Consumer medicine information

Dotarem

Gadoteric acid

BRAND INFORMATION

Brand name

Dotarem

Active ingredient

Gadoteric acid

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Dotarem.

WHAT IS IN THIS LEAFLET

This leaflet provides only a summary of the information known about DOTAREM. It does not contain all the available information. It does not take the place of talking to your doctor or health care professional.

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

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

If you have any questions, want to know more about DOTAREM or are unsure about anything, ask your specialist or radiologist.

Keep this leaflet. You may need to read it again.

Remember that this injection is only for you. Only a doctor can prescribe it for you.

WHAT DOTAREM IS USED FOR

DOTAREM contains gadoteric acid, which is made from gadolinium oxide (a magnetic agent) and DOTA, which binds with the gadolinium oxide to make a contrast agent to help diagnosis in MRI (magnetic resonance imaging).

This is injected into your veins just before a MRI examination.

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.

BEFORE YOU ARE GIVEN DOTAREM

When you must not be given it

You must not be given DOTAREM if you have:

  • ever had an allergic (hypersensitive) reaction to the active substance, gadoteric acid, or to the other ingredients in DOTAREM. Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.
  • any metallic foreign objects in your body such as a pacemaker or vascular clips. Before the examination, remove all metallic objects that you wear. This is very important because metals could cause serious disorders, since MRI machines use very strong magnetic fields.

Before you are given it

Tell your doctor know if you are allergic to any other medicines or any foods, dyes or preservatives.

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

  • bronchial asthma
  • very poor kidney function or severe kidney problems
  • you have had or will soon have a liver transplant
  • a low threshold for seizures
  • any allergies (e.g. seafood allergy, hayfever, hives)
  • Severe heart and circulatory disorders

There have been reports of a serious disease called nephrogenic systemic fibrosis (NSF) in kidney disease and liver transplant patients when they have used these types of products.

Tell your doctor if you are pregnant, breast feeding or if you are likely to become pregnant shortly.

Taking other medicines

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

Some medicines may interfere with DOTAREM. These include medicines used to treat hypertension.

HOW DOTAREM IS GIVEN

How much is given

The doctor will determine the lowest effective dose that you will receive and will supervise the injection. The usual dose for adults, children and infants is 0.2 mL/kg.

How it is given

DOTAREM will be given to you as a single intravenous injection. You will be monitored for any side effects for at least 30 minutes after the injection.

When opened, this product should be used once only and any residue discarded.

If you are given too much (overdose)

As you will be administered the injection under the supervision of your doctor in a hospital, it is highly unlikely that you will be given too much.

However, if you experience any side effects after being given DOTAREM Injection, tell your doctor or nurse immediately. You may need urgent medical attention.

Also, immediately tell the doctor or 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 a child or anyone else may have been given too much DOTAREM. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

AFTER HAVING DOTAREM

Things you must do

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

Things to be careful of

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

SIDE EFFECTS

DOTAREM, like most other medicines and diagnostic agents can cause side effects in some people. These side effects can sometimes be serious but they are usually mild to moderate and short-lasting.

Most side effects occur during injection or during the first hour after the injection. Some side effects may appear several days after the injection of DOTAREM.

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

The most common side effects during administration of DOTAREM include headache, dizziness, changes to taste, tingling sensation, sensation of warmth or cold and/or pain at the injection site, nausea, vomiting, hypertension, hypotension, abdominal pain and mild allergic reactions (usually affecting the skin such as rash and itchiness).

