Magnevist injection to exclude the possibility of increased haemolysis.

Hypotension.

Hypotension may occur in some patients after injection of Magnevist. In clinical trials, two cases were reported and in addition, there was one case of a vasovagal reaction and two cases of pallor with dizziness, sweating and nausea in one and substernal pain and flushing in the other. These were reported within 25 to 85 minutes after injection except for the vasovagal reaction which was described as mild by the patient and occurred after 6½ hours. In a study in normal volunteers one subject experienced syncope after arising from a sitting position two hours after administration of the drug. Although the relationship of dimeglumine gadopentetate to these events is uncertain, patients should be observed for several hours after drug administration.

Impaired renal function.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with the use of contrast agents containing gadolinium, including Magnevist, 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 (see Contraindications).
NSF is a debilitating and sometimes fatal disease affecting the skin, muscle and internal organs.
Prior to administration of Magnevist all patients should be screened for renal dysfunction by obtaining a history and/or laboratory tests.
When administering Magnevist injection, do not exceed the dose recommended in the product labelling.
Because gadopentetate is renally excreted, a sufficient period of time for elimination of the contrast agent from the body should be ensured prior to any readministration in patients with renal impairment. Elimination half-life in patients with mild or moderate renal impairment is 3 to 4 hours. Elimination half-life in patients with severe renal impairment is about 11 hours, and about 75% of the administered dose was recovered in the urine within two days (see Pharmacology, Pharmacokinetics).
Magnevist may be removed from the body by haemodialysis. After 3 dialysis sessions of 3 hours each, about 97% of the administered dose is eliminated from the body. With each dialysis session, about 70% of the administered dose is eliminated.
For patients receiving haemodialysis, prompt initiation of haemodialysis following the administration of Magnevist should be considered, in order to enhance the contrast agent's elimination (see Adverse Effects).

Seizure disorders.

Patients with seizure disorders or intracranial lesions may be at increased risk of seizure activity as has been reported rarely in association with Magnevist administration (see Adverse Effects).
For patients predisposed to seizures, precautionary measures should be taken, e.g. close monitoring, all equipment and drugs necessary to manage convulsions should they occur must be made ready for use beforehand.

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 Tl 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 minimise 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.

General.

Animal studies suggest that dimeglumine gadopentetate may alter red cell membrane morphology resulting in a slight degree of extravascular (splenic) haemolysis. In clinical trials 15-30% of the patients experienced an asymptomatic transient rise in serum iron. Serum bilirubin levels were slightly elevated in approximately 3.4% of patients. Levels generally returned to baseline within 24 to 48 hours. Haematocrit and red blood cell count were unaffected and liver enzymes were not elevated in these patients. While the effects of dimeglumine gadopentetate on serum iron and bilirubin have not been associated with clinical manifestations, the effect of Magnevist in patients with severe hepatic disease is not known and caution is, therefore, advised.

Effects on fertility.

The results of a reproductive study in rats showed that dimeglumine gadopentetate administered in daily doses of 0.1-2.5 mmol/kg did not cause a significant change in the pregnancy rate in comparison to a control group. However, suppression of bodyweight gain and food consumption and a decrease in the mean weights of testis and epididymis occurred in male rats at the 2.5 mmol/kg dose.
In a separate experiment, 16 daily intravenous injections were administered to male rats. At a dose of 5 mmol/kg of dimeglumine gadopentetate, spermatogenic cell atrophy was observed. This atrophy was not reversed within a 16 day observation period following the discontinuation of the drug. This effect was not observed at a dose of 2.5 mmol/kg.

Use in pregnancy.

(Category B2)
Dimeglumine gadopentetate has been shown to retard development slightly in rats when given in doses of 0.25 mmol/kg and in rabbits when given in doses of 0.75 mmol/kg and 1.25 mmol/kg. The drug did not exhibit this effect in rabbits when given in doses of 0.25 mmol/kg. No congenital anomalies were noted in either species. The potential risk for humans is unknown.
There are no adequate and well controlled studies in pregnant women. Magnevist injection should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Use in lactation.

Patients receiving Magnevist injection should be instructed to inform their physician if they are pregnant or if they are breastfeeding.
Intravenous administration of Magnevist to 18 lactating women with normal renal function demonstrated that most probably, gadopentetic acid-dimeglumine salt is excreted in human milk. Analysis of milk samples (n = 18) indicated excretion of Magnevist equivalent to 0.052 to 3 micromol of gadolinium during a 24 hour period. This led to excretion of a maximum of 0.04% of the administered gadolinium dose into the breast milk during a 24 hour period (overall duration of excretion not studied). There is evidence from nonclinical data in rats that indicate the absorption via the gastrointestinal tract is poor; however, the extent of the absorption of dimeglumine gadopentetate in infants and its effects on the breastfed child remains unknown. Caution should be exercised when Magnevist is administered to a nursing mother.

Paediatric use.

