Consumer medicine information

Visipaque

Iodixanol

BRAND INFORMATION

Brand name

Visipaque Injection

Active ingredient

Iodixanol

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Visipaque.

What is in this leaflet?

This leaflet answers some common questions about VISIPAQUE. It does not contain all the available information. It does not take the place of talking to your radiologist (the specialist doctor who does X-rays), doctor or pharmacist.

All preparations of this type have risks and benefits. Your radiologist and/or your doctor have weighed the risks of you receiving VISIPAQUE against the benefits they expect it will have for you.

If you have any concerns about being given this preparation, ask your radiologist, doctor or pharmacist.

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

What VISIPAQUE is used for

VISIPAQUE is one of a group of medicines known as “contrast media” for diagnostic use. VISIPAQUE is used to improve the clarity of X-ray images of the internal organs of the body by increasing the degree of contrast of different structures within the body.

VISIPAQUE is used to study the heart, veins and arteries in the body's circulatory system and the urinary tract.

VISIPAQUE is intended for use in hospitals and radiology clinics only and will be given to you as an injection. Your doctor may have prescribed VISIPAQUE for another reason. Ask your doctor if you have any questions about why VISIPAQUE has been prescribed for you.

How does VISIPAQUE work?

As VISIPAQUE flows through your blood vessels and organs, the Iodine in VISIPAQUE makes them appear darker during radiographic examinations. This makes them stand out on the X-ray film. This aids the doctor in identifying any problems with a particular organ.

Before you are given VISIPAQUE

When you must not be given it.

VISIPAQUE should not be given to you if:

  1. You have ever had an allergic reaction to VISIPAQUE or, to any of the ingredients listed at the end of this leaflet (see Product Description) or to any other contrast medium. Symptoms of an allergic reaction may include wheeziness, difficulty in breathing or tightness or pain in the chest, skin rash, swelling or itching.
  2. You have thyroid gland problems.
  3. The expiry date on the pack has passed. If you use it after the expiry date, it may have no effect at all, or worse, an entirely unexpected effect.

Before you are given it.

You must tell your doctor if:

  1. You are pregnant, intend to become pregnant or breast-feeding or plan to breast-feed. If you receive Visipaque whilst pregnant, your newborn should be tested to ensure they are producing the correct amount of thyroid hormone.
  2. You have, or have had, the following medical conditions:
  • Asthma
  • Allergies, for example hay fever or hives, or allergies to iodine-containing contrast media, any medicines or other substances, such as foods, preservatives or dyes.
  • Thyroid gland problems.
  • Sickle cell disease
  • Diabetes
  • Kidney and/or liver disease
  • Epilepsy
  • Problems with your body producing certain enzymes (homocystinuria)
  • Heart disease and/or circulatory system problems
  • Multiple myeloma (cancer of blood cells) and other blood problems (paraproteinaemia)
  • Phaeochromocytoma (a tumour which raises blood pressure).
  1. You plan to have surgery

If you have not told your doctor about any of the above, tell them before you are given VISIPAQUE.

Taking other medicines

Tell the doctor if you are taking any other medicines, including medicines you buy without a prescription from a pharmacy, supermarket or health food shop. Some medicines may interfere with VISIPAQUE. These include:

  • Biguanides (eg metformin) a medicine for diabetes. Your doctor may ask you not to take biguanides for 48 hours before receiving an injection of VISIPAQUE.
  • Medicines used to treat high blood pressure or irregular heart beats (Adrenergic beta-blockers)
  • Medicines used to treat cancer
  • Contrast agents for the study of the gall bladder and bile ducts
  • General anaesthetics

These medicines may interact or affect the way VISIPAQUE works. Your doctor or pharmacist has more information to be careful with or avoid when using VISIPAQUE.

How VISIPAQUE is used

You will be given VISIPAQUE before or during your X-ray examination. VISIPAQUE will be injected into a vein by a qualified person. The amount injected can vary depending on the type of examination used, your age and your weight.

If you receive an overdose

As VISIPAQUE will be administered by a qualified person familiar with the procedure, overdosage is unlikely. In the event of overdosage, qualified personnel will be equipped to handle such an occurrence.

While you are using VISIPAQUE

If you need to have a thyroid function test within the next 14 days after examination with VISIPAQUE, please tell your doctor before the test is done.