There is a small risk that you may have an allergic reaction to DOTAREM. Such reactions can be severe and result in shock (case of allergic reaction that could put your life in danger). The following symptoms may be the first signs of a shock. Inform your doctor, radiologist or health professional immediately if you feel any of them:

  • swelling of the face, mouth or throat which may cause you difficulties in swallowing or breathing
  • swelling of hands or feet
  • lightheadedness (hypotension)
  • breathing difficulties
  • whistling respiration
  • coughing
  • itching
  • runny nose
  • sneezing
  • eye irritation
  • hives
  • skin rash

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

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

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

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

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

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

There have been reports of nephrogenic systemic fibrosis (which causes hardening of the skin and may affect also soft tissue and internal organs), most of which were in patients who received DOTAREM together with other gadolinium-containing contrast agents. If, during the weeks following the MRI examination, you notice changes in the colour and/or thickness of your skin in any part of your body, inform the radiologist who performed the examination

AFTER USING IT

Storage

As this is being given to you by your doctor, it is extremely unlikely that you will be expected to look after the injection. However, in the case that you may have to transport it from the pharmacy to your doctor, it is important to store it in a safe place, away from light, where the temperature stay below 30°C. The pre-filled DOTAREM syringes should not be frozen.

Do not use DOTAREM if the packaging is torn or shows signs of tampering or after the expiry date printed on the label.

Keep all medicines in a safe place where children cannot reach them. They may be dangerous to children.

PRODUCT DESCRIPTION

What it looks like

DOTAREM is a clear, colourless to yellow solution available in a glass vial or glass or plastic pre-filled syringe intended for intravenous injection.

DOTAREM contains gadoteric acid 279.32 mg/mL. It also contains the inactive ingredients meglumine and water for injections.

DOTAREM is registered in packs of 1 glass vial, with volume fill of 5 mL, 10 mL, 15 mL and 20 mL.

DOTAREM is registered in packs of 1 glass pre-filled syringe, with volume fill of 10 mL, 15 mL and 20 mL.

DOTAREM is registered in packs of 10 plastic pre-filled syringes, with volume fill of 10 mL, 15 mL and 20 mL.

The Australian Registration numbers are:

20 mL vial - AUST R 76923

15 mL vial - AUST R 76924

10 mL vial - AUST R76925

5 mL vial - AUST R 76926

20 mL PFS - AUST R 160800

15 mL PFS - AUST R 160799

10 mL PFS - AUST R 160798

SPONSOR

Guerbet Australia Pty Ltd
166 Epping Road, Level 2
Lane Cove, NSW,
2066 Australia.
Telephone: 1800 859 436
Email: [email protected]

This leaflet was revised in August 2020.

Published by MIMS November 2020

BRAND INFORMATION

Brand name

Dotarem

Active ingredient

Gadoteric acid

Schedule

Unscheduled

 

1 Name of Medicine

Gadoteric acid.

2 Qualitative and Quantitative Composition

Dotarem (gadoteric acid) paramagnetic contrast media for magnetic resonance imaging (MRI).
Each vial or pre-filled syringe contains the active ingredient gadoteric acid 279.32 mg/mL (equivalent to 0.5 mmol/mL). Gadoteric acid is a complex of the paramagnetic ion gadolinium oxide 90.62 mg/mL with DOTA (1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) 202.46 mg/mL.

Chemical characteristics of the formulation.

Osmolality: 1350 mOsm.kg-1.
Viscosity at 20°C: 3.2 mPa.s.
Viscosity at 37°C: 2.0 mPa.s.
pH: 6.5 - 8.0.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Dotarem is a clear, colourless to yellow solution available in vials or pre-filled syringes intended for intravenous injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Dotarem is indicated, in adults and children, for use with magnetic resonance imaging to provide contrast enhancement for intracranial and spinal lesions with abnormal blood brain barrier or abnormal vascularity, and for whole body imaging (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

The lowest effective dose should be used. The dose should be calculated based on the patient's body weight and should not exceed the recommended dose per kilogram of body weight detailed in this section.

Adults (≥ 18 years).

The maximum recommended dose is 0.1 mmol/kg, i.e. 0.2 mL/kg for adults.

Paediatrics (0 to 18 years).

The maximum recommended dose is 0.1 mmol/kg, i.e. 0.2 mL/kg for children and infants.

Method of administration.

