Gadoxetic Acid, Disodium

Registered South African indications:

• T1-weighted magnetic resonance imaging (MRI) of the liver

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions
South African manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
  - Acute or chronic severe renal impairment (GFR<30ml/min/1.73m²)
  - Acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period
• Severe cardiovascular problems
• Existing cardiac conductance disorders
• Previous reaction to contrast media 
• History of bronchial asthma 
• History of allergic disorders
• Coadministration with beta-blockers, particularly with existing bronchial asthma (See additional prescribing points)
• Controlled sodium diet

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Renal impairment
  - Chronic severe renal impairment (GFR<30ml/min/1.73m²)
  - Perioperative liver transplantation period
• Elderly
• Severe cardiovascular problems
  - Uncorrected hypokalemia
  - Known congenital long QT syndrome or a family history of congenital long QT syndrome
  - Known previous arrhythmias when on agents that prolong cardiac repolarisation
  - Coadministration with an agent that is known to prolong cardiac repolarisation e.g. a class III antiarrhythmic, (e.g. amiodarone, sotalol)
• Presence of cardiac pacemakers and ferromagnetic implants
• Previous reaction to contrast media 
• History of bronchial asthma 
• History of allergic disorders
• Repeated use (See additional prescribing points)
• Coadministration with beta-blockers, particularly with existing bronchial asthma (See additional prescribing points)
• Controlled sodium diet

Forms avail. in SA and covered in this monograph: sol

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

T1-weighted magnetic resonance imaging (MRI) of the liver
- In dynamic and delayed imaging, for the improved detection of focal hepatic lesions (e.g. number, size, segmental distribution and visualisation) and to provide additional information regarding characterisation and classification of focal liver lesions, thus increasing diagnostic confidence

• IV: 0.1ml/kg, bolus (equivalent to 25µmol/kg)

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Intravenous administration only

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The usual safety rules for magnetic resonance imaging must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants

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Anaphylactoid/hypersensitivity or other idiosyncratic reactions occur within 30 minutes after administration of contrast media. Therefore, postprocedure observation of the patient is recommended

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Method of administration: See additional prescribing points

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International manufacturer recommendations

Detection of focal liver lesions and to provide information on the character of lesions in T1- weighted magnetic resonance imaging (MRI)

• IV: 0.1ml/kg, bolus

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The usual safety precautions for MRI must be observed, e.g. exclusion of cardiac pacemakers and ferromagnetic implants

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

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Should be used only when diagnostic information is essential and not available with unenhanced magnetic resonance imaging (MRI) and when delayed phase imaging is required

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Intravenous administration only

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The lowest dose that provides sufficient enhancement for diagnostic purposes should be used. The dose should be calculated based on the patient's body weight, and should not exceed the recommended dose per kilogram of body weight

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Method of administration: See additional prescribing points

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After the injection, the patient should be kept under observation for ≥30 minutes, since experience with contrast media shows that the majority of undesirable effects occur within this time

Not established for use in children below 18 years

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No dose adjustment according to age is necessary in paediatric patients (South African manufacturer recommendations)

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The safety and effectiveness of gadoxetic acid, disodium have not been established in premature infants (South African manufacturer recommendations)

Pregnancy
South African manufacturer recommendations

• Caution; not recommended
• For gadoxetic acid, disodium no clinical study data on exposed pregnancies are available
• Animal studies at clinically relevant doses have not shown reproductive toxicity after repeated administration. The potential risk for humans is unknown
• Gadoxetic acid, disodium should only be used during pregnancy if the clinical condition of the woman requires the use of gadoxetic acid, disodium

International manufacturer recommendations

• Caution; not recommended
• There are no data from the use of gadoxetic acid, disodium in pregnant women
• Animal studies have shown reproductive toxicity at repeated high doses
• Gadoxetic acid, disodium should not be used during pregnancy unless the clinical condition of the woman requires use of gadoxetic acid, disodium

Breastfeeding
South African manufacturer recommendations

• Caution 
• It is unknown whether gadoxetic acid, disodium is excreted in human milk
• There is evidence from non-clinical data that gadoxetic acid, disodium is excreted into breast milk in very small amounts (<0.5% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor (about 0.4% of the dose orally administered were excreted in the urine)
• At clinical doses, no effects on the infant are anticipated and gadoxetic acid, disodium can be used during breastfeeding