If you have any blood or urine tests on the day of your examination with VISIPAQUE, tell your doctor you are using VISIPAQUE. VISIPAQUE may affect the results of some laboratory tests.

If you are about to start on any new medicine within the next day or two, tell your doctor and pharmacist that you have been given VISIPAQUE.

If you plan to have surgery that needs general anaesthetic, tell your doctor or dentist that you have been given VISIPAQUE.

Tell all doctors, dentists and pharmacists who are treating you that you have been given VISIPAQUE.

Things to be careful of

Delayed reactions of iodine-containing dyes may occur.

If you feel light-headed, dizzy or faint as a result of the procedure, get up slowly when getting out of bed or standing up. Be careful if you are elderly, unwell or taking other medicines. Some people may experience side effects such as dizziness and unsteadiness as a result of the procedure, which may increase the risk of a fall.

Side effects

During and after your examination

Tell your doctor or healthcare worker as soon as possible if you do not feel well while you are being given, or after you have been given VISIPAQUE.

Usually, VISIPAQUE does not cause any serious side effects. It can, however, sometimes cause unwanted effects in some people. All medicines can have side effects. You may need medical treatment if you get some of the side effects during or after the procedure. Although there is a risk that you might get an unwanted effect, your doctor will have chosen this contrast medium by considering these risks and the benefits of the examination.

The type of side effect experienced may depend on the area of the body under examination.

The most frequent side effects are headache, nausea, changes in your sensation of taste, dizziness, rash, chest pain, itching and visual disturbances.

If you get any of the following during, or after, the examination:

  • swelling of the face, lips, mouth or throat which may cause wheeziness, difficulty in breathing or tightness, pain in the chest or changes in the way your heart beats
  • fainting
  • hives, lumps, swelling, itching throat or spots or other allergic symptoms,

you should tell the doctor straight away or go to Accident and Emergency at your nearest hospital as delayed reactions may occur occasionally. These are very serious side effects. If you have them, you may have had a serious allergic reaction to VISIPAQUE. You may need urgent medical attention or hospitalisation.

Other unwanted effects which may occur during, or after the examination include:

  • pain at the site of injection
  • headache, dizziness, fainting, seizure, altered taste or smell sensation or other types of sensory disturbance
  • weakness
  • fluid retention
  • neck stiffness
  • numbness, paralysis, amnesia, hallucination or speech disturbance
  • twitching
  • hearing disturbance
  • muscle cramps or back pain
  • blurred vision or visual impairment
  • confusion, anxiety or trembling
  • warmth or rash
  • flushing, feeling hot, feeling cold, chills
  • shortness of breath, cough, sneezing, throat irritation or tightness
  • chest pain, heart attack, change in blood pressure or heart rate
  • nausea, vomiting, abdominal pain, diarrhoea, swelling or enlargement of salivary glands
  • Hypothyroidism (a condition in which your thyroid gland does not product enough thyroid hormone).

These effects are usually mild to moderate and of short duration, resolving without any treatment. If they become severe or last more than a few days, tell your doctor.

If you experience any other unwanted effects, please tell your doctor. Do not be alarmed by this list of possible side effects. You may not experience any of them.

Other side effects not listed above may also occur in some patients. Tell your doctor if you notice anything else that is making you feel unwell.

Product description

What it looks like

VISIPAQUE is a colourless to pale yellow injectable solution.

Ingredients

Active Ingredient:

Iodixanol

Other Ingredients

trometamol, sodium calcium edetate, sodium chloride, calcium chloride dihydrate, water for injection and hydrochloric acid

Storage

VISIPAQUE should be stored below 30°C, protected from the light. Do not freeze.

Supplier

VISIPAQUE is supplied in Australia by GE Healthcare Australia Pty Limited
241 O'Riordan St
Macot NSW 2020
Tel: 1300 88 77 64
Fax: 1300 434 232

It is available in the following strengths:*

270 mg 1/mL: In pack sizes of

20mL glass vial - AUST R 154369
50mL glass and PPE bottle - AUST R 49603
100mL glass and PPE bottle - AUST R 49604
150mL glass and PPE bottle - AUST R 49605
200mL glass and PPE bottle - AUST R 49606
10mL PPE ampoule - AUST R 75923
20mL PPE ampoule - AUST R 75924
40mL PPE ampoule - AUST R 75929
50mL PPE ampoule - AUST R 75925
100mL injection bag - AUST R 49607
150mL injection bag - AUST R 49608
200mL injection bag - AUST R 49609