Dotarem is intended for intravenous administration only.
Volumes required for doses of 0.1 mmol/kg are shown in Table 1.
If Dotarem is drawn into a disposable syringe, it should be used immediately.
Dotarem is for one dose in one patient only. Discard any remaining contents.
Intravascular administration of contrast media should be, if possible, be done with the patient lying down. After administration, the patient must be kept under observation for at least 30 minutes, as the majority of serious adverse reactions occur during this period.

Dosage adjustment.

Paediatrics (0-18 years).

Depending on the amount of Dotarem to be given to the child, it is preferable to use Dotarem vials with a single use syringe of a volume adapted to this amount in order to have a better precision of the injected volume.
In neonates and infants the required dose should be administered by hand.
Due to immature renal function in neonates up to 4 weeks of age and infants up to 1 year of age, Dotarem should only be used in these patients after careful consideration, at a dose not exceeding 0.1 mmol/kg body weight. Due to the lack of information on repeated administration, Dotarem injections should not be repeated unless the interval between injections is at least 7 days.

Renal impairment and liver transplant patients.

The adult dose applies to patients with mild to moderate renal impairment (GFR ≥ 30 mL/min/1.73 m2). Dotarem should only be used in patients with severe renal impairment (GFR < 30 mL/min/1.73 m2) and in patients in the perioperative liver transplantation period after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI (see Section 4.4 Special Warnings and Precautions for Use).
If it is necessary to use Dotarem, the dose should not exceed 0.1 mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, Dotarem injections should not be repeated unless the interval between injections is at least 7 days.

Elderly.

No dosage adjustment is considered necessary. Caution should be exercised in elderly patients (see Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

The adult dose applies to these patients. Caution is recommended, especially in the case of perioperative liver transplantation period.

4.3 Contraindications

Hypersensitivity to gadoteric acid, meglumine or any products containing gadolinium.
Contraindications related to magnetic resonance imaging: patients with pacemakers, patients with ferromagnetic vascular clips, infusion pumps, nerve stimulators, cochlear implants, or suspected intracorporal metallic foreign bodies, particularly in the eye.

4.4 Special Warnings and Precautions for Use

Warning: nephrogenic systemic fibrosis.

Gadolinium based contrast agents increase the risk for 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.

Severe renal impairment and liver transplant patients.

There have been reports of nephrogenic systemic fibrosis (NSF) associated with use of some gadolinium-based contrast agents (GBCAs) in patients with acute or chronic severe renal impairment (a glomerular filtration rate < 30 mL/min/1.73 m2) and patients with acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period. As there is a possibility that NSF may occur with gadoteric acid, it should only be used in patients with severe renal impairment and in patients with perioperative liver transplantation after careful risk/benefit assessment and if the diagnostic information is essential and not available with non-contrast enhanced MRI.
Haemodialysis shortly after gadoteric acid administration may be useful at removing gadoteric acid from the body.
NSF is a debilitating and sometimes fatal disease affecting the skin, muscle, and internal organs.
Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests.
When administering a GBCA, do not exceed the dose recommended in the product labelling. Allow sufficient time for elimination of the GBCA prior to any re-administration.

Warnings.

Caution should be exercised in patients suffering from severe renal failure. There is no clinical data concerning the elimination of gadoteric acid in patients with renal failure requiring dialysis.
Do not use by intrathecal route. For intravenous injection only.
In the event of extravasation, local intolerance reactions may be observed necessitating short term local treatment.
Diagnostic procedures involving the use of MRI contrast agents should be conducted under supervision of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reaction to the contrast itself.
The possibility of a reaction, including serious, life threatening, fatal anaphylactoid or cardiovascular reactions or other idiosyncratic reactions should always be considered (see Section 4.8 Adverse Effects (Undesirable Effects)) especially in patients with a history of hypersensitivity.

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.

Central nervous system disorders.

Like with other GBCAs special precaution is necessary in patients with a low threshold for seizures. Precautionary measures should be taken, e.g. close monitoring. All equipment and therapies necessary to counter any convulsions which may occur must be made ready for use beforehand.

Hypersensitivity.