International manufacturer recommendations

• Caution 
• Gadolinium-containing contrast agents are excreted into breast milk in very small amounts
• At clinical doses, no effects on the infant are anticipated due to the small amount excreted in milk and poor absorption from the gut
• Continuing or discontinuing breastfeeding for a period of 24 hours after administration of gadoxetic acid, disodium should be at the discretion of the doctor and breastfeeding mother

Fertility
South African manufacturer recommendations

• Gadoxetic acid, disodium had no effect on fertility and general reproductive performance of male and female rats at doses 6.5 times (based on body surface area) or 40 times (based on body weight) the human single dose

International manufacturer recommendations

• Animal studies did not indicate impairment of fertility

Renal Impairment
South African manufacturer recommendations

• Caution; no dose adjustment recommended 
  In clinical studies, no overall differences in safety and efficacy were observed between patients with renal impairment and patients with normal kidney function. The elimination of gadoxetic acid, disodium is prolonged in renally impaired patients. To ensure diagnostically useful images, no dosage adjustment is recommended

International manufacturer recommendations

• GFR≥30ml/min/1.73m²: Caution; no dose adjustment recommended 
• GFR<30 ml/min/1.73m²: Caution; dose adjustment recommended 
  IV: 0.025mmol/kg, bolus
  Use of gadoxetic acid, disodium should be avoided in patients with severe renal impairment and in patients in the perioperative liver transplantation period unless the diagnostic information is essential and not available with non-contrast enhanced MRI
  If use of gadoxetic acid, disodium cannot be avoided, the dose should not exceed 0.025mmol/kg body weight. More than one dose should not be used during a scan. Because of the lack of information on repeated administration, gadoxetic acid, disodium injections should not be repeated unless the interval between injections is at least 7 days

Hepatic Impairment
South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations

• No dose adjustment recommended 

Elderly 
South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations

• Caution; no dose adjustment recommended 
  As the renal clearance of gadoxetic acid, disodium may be impaired in the elderly, it is particularly important to screen patients aged 65 years and older for renal dysfunction

Porphyria Information 

• Probably not porphyrinogenic (PNP) 

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Vertigo
• Dizziness
• Dysgeusia
• Paraesthesia
• Parosmia
• Tremor
• Akathisia
• Restlessness
• Malaise

Cardiovascular Disorders 

• Bundle branch block
• Palpitation
• Tachycardia
• Increased blood pressure
• Flushing
• Transient QT prolongation 

Respiratory Disorders 

• Dyspnoea
• Respiratory distress
• Chest pain

Gastrointestinal Disorders 

• Nausea and vomiting
• Dry mouth
• Oral discomfort
• Salivary hypersecretion

Hepatobiliary Disorders 

• Increased bilirubin
• Increased liver transaminases

Genitourinary Disorders

• Leukocyturia
• Increased urine albumin

Endocrine and Metabolic Disorders

• Hyperglycaemia

Musculoskeletal Disorders 

• Back pain

Skin and Subcutaneous Tissue Disorders 

• Rash
  - Maculopapular rash
• Pruritus
  - Generalized pruritus
  - Eye pruritus
• Hyperhidrosis
• Injection site reactions
  - Extravasation
  - Burning
  - Coldness
  - Irritation
  - Pain

Immune, Blood and Lymphatic System Disorders 

• Hypersensitivity/anaphylactoid reaction
  - Shock
  - Hypotension
  - Pharyngolaryngeal oedema
  - Urticaria
  - Face oedema
  - Rhinitis
  - Conjunctivitis
  - Abdominal pain
  - Hypoesthesia
  - Sneezing
  - Cough
  - Pallor 
• Chills
• Increased serum iron
• Decreased haemoglobin
• Hyponatraemia
• Leukocytosis
• Hypokalaemia
• Increased inorganic phosphate
• Increased lactate dehydrogenase (LDH)
• Decreased serum protein
• Increased amylase
• Nephrogenic systemic fibrosis (NSF)

Others

• Discomfort
• Feeling hot
• Feeling abnormal

Other interactions

• Increased bilirubin or ferritin levels (See additional prescribers points)
• Diagnostic tests (See additional prescribers points)

• Renal function (prior to administration)

Additional observations

• Signs of hypersensitivity (during and for several hours post-procedure)
• Injection site for extravasation
• Signs and symptoms of nephrogenic systemic fibrosis (NSF) (short- and long-term)
  - Burning
  - Itching
  - Swelling, hardening and/or tightening of skin
  - Joint stiffness
  - Deep hip or rib bone pain
  - Muscle weakness
  - Limited range of motion
  - Yellowed/raised spots on whites of eye