320 mg 1/mL: In pack sizes of

20mL glass vial - AUST R 154370
50mL glass and PPE bottle - AUST R 49594
100mL glass and PPE bottle - AUST R 49597
150mL glass and PPE bottle - AUST R 49598
200mL glass and PPE bottle - AUST R 49599
10mL PPE ampoule - AUST R 75927
20mL PPE ampoule - AUST R 75928
40mL PPE ampoule - AUST R 75930
50mL PPE ampoule - AUST R 75926
100mL injection bag - AUST R 49600
150mL injection bag - AUST R 49601
200mL injection bag - AUST R 49602

  • Some presentations may not be marketed in Australia

Revision date of the Leaflet

March 2024

Visipaque is a trademark of GE HealthCare

GE is a trademark of General Electric Company, used under trademark license

Published by MIMS April 2024

BRAND INFORMATION

Brand name

Visipaque Injection

Active ingredient

Iodixanol

Schedule

Unscheduled

 

1 Name of Medicine

Iodixanol.

2 Qualitative and Quantitative Composition

Visipaque 270 mg I/mL and 320 mg I/mL Solution for Injection. See Table 1.
Solution for injection. Visipaque is supplied ready to use as clear, colourless to pale yellow aqueous solutions.
All solutions are terminally sterilised by autoclaving and contain no preservatives.
Iodixanol is a non-ionic, dimeric, hexaiodinated, water soluble X-ray contrast medium.
Pure aqueous solutions of iodixanol in all clinical relevant concentrations have a lower osmolality than whole blood and the corresponding strengths of the non-ionic monomeric contrast media. Visipaque is made isotonic with normal body fluids by addition of electrolytes.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

4 Clinical Particulars

4.1 Therapeutic Indications

This medicinal product is for diagnostic use only.
Visipaque is indicated, in adult patients, for angiocardiography, peripheral arteriography, visceral arteriography, cerebral arteriography, contrast enhanced computed tomography of the head and body, excretory urography and venography. In arteriography, Visipaque may be used for both conventional radiography and digital subtraction angiography (DSA).
In children, Visipaque is indicated for cardioangiography, urography, CT enhancement and studies of the upper gastrointestinal tract.

4.2 Dose and Method of Administration

Diagnostic procedures that involve the use of radiopaque imaging agents should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed.
Preparation of the patient will vary with the particular agent used, preference of the radiologist and the type of radiologic procedure performed. Specific radiographic procedures used will depend on the state of the patient and the diagnostic indications.
The combination of volume and concentration of Visipaque to be used should be carefully individualised, accounting for factors such as age, body weight, size of the vessel, rate of blood flow within the vessel, cardiac output, indication for examination, and timing of the X-ray or CT scan. Other factors to be considered are anticipated pathology, degree and extent of opacification required, structure or area to be examined, disease processes affecting the patient, and equipment and technique used.
Usually approximately the same iodine concentration and volume is used as with other iodinated X-ray contrast media in current use, but adequate diagnostic information has also been obtained in some studies with iodixanol injection with somewhat lower iodine concentration.
Generally recommended doses are contained in Tables 2 and 3. The doses given for intra-arterial use are for single injections that may be repeated.

Elderly.

As for other adults.
Visipaque may be warmed to body temperature (37°C) before administration.

4.3 Contraindications

Hypersensitivity to the active substance or iodine or hypersensitivity to any of the excipients.
History of serious hypersensitivity reaction to Visipaque.
Manifest thyrotoxicosis.

4.4 Special Warnings and Precautions for Use

Precautions in general.

The risk of serious reactions in connection with use of Visipaque is regarded as minor. However, iodinated contrast media may provoke anaphylactoid reactions or other manifestations of hypersensitivity. A course of action should therefore be planned in advance, with necessary drugs and equipment available for immediate treatment, should a serious reaction occur. It is advisable always to use an indwelling cannula or catheter for quick intravenous access throughout the entire X-ray procedure.
The use of beta-adrenergic blocking agents may lower the threshold for bronchospasm in asthmatic patients after contrast medium administration and reduce the responsiveness of treatment with adrenaline.
As with other iodinated contrast agents, the use of Visipaque injection contrast enhancement may obscure some lesions which are seen on previously unenhanced CT scans.
Encephalopathy has been reported with the use of iodixanol (see Section 4.8 Adverse Effects (Undesirable Effects)). Contrast encephalopathy may manifest with symptoms and signs of neurological dysfunction such as headache, visual disturbance, cortical blindness, confusion, seizures, loss of coordination, hemiparesis, aphasia, unconsciousness, coma and cerebral oedema within minutes to hours after administration of iodixanol and generally resolves within days.
The product should be used with caution in patients with conditions that disrupt the integrity of the blood brain barrier (BBB), potentially leading to increased permeability of contrast media across the BBB and increasing the risk of encephalopathy. If contrast encephalopathy is suspected, administration of iodixanol should be discontinued and appropriate medical management should be initiated.
Enhancement of the inferior vermis following contrast agent administration has resulted in false-positive diagnosis.