Safety and effectiveness of Magnevist injection in children, including neonates and infants, has been established in the evaluation of lesions within the brain and spine. However, caution should be exercised with neonates and infants up to 1 year of age, due to their immature renal function.

Use in the elderly.

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

Genotoxicity.

Dimeglumine gadopentetate did not evoke any evidence of mutagenic potential in a number of in vivo and in vitro tests.

Carcinogenicity.

In a tumourigenicity study in which rats were administered up to 15 intravenous doses of dimeglumine gadopentetate 0.5 mmol/kg/day over 3 weeks, and observed for 1 or 2 years, no compound related tumours were observed.

Effect on laboratory tests.

Transitory changes in serum iron and bilirubin levels have been reported in patients with normal and abnormal liver function (see Precautions, General).

Interference with diagnostic tests.

Serum iron determination using methods measuring complexes (e.g. bathophenanthroline) may result in falsely low values for up to 24 hours after the administration of Magnevist due to the free DTPA contained in Magnevist.

Effect on ability to drive or use machines.

Not known.

Interactions

No interaction studies with other medicinal products have been conducted.

Adverse Effects

The overall safety profile of Magnevist is based on data from postmarketing surveillance and from more than 11,000 patients in clinical trials.
The most frequently observed adverse drug reactions in patients receiving Magnevist in clinical trials are: various injection site reactions, headache, nausea, dizziness, vomiting, dysgeusia.
Most of the adverse drug reactions in the clinical trials were of mild to moderate intensity.
Overall, the most serious adverse drug reactions in patients receiving Magnevist are:
nephrogenic systemic fibrosis;
anaphylactoid reactions/ anaphylactoid shock.
Delayed hypersensitivity/ anaphylactoid reactions (hours later up to several days) have been observed rarely (see Precautions, Hypersensitivity reactions). Severe and life threatening reactions as well as deaths have been reported.
Localised pain and vomiting occurred in less than 2% of the patients.

Adverse drug reactions from clinical trial data.

Adverse drug reactions observed with Magnevist in clinical trials are listed below. They are classified according to System Organ Class (MedDRA version 12.1). The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.
Adverse drug reactions from clinical trials are classified according to their frequencies. Frequency groupings are defined according to the following convention: uncommon ≥ 1/1,000 to < 1/100; rare ≥ 1/10,000 to < 1/1,000.

Immune system disorders.

Rare: hypersensitivity/ anaphylactoid reaction (e.g. anaphylactoid shock*, conjunctivitis, throat tightness*, sneezing, urticaria, pruritus, rash, erythema, dyspnoea*, wheezing, oedema face*).

Psychiatric disorders.

Rare: disorientation.

Nervous system disorders.

Uncommon: dizziness, headache, dysgeusia.
Rare: convulsion*, paraesthesia, burning sensation, tremor.

Cardiac disorders.

Rare: tachycardia*, arrhythmia.

Vascular disorders.

Rare: thrombophlebitis, flushing, vasodilatation.

Respiratory, thoracic and mediastinal disorders.

Rare: Throat irritation, pharyngolaryngeal pain/ pharynx discomfort, cough.

Gastrointestinal disorders.

Uncommon: vomiting, nausea.
Rare: abdominal pain, stomach discomfort, diarrhoea, toothache, dry mouth, oral soft tissue pain and paraesthesia.

Musculoskeletal, connective tissue and bone disorders.

Rare: pain in extremity.

General disorders and administration site conditions.

Uncommon: pain, feeling hot, feeling cold, injection site reactions (e.g. injection site coldness, paraesthesia, swelling, warmth, pain, oedema, irritation, haemorrhage, erythema, discomfort).
Rare: chest pain, pyrexia, oedema peripheral, malaise, fatigue, thirst, asthenia.
*Life threatening and/or fatal cases have been reported.

Adverse drug reactions from postmarketing experience.

Adverse drug reactions identified only during postmarketing surveillance (spontaneous reporting) are listed below by system organ class (MedDRA), frequency not known.

Blood and lymphatic system disorders.

Iron serum increased*.

Immune system disorders.

Hypersensitivity/ anaphylactoid reactions (e.g. anaphylactoid reaction*, hypersensitivity reactions*, shock*, hypotension*, loss of consciousness*, respiratory arrest*, bronchospasm*, laryngospasm*, laryngeal oedema*, pharyngeal oedema*, cyanosis*, rhinitis, angioedema*, reflex tachycardia).

Psychiatric disorders.

Agitation, confusion.

Nervous system disorders.

Coma*, somnolence*, speech disorder, parosmia.

Eye disorders.

Visual disturbance, eye pain, lacrimation.

Ear and labyrinth disorders.

Hearing impaired, ear pain.

Cardiac disorders.

Cardiac arrest*, heart rate decreased/ bradycardia*.

Vascular disorders.

Syncope*, vasovagal reaction, blood pressure increased.

Respiratory, thoracic and mediastinal disorders.