Administration directions

• Intramuscular administration must be strictly avoided, because it may cause local intolerance reactions, including focal necrosis, and should therefore be strictly avoided

Method of administration (South African manufacturer recommendations)

• Gadoxetic acid, disodium is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection. After injection of gadoxetic acid, disodium the intravenous cannula/line should be flushed using sterile physiological saline solution
• After bolus injection of gadoxetic acid, disodium, dynamic imaging during arterial, portovenous, and equilibrium phases utilizes the different temporal enhancement pattern of different liver lesion types to obtain information about their classification (benign/malignant) and the specific characterization. It further improves visualization of hypervascular liver lesions
• The delayed (hepatocyte) phase starts at about 10 minutes post-injection (in confirmatory studies most of the data were obtained at 20 minutes post-injection) with an imaging window lasting at least 120 minutes. The imaging window is reduced to 60 minutes in patients requiring haemodialysis and in patients with elevated bilirubin values (>3mg/dl) 
• The enhancement of liver parenchyma during the hepatocyte phase assists in the identification of the umber, segmental distribution, visualization, and delineation of liver lesions, thus improving lesion detection. The different enhancement/washout patterns of liver lesions contribute to the information from the dynamic phase. Hepatic excretion of gadoxetic acid, disodium results in enhancement of biliary structures

Method of administration (International manufacturer recommendations)

• Gadoxetic acid, disodium is a ready-to-use aqueous solution to be administered undiluted as an intravenous bolus injection at a flow rate of about 2ml/sec. After the injection of the contrast medium the intravenous cannula/ line should be flushed using sterile 9mg/ml (0.9%) saline solution

Increased bilirubin or ferritin levels

• Increased levels of bilirubin or ferritin can reduce the hepatic contrast effect of gadoxetic acid, disodium

Diagnostic tests

• Serum iron determination using complexometric methods (e.g. Ferrocine complexation method) may result in false values for up to 24 hours after the examination with gadoxetic acid, disodium because of the free complexing agent contained in the contrast medium solution

Hypersensitivity

• If hypersensitivity reactions occur, injection of the contrast medium must be discontinued immediately. It is advisable to use a flexible indwelling cannula for intravenous contrast medium administration in order to give instant specific therapy – if necessary. To permit immediate countermeasures to be taken in emergencies, appropriate drugs, an endotracheal tube and a respirator should be ready at hand

Renal impairment

• 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. A sufficient period of time for elimination of the contrast agent from the body prior to any re-administration in patients with renal impairment should be ensured
• Gadoxetic acid, disodium can be removed from the body by haemodialysis. About 30% of the administered dose is eliminated from the body by a single dialysis session of 3 hours starting 1-hour post-injection. In end-stage renal failure patients, gadoxetic acid, disodium was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, the majority within 3 days
• For patients already receiving haemodialysis at the time of gadoxetic acid, disodium administration, prompt initiation of haemodialysis following the administration of gadoxetic acid, disodium 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 some contrast agents containing gadolinium in patients with: acute or chronic severe renal impairment (GFR<30ml/min/1.73m²) or  acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period

Coadministration with beta-blockers

• Hypersensitivity reactions can be more intense in patients on beta-blockers, particularly in the presence of bronchial asthma. It should be considered that patients on beta-blockers may be refractory to standard treatment of hypersensitivity reactions with beta-agonists

Existing cardiac conductance disorders

• Patients with existing cardiac conductance disorders should be carefully monitored during and after procedures

Repeated use

• After administration of gadoxetic acid, disodium, gadolinium can be retained in the brain and in other tissues of the body (bones, liver, kidneys, skin) and can cause dose-dependent increases in T1-weighted signal intensity in the brain, particularly in the dentate nucleus, globus pallidus, and thalamus. Clinical consequences are unknown. The possible diagnostic advantages of using gadoxetic acid, disodium in patients who will require repeated scans should be weighed against the potential for deposition of gadolinium in the brain and other tissues

Gadoxetic acid, disodium is a paramagnetic contrast agent for magnetic resonance imaging. The contrast-enhancing effect is mediated by gadoxetate (Gd EOB DTPA), an ionic complex consisting of gadolinium (III) and the ligand ethoxybenzyl-diethylenetriamine-pentaacetic acid (EOB-DTPA). 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.

Solution (per ml) 181,43mg

• Primovist (Bayer) originator