Hydration.

Patients should be well hydrated prior to, and following, administration of any contrast medium, including Visipaque, in order to prevent from acute renal failure. This applies especially to patients with multiple myeloma, diabetes mellitus, renal dysfunction and elderly patients. Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with pre-existing renal insufficiency, diabetes or advanced vascular disease. It is believed that overnight fluid restriction prior to excretory urography generally does not provide better visualisation in normal patients.
To avoid contrast induced nephropathy, the following should be considered.
Identification of high risk patients.
Ensuring adequate hydration. The patient should be hydrated (e.g. at least 100 mL per hour of soft drinks or intravenous saline up to 24 hours after contrast medium administration. In warm areas more fluid should be given).
If necessary by maintaining an i.v. infusion from before the procedure until the contrast medium has been cleared by the kidneys.
Avoiding additional strain on the kidneys in the form of nephrotoxic drugs, oral cholecystographic agents, arterial clamping, renal arterial angioplasty, or major surgery, until the contrast medium has been cleared.
Postponing a repeat contrast medium examination until renal function returns to pre-examination levels.
Monitor renal function (serum creatinine), serum lactic acid and pH of blood.
Look for symptoms of lactic acidosis (vomiting, somnolence, nausea, epigastric pain, anorexia, hyperpnea, lethargy, diarrhoea and thirst). Blood test results indicative of lactic acidosis: pH < 7.25 and lactic acid > 5 mmol.

Risk/ benefit should be considered when the following medical problems exist.

Patients with thyrotoxicosis or hyperthyroidism.

Iodinated contrast media should not be administered to patients with thyrotoxicosis (see Section 4.3 Contraindications).
Special care should be exercised in patients with hyperthyroidism. Patients with manifest but not yet diagnosed hyperthyroidism, patients with latent hyperthyroidism (e.g. nodular goitre) and patients with functional autonomy (often e.g. elderly patients especially in regions with iodine deficiency) are at higher risk of acute thyrotoxicosis after use of iodinated contrast media. The additional risk should be evaluated in such patients before use of an iodinated contrast medium. Testing of thyroid function prior to contrast medium administration and/or preventative thyreostatic medication may be considered in patients with suspected hyperthyroidism. The patients at risk should be monitored for the development of thyrotoxicosis in the weeks following injection.
Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration to adult and paediatric patients, including infants. Some patients were treated for hypothyroidism.

Patients with history of allergic reactions.

A positive history of allergy, asthma, or untoward reactions to iodinated contrast media indicates a need for special caution. Premedication with corticosteroids or histamine H1 and H2 antagonists might be considered in these cases. Recent reports of the use of iodinated contrast agents indicate that such pretreatment does not prevent serious life threatening reactions but may reduce both their incidence and severity.

Patients with multiple myeloma.

Radiopaque contrast agents are potentially hazardous in patients with multiple myeloma or other paraproteinemias, particularly in those with the therapeutically resistant anuria. Although neither the contrast agent nor dehydration have been proved separately to be the cause of anuria in myelomatous patients, it has been speculated that the combination of both may be causative. The risk in myelomatous patients is not a contraindication; however, they require special precautions. Preparatory dehydration of these patients is not recommended since it may predispose the patient to precipitation of the myeloma protein in the renal tubules. The presence of myeloma should be considered before instituting intravascular administration of contrast agents.

Patients with phaeochromocytoma.

Administration of radiopaque materials to patients known to have, or suspected of having, phaeochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed; however, the amount of radiopaque medium injected should be kept to an absolute minimum. The patient's blood pressure should be assessed throughout the procedure, and measures for the treatment of hypertensive crisis should be readily available.