As with other GBCAs, hypersensitivity reactions can occur including life threatening (see Section 4.8 Adverse Effects (Undesirable Effects)). Hypersensitivity reactions may be either allergic (described as anaphylactic reactions when serious) or non allergic. They can be either immediate (less than 60 minutes), or delayed (up to 7 days). However, as with other contrast media of this class, the occurrence of delayed reactions up to several days cannot be excluded. Anaphylactic reactions occur immediately and can be fatal. They are independent of the dose, can occur after even the first dose of the product and are often unpredictable.
There is always a risk of hypersensitivity regardless of the dose injected.
Patients with hypersensitivity or who have already experienced a reaction during previous administration of a gadolinium-containing MRI contrast media present an increased risk of experiencing another reaction on subsequent administration of the same product, or possibly other products, and are therefore considered to be at high risk.
As known from the use of iodinated contrast media, hypersensitivity reactions can be aggravated in patients on beta-blockers, and particularly in the presence of bronchial asthma. These patients may be refractory to standard treatment of hypersensitivity reactions with beta-agonists.
The injection of Dotarem may aggravate symptoms of an existing asthma. In patients with asthma unbalanced by the treatment, the decision to use Dotarem must be made after careful evaluation of the risk-benefit ratio.
Before any contrast media is injected, the patient should be questioned for a history of allergy (e.g. seafood allergy, hay fever, hives), sensitivity to contrast media and bronchial asthma as the reported incidence of adverse reactions to contrast media is higher in patients with these conditions and premedication with antihistamines and/or glucocorticoids may be considered. In such patients, the decision to use Dotarem must be made after careful evaluation of the risk-benefit ratio.
During the examination, supervision by a physician is necessary. If hypersensitivity reactions occur, administration of Dotarem must be discontinued immediately and, if necessary, specific therapy instituted. A venous access should thus be kept during the entire examination. To permit immediate emergency countermeasures, appropriate therapies (e.g. epinephrine and antihistamines), an endotracheal tube and a respirator should be ready at hand.

Use in the elderly.

As the renal clearance of gadoteric acid may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction.

Paediatric use.

Neonates and infants.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interactions with other medicinal products have been observed. Formal interaction studies have not been carried out.

Concomitant medications to be taken into account.

Beta-blockers, vasoactive substances, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists: these medicinal products decrease the efficacy of the mechanisms of cardiovascular compensation for blood pressure disorders. The radiologist must be informed before injection of gadolinium complexes and resuscitation equipment must be at hand.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Gadoteric acid had no effects on the reproduction and fertility of male or female rats at repeat doses up to 1.6 mmol/kg/day, or approximately 2.6 times the clinical dose, adjusted for body surface area. No peri-postnatal toxicity studies have been conducted with gadoteric acid in animals.
The safety of gadoteric acid in human pregnancy has not been demonstrated. Administration during pregnancy should be avoided unless absolutely necessary.
Following administration of an intravenous dose of gadoteric acid to rats on gestation day 18, the maximum total fetal concentration of gadolinium was 5% of the maternal plasma concentration, and the maximum quantity of gadolinium in the whole litter was 0.07% of the total dose.
Teratology studies in which rats and rabbits were administered gadoteric acid at an intravenous dose up to 0.8 mmol/kg/day, or approximately 1.3 times (rats) or 2.4 times (rabbits) the clinical dose, adjusted for body surface area, showed no evidence of embryotoxicity or teratogenicity. In the rat study, bodyweights of high-dose offspring were reduced up to mid-lactation, but subsequent mating performance and fertility were unaffected.
 No studies have been carried out concerning the passage of gadoteric acid into human breast milk. If an investigation is indicated during lactation, it is advisable that lactation woman discard their milk for the 24 hours following administration.
In goats administered an intravenous dose of gadoteric acid, excretion in milk accounted for 0.02% of the total dose, and gadoteric acid excretion was only detectable during the first 24 hours.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. Ambulant patients while driving vehicles or operating machinery should take into account that nausea may incidentally occur.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial.