Respiratory distress, respiratory rate increased or respiratory rate decreased, pulmonary oedema*.

Gastrointestinal disorders.

Salivation.

Hepatobiliary disorders.

Blood bilirubin increased, hepatic enzyme increased.

Skin and subcutaneous tissue disorders.

Nephrogenic systemic fibrosis (NSF)*.

Musculoskeletal, connective tissue and bone disorders.

Back pain, arthralgia.

Renal and urinary disorders.

Acute renal failure*, **, increased serum creatinine**, urinary incontinence, urinary urgency.

General disorders and administration site conditions.

Chills, sweating, body temperature increased or body temperature decreased, injection site reactions (e.g. necrosis, thrombophlebitis, phlebitis, inflammation, extravasation).
*Life threatening and/or fatal cases have been reported.
**In patients with pre-existing renal impairment.
In patients with dialysis dependent renal failure who received Magnevist, delayed and transient inflammatory-like reactions such as fever, chills and C-reactive protein increase have been observed commonly. These patients had the MRI examination with Magnevist on the day before haemodialysis.

Dosage and Administration

Method of administration.

Magnevist is to be administered only by intravenous injection.
The safety rules customary for MRI must be observed, e.g. exclusion of cardiac pacemakers, ferromagnetic implants.
Magnevist is for use as a single dose in one patient only. Discard any remaining content.
For additional information see Instructions for use and handling.

Dosage regimen.

Cranial and spinal MRI.

The lowest effective dose should be used.
The recommended dosage of Magnevist injection in both adults and children is 0.2 mL/kg (0.1 mmol/kg), administered intravenously, at a rate not to exceed 10 mL/minute. (See Table 1.)
If a strong clinical suspicion of a lesion persists despite a normal contrast enhanced MRI, a further injection of Magnevist 0.2 mL/kg or, in adults, even of 0.4 mL/kg bodyweight within 30 minutes, immediately following MRI, may increase the diagnostic yield of the examination.
For the exclusion of metastases or recurrent tumours in adults the injection of Magnevist 0.6 mL/kg bodyweight often leads to higher diagnostic confidence.

Maximum single dose.

Magnevist 0.6 mL/kg (for adults) or 0.4 mL/kg (for children) bodyweight.

Whole body MRI.

The lowest effective dose should be used.
In general, the administration of Magnevist 0.2 mL/kg bodyweight is sufficient for good opacification and to answer the clinical question.
In special cases, e.g. in lesions with poor vascularisation and/or a small extracellular space, Magnevist 0.4 mL/kg bodyweight may be necessary for an adequate contrast effect especially on use of relatively slightly T1-weighted scanning sequences.
To ensure complete injection of the contrast medium, the injection should be followed by a 5 mL normal saline flush. The imaging procedure should be completed within 1 hour of injection of Magnevist injection.

Maximum single dose.

Magnevist 0.6 mL/kg (for adults) or 0.4 mL/kg (for children) bodyweight.

Children (under two years).

Limited experience in whole body MRI.

Instructions for use and handling.

Parenteral products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit. Magnevist should not be used in case of severe discolouration, the occurrence of particulate matter or a defective container.
In children below two years of age the required dose should be administered manually and not in combination with an autoinjector to avoid injury.

Vials.

Magnevist 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 examination. 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.

Large volume containers.

In addition, the following applies to use of the infusion bottle containing 100 mL.
The contrast medium must only be administered by means of an approved procedure which ensures sterility of the contrast medium. If using a device, instructions of the device manufacturer must be followed.
Unused Magnevist in opened containers must be discarded at the end of the examination day.

Incompatibilities.

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

Overdosage

There is currently no information on the clinical consequences of Magnevist overdosage. In case of inadvertent overdose, renal function should be monitored in patients with renal impairment.
Magnevist can be removed from the body by haemodialysis (see Precautions).
For information on the management of overdose to contact the Poisons Information Centre on 131 126 (Australia) for recommendations on the treatment and management of overdosage.

Presentation

Magnevist injection is a clear, colourless to slightly yellow solution containing 469 mg/mL of dimeglumine gadopentetate as active ingredient.
Magnevist is registered in glass vials, prefilled syringes and bottle as:
15 mL* and 20 mL* glass vials, packs of 1; 10 mL and 30 mL glass vials, packs of 1* or 10; 100 mL glass bottles*, packs of 1; 10 mL, 15 mL and 20 mL* prefilled glass syringes, packs of 5.
Magnevist is also available in plastic prefilled syringes* as: 10 mL and 15 mL prefilled plastic syringes, packs of 5.
* Not all pack sizes are marketed for the both the glass and plastic presentations.

Storage

Magnevist injection should be stored at controlled room temperature below 30°C. Do not freeze. Magnevist is sensitive to light when packed in the glass presentations. Keep the container in the outer carton to protect from light. Avoid exposure to secondary X-rays.
Protect from secondary X-rays and do not freeze in the plastic prefilled syringe.

Poison Schedule

Unscheduled.