Patients with homocystinuria.

Angiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing embolism.

Patients with a history of seizures.

Patients with acute cerebral pathology, tumours or a history of epilepsy are predisposed for seizures and merit particular care. Also alcoholics and drug addicts have an increased risk for seizures and neurological reactions.

Patients with serious cardiac disease and pulmonary hypertension.

Care should also be taken in patients with serious cardiac disease and pulmonary hypertension as they may develop haemodynamic changes or arrhythmias.

Diabetic patients treated with metformin.

To prevent lactic acidosis, serum creatinine level should be measured in diabetic patients treated with metformin prior to intravascular administration of iodinated contrast medium.
Normal serum creatinine/ renal function: administration of metformin should be stopped at the time of administration of the contrast medium and not resumed for 48 hours or until renal function/ serum creatinine is normal.
Abnormal serum creatinine/ renal function: metformin should be stopped and the contrast examination delayed for 48 hours. Metformin should only be restarted if renal function (serum creatinine) is unchanged.
In emergency cases where renal function is abnormal or unknown, the physician should evaluate the risk/ benefit of the contrast medium examination, and precautions should be implemented: metformin should be stopped, patient hydrated, renal function monitored and patient observed for symptoms of lactic acidosis.

Patients with pre-existing renal impairment.

A benefit to risk assessment should be made before use of an iodinated contrast medium in patients with pre-existing renal impairment (serum creatinine > 1.5 mg/dL).
Iso-osmolar or low-osmolar contrast media should always be used in these patients.

Contrast medium induced nephrotoxicity.

Contrast medium induced nephrotoxicity is a condition in which impaired renal function (an increase in serum creatinine by more than 25% or 44 micromol/L) occurs within three days following the intravascular administration of a contrast medium in the absence of an alternative aetiology.
Dialysis has been used in the prevention of contrast media induced nephrotoxicity. If clinically indicated, haemodialysis is an effective method for eliminating iodinated contrast medium from the body. Correlating the time of contrast medium to the dialysis schedule is unnecessary, because there is no evidence that haemodialysis protects patients with impaired renal function from contrast media induced nephropathy. The patient should not be re-exposed to contrast media before the kidney function has returned to its previous function. If contrast medium is to be given again, the patient must be adequately hydrated.
Patients on haemodialysis may receive contrast media for radiological procedures.

Complications of catheterisation.

In angiographic procedures, the possibility of dislodging plaques, rupturing aneurysms, or damaging or perforating the vessel wall should be borne in mind during catheter manipulations and contrast medium injection. Test injections to ensure proper catheter placement are recommended.
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and non-ionic contrast media. Nonionic contrast media have less effect on the coagulation system in vitro, compared to ionic contrast media. For these reasons, meticulous intravascular administration technique is necessary, particularly during angiographic procedures. Close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinised saline solutions, and minimising the length of the procedure may minimise thromboembolic events. Numerous factors, including catheter and syringe material, underlying disease state, and concomitant medications may contribute to the development of thromboembolic events. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
No safety data have been submitted regarding the following:
pregnant and lactating women;
patients with unstable medical conditions;
severe pulmonary hypertension;
uncontrolled arrhythmias;
decompensated congestive cardiac failure;
aortic stenosis;
acute intracranial haemorrhage;
recent head trauma;
patients who have had a myocardial infarction in the previous three days.

Extravasation.

It is likely that extravasation of Visipaque, due to its isotonicity, gives rise to less local pain and extravascular oedema than hyperosmolar contrast media. In case of extravasation, elevating and cooling the affected site is recommended as routine measures. Surgical decompression may be necessary in cases of compartment syndrome.

Observation time.

After contrast medium administration the patient should be observed for at least 30 minutes, since the majority of serious side effects occurs within this time. However, experience shows that hypersensitivity reactions, mostly mild to moderate skin reactions, may appear up to several hours or days post injection.

Special precautions by indication.

Cardioangiography.

Selective coronary arteriography should be performed only in those patients in whom the expected benefits outweigh the risk. The inherent risks of angiocardiography in patients with chronic obstructive pulmonary disease must be weighed against the necessity for performing this procedure.
During left ventriculography and coronary arteriography, vital signs and the ECG should be monitored routinely throughout the procedure. Caution is advised in the administration of large volumes to patients with incipient heart failure because of the possibility of aggravating the pre-existing condition. Hypotension should be corrected promptly.
Special care regarding dosage should be observed in patients with right ventricular failure, pulmonary hypertension, or stenotic pulmonary vascular beds, because of the haemodynamic changes that may occur after injection into the right heart outflow tract.