Table 2 shows the adverse experiences reported among patients in controlled clinical trials of intravenous gadoteric acid, in the management of brain, spine and whole body pathologies.
Adverse reactions are presented in Table 2 by system organ class and by frequency according to the following categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) not known (cannot be estimated from the available data).
Table 3 shows the adverse event experience reported in a study which compared gadoteric acid and dimeglumine gadopentetate in imaging of brain and spine pathologies. The adverse events reported in subjects who received gadoteric acid are also included in the adverse experiences reported in Table 2.

Post-marketing experience.

Since post-marketing, the most commonly reported adverse reactions following administration of Dotarem are nausea, vomiting, pruritus and hypersensitivity reactions.
In hypersensitivity reactions, the reactions most frequently observed are skin reactions, which can be localised, extended or generalised. These reactions are usually immediate (during the injection or within one hour after the start of injection) or sometimes delayed (one hour to several days after injection), presenting as skin reactions.
Immediate reactions include one or more effects which appear simultaneously or sequentially, which are most often cutaneous, respiratory, gastrointestinal, articular and/or cardiovascular reactions.
Each sign may be a warning sign of a shock starting, however, it is very rarely fatal.
Rare anaphylactoid reactions have been reported that may be very rarely severe, life threatening or have a fatal outcome, particularly in patients with a history of allergy. These allergic reactions can occur irrespective of the amount administered and the mode of administration and may take the form of one or more of the following symptoms: Angioedema, anaphylactic shock, circulatory and cardiac arrest, hypotension, larynx oedema, bronchospasm, laryngospasm, pulmonary oedema, dyspnoea, stridor, coughing, pruritus, rhinitis, sneezing, conjunctivitis, urticaria and rash. Some of these symptoms may be the first signs of incipient state of anaphylactic shock.
Isolated cases of nephrogenic systemic fibrosis (NSF) have been reported with gadoteric acid, most of which were in patients co-administered other GBCAs (see Section 4.4 Special Warnings and Precautions for Use).
The following adverse reactions were reported with other intravenous contrast agents for MRI.

Adverse reaction in paediatrics.

Safety of paediatric patients was considered in clinical trials and post-marketing studies. As compared to adult, the safety profile of gadoteric acid did not show any specificity in children. Most of reactions are gastrointestinal symptoms or signs of hypersensitivity.

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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience to date of overdose with gadoteric acid.
Gadoteric acid can be removed by haemodialysis. However, there is no evidence that haemodialysis is suitable for prevention of nephrogenic systemic fibrosis (NSF).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Gadoteric acid has paramagnetic properties which increase contrast enhancement in MRI. The presence of seven (7) unpaired electrons in the gadolinium outer shell explains that this ion has a high magnetic moment and thus a strong paramagnetic effect. Gadoteric acid shortens the longitudinal relaxation time (T1) and the transverse relaxation time (T2) of water protons in tissues where it is distributed. At clinical doses the major effect is on T1 relaxation time. This results in an increased signal intensity in T1-weighted sequences and allows a better visualisation of abnormal structures or lesions.
Gadoteric acid has no specific pharmacodynamic activity and is biologically inert.

Clinical trials.

Two randomised, double blind studies compared diagnostic information from gadoteric acid and dimeglumine gadopentetate, both administered at 0.1 mmol/kg, in enhancement of MRI of intracranial and spinal lesions. A total of 319 adult patients with CNS or spinal pathology were enrolled in the two studies. Efficacy was evaluated by comparison of pre- and post-contrast MRI by investigators. Diagnostic efficacy scores (diagnostic quality, diagnostic consequences and management consequences) were similar in the two treatment groups.
Open label clinical studies evaluated the pre- and post-contrast diagnostic efficacy of gadoteric acid in MRI of histologically confirmed primary and secondary liver tumours, bone and soft tissue tumours, uterine and ovarian tumours and local recurrence of breast cancers.
Three open label studies evaluated the efficacy and safety of 0.1 mmol/kg gadoteric acid in pediatric populations. A total of 99 children, in the age range 0.04 to 17 years, were evaluated who required neurological examination by MRI. Only one child aged less than one month received gadoteric acid. There is limited information in children (n = 9) aged less than 2 years.