Peripheral arteriography.

Pulsation should be present in the artery to be injected. In thromboangiitis obliterans or ascending infection associated with severe ischaemia, arteriography should be performed only if the benefits clearly outweigh the risks.

Visceral arteriography/ selective visceral i.a. DSA.

In thromboangiitis obliterans or ascending infection associated with severe ischaemia, arteriography should be performed only if the benefits clearly outweigh the risks.

Cerebral arteriography.

Cerebral arteriography should be undertaken with extreme care, especially in elderly patients, patients in poor clinical condition, or patients with advanced arteriosclerosis, severe arterial hypertension, cardiac decompensation or recent cerebral embolism or thrombosis.
Since Visipaque is given by rapid injection, the patient should be monitored for possible untoward reactions. In cerebral arteriography, patients should be appropriately prepared consistent with existing or suspected disease states.
In patients with cerebral haemorrhage, a rare association between contrast administration and clinical deterioration, including severe headache and death, has been reported. Therefore, administration of intra-arterial iodinated contrast media in these patients should be undertaken with caution.

Venography.

In thromboangiitis obliterans or ascending infection associated with severe ischaemia, venography should be performed only if the benefits clearly outweigh the risks.

Excretory urography.

Urography should be performed with caution in patients with impaired renal function, patients with combined renal and hepatic disease, and patients with diabetic nephropathy.

Use in the elderly.

No data available.

Paediatric use.

In the paediatric population, prolonged fasting and the administration of a laxative before Visipaque injection are to be avoided.
Adequate hydration should be ensured; infants and especially neonates are susceptible to electrolyte disturbance and haemodynamic changes.

Infants.

Special attention should be paid to paediatric patients because an incident of underactive thyroid during early life may be harmful for motor, hearing and cognitive development and may require transient T4 replacement therapy. Neonates may also be exposed through the mother during pregnancy. Thyroid function in infants exposed to iodinated contrast media (ICM) should be evaluated and monitored. Decreased levels of thyroxine (T4) and triiodothyronine (T3) and increased level of thyroid stimulating hormone (TSH) were reported after exposure to ICM in infants, especially preterm infants, which remained for up to a few weeks or more than a month. Thyroid function in infants exposed to ICM should therefore be evaluated and monitored until thyroid function is normalised. Some patients were treated for hypothyroidism.

Effects on laboratory tests.

Protein bound iodine (PBI) and total serum organic iodine: transient increases of both tests following urography have been noticed. The results of PBI and radioactive iodine uptake studies which depend on iodine estimations will not accurately reflect thyroid function for up to 16 days following administration of iodinated urographic media. However, thyroid function tests not depending on iodine estimations, such as T3, resin uptake or free thyroxine assays, are not affected.
Visipaque interferes with Multistix measurements of specific gravity and produces a false positive result for protein in the urine via Multistix. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of Visipaque.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interaction with other medicines.

Use of iodinated contrast media may result in a transient impairment of renal function and this may precipitate lactic acidosis in diabetics who are taking biguanides/ metformin (see Section 4.4 Special Warnings and Precautions for Use).
Patients treated with interleukin-2 less than two weeks previous to an iodinated contrast medium injection have been associated with an increased risk for delayed reactions (flu-like symptoms or skin reactions).
All iodinated contrast media may interfere with tests on thyroid function, thus the iodine binding capacity of the thyroid may be reduced for up to several weeks.
General anaesthesia may be indicated in the performance of some procedures in selected patients. However, a higher incidence of adverse reactions following administration of contrast agents has been reported in anaesthetised patients. This may be attributable either to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anaesthesia, which can reduce cardiac output and increase the duration of exposure to a contrast agent.
Patients using beta blockers may present with atypical symptoms of anaphylaxis which may be misinterpreted as a vagal reaction (see Section 4.8 Adverse Effects (Undesirable Effects)).
Addition of an inotropic agent to contrast agents may produce a paradoxical depressant response, which can be deleterious to the ischaemic myocardium.
Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs. Therefore, other pharmaceuticals should not be mixed with contrast agents, including Visipaque, in the same syringe.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Visipaque did not affect male or female fertility in rats at IV doses up to 2 g I/kg/day.
(Category B1)
Since, wherever possible, radiation exposure should be avoided during pregnancy, the benefits of any X-ray examination, with or without contrast media, should be carefully weighed against the possible risk. The product should not be used in pregnancy unless benefit outweighs risk and it is considered essential by the physician.
Reproduction studies have been performed in rats and rabbits at doses up to 2 g I/kg/day and have revealed no evidence of harm to the foetus due to Visipaque. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, the drug should be used during pregnancy only if clearly needed.
Infants born to women who received iodinated contrast media while pregnant should have testing for hypothyroidism in the neonatal period. Some patients were treated for hypothyroidism. Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use.