5.2 Pharmacokinetic Properties

After intravenous injection, gadoteric acid is distributed in the extracellular fluid of the body. It does not bind with plasma albumin.
Current evidence suggests that gadolinium accumulates in the brain after repeated administrations of GBCAs although the exact mechanism of gadolinium passage into the brain has not been established.
In patients with normal renal function, the plasma half-life is approximately 90 minutes. The volume of distribution is approximately 0.25 L/kg, the plasma clearance rate is approximately 0.1 L/h/kg and about 90% of the product is excreted in urine in 24 hours. It is eliminated by glomerular filtration in unchanged form. Plasma clearance is decreased to 0.036 L/h/kg in moderate renal failure and to 0.012 L/h/kg in severe renal failure.

5.3 Preclinical Safety Data

Animal toxicity.

The acute toxicity of gadoteric acid injected intravenously (2 mL min-1) was studied in mice (at doses between 8 and 13 mmol/kg) and in rats (at a dose of 12.6 mmol/kg). Clinical signs of toxicity were convulsions and transient respiratory disorders. Deaths occurred in the two studies, in mice from a dose of 9 mmol/kg upwards, or approximately 7 times the clinical dose (20 times in rats), adjusted for body surface area. Necropsy revealed a haemorrhagic appearance in the lungs and sometimes in the kidney. In studies of the proconvulsive potential of gadoteric acid, and intravenous dose up to 8 mmol/kg had no convulsive effects in mice, but an intravenous dose of 4 mmol/kg in mice, or an intracisternal dose of 1 or 2 micromol in rats, slightly potentiated the convulsive effects of a subthreshold dose of picrotoxin. In toxicity studies, rats and dogs administered gadoteric acid for 28 days at daily intravenous doses up to 1.5 mmol/kg, or approximately 2.4 times and 8 times, respectively, the clinical dose, adjusted for body surface area, caused vacuolisation of the proximal tubular cells of the kidney. This effect was fully reversible in dogs, and partly reversible in rats, over a 28-day recovery period.

Genotoxicity.

Gadoteric acid was not mutagenic in Salmonella typhimurium, nor in Chinese hamster V79 cells, and did not induce chromosomal aberrations in Chinese hamster ovary cells in vitro, with or without metabolic activation. Gadoteric acid did not induce micronuclei in mice following an intravenous dose of up to 3.5 mmol/kg.

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Meglumine, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Glass vials.

Store below 30°C.

Glass pre-filled syringes.

Store below 30°C. Protect from light. Do not freeze.

Plastic pre-filled syringes.

Store below 30°C. Do not freeze.

6.5 Nature and Contents of Container

Glass vials.

5 mL, 10 mL, 15 mL, 20 mL in packs of 1.
Type II clear glass vials of 10 mL (filled to 5 mL or 10 mL) and 20 mL (filled to 15 mL or 20 mL), sealed with a stopper of chlorobutyl rubber and crimped with an aluminium cap.

Glass pre-filled syringes.

10 mL, 15 mL and 20 mL in packs of 1.
Type I clear glass syringes of 10 mL (filled to 10 mL) and 20 mL (filled to 15 mL or 20 mL) graduated per mL, without a needle, with a rubber latex-free plunger and capped with a latex free rubber tip.

Plastic pre-filled syringes.

10 mL, 15 mL and 20 mL in packs of 1 and 10.
Polypropylene plastic syringes of 20 mL (filled to 10 mL, 15 mL or 20 mL) graduated per mL, without a needle, with a rubber latex-free plunger and capped with a latex-free rubber tip.
Note: Not all presentations may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

The structural formula of gadoteric acid is:

CAS number.

The CAS Registry Number is 72573-82-1.

7 Medicine Schedule (Poisons Standard)

Not scheduled.

Summary Table of Changes