Labour and delivery.

It is not known whether the use of contrast agents during labour or delivery has immediate or delayed effects on the foetus, prolongs the duration of labour or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.
 Occurrence of serious adverse reactions has not been established in nursing infants.
The amount of contrast medium excreted in human milk appears to be low. Nursing may be continued normally when iodinated contrast media are given to the mother.
Also see Section 4.4 Special Warnings and Precautions for Use, Paediatric use.

4.7 Effects on Ability to Drive and Use Machines

None known.

4.8 Adverse Effects (Undesirable Effects)

Below are listed possible side effects in relation with radiographic procedures which include the use of Visipaque.
Serious reactions as well as fatalities are only seen on very rare occasions.
Hypersensitivity reactions usually present as respiratory or cutaneous symptoms like dyspnoea, rash, erythema, urticaria, pruritus, skin reaction, angioneurotic oedema, hypotension, fever, laryngeal oedema, bronchospasm or pulmonary oedema. They may appear either immediately after the injection or up to a few days later.
Hypersensitivity reactions may occur irrespectively of the dose and mode of administration and mild symptoms may represent the first signs of a serious anaphylactoid reaction/ shock. Administration of the contrast medium must be discontinued immediately and, if necessary, specific therapy instituted via the vascular access. Patients using beta blockers may present with atypical symptoms of hypersensitivity which may be misinterpreted as a vagal reaction.
A minor transient increase in serum creatinine is common after iodinated contrast media, but is usually of no clinical relevance.
An undesirable effect is said to be: very common if its frequency is ≥ 10%; common if its frequency is between ≥ 1% and < 10%; uncommon if its frequency is between ≥ 0.1% and < 1%; rare if its frequency is between ≥ 0.01% and < 0.1%; very rare if its frequency is < 0.01%.
Reactions, for which no frequency rate can be provided due to lack of clinical data, have been entered with 'not known'.
The listed frequencies are based on internal clinical documentation and published studies, comprising more than 48,000 patients. See Table 4.

Paediatrics.

In general, the type of adverse events reported are similar to those of adults. Although the frequency of events appears to be comparable, the frequency cannot be confirmed because of the different ability of paediatric and adult patients to report adverse events.
The overall character, quality, and severity of adverse reactions in paediatric patients is similar to that reported in adult populations from domestic and foreign postmarketing surveillance and other information. Selected commonly reported adverse events in paediatrics include: vomiting, nausea, fever, rash, pruritus and injection associated discomfort and distress. Diarrhea and taste perversion were reported in gastrointestinal studies.

Infants.

Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following exposure to iodinated contrast media. Some patients were treated for hypothyroidism.

Reporting suspected adverse events.

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

Overdosage is unlikely in patients with a normal renal function. The duration of the procedure is important for the renal tolerability of high doses of contrast media (t1/2 ~ 2 hours). In the event of accidental overdosing, the water and electrolyte losses must be compensated by infusion. Renal function should be monitored for at least the next three days. If needed, haemodialysis may be used to remove iodixanol from the patient's system. There is no specific antidote.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

The organically bound iodine attenuates radiation in the blood vessels/ tissues when it is injected.
For most of the haemodynamic, clinical chemical and coagulation parameters examined following intravenous injection of iodixanol in healthy volunteers, no significant deviation from preinjection values has been found. The few changes observed in the laboratory parameters were minor and considered to be of no clinical importance.
In a study involving 129 diabetic patients with serum creatinine levels of 1.5-3.5 mg/dL, use of Visipaque resulted in 3% of patients experiencing a rise in creatinine of ≥ 0.5 mg/dL and no patients with a rise of ≥ 1.0 mg/dL. The peak increase in the serum creatinine concentration within three days after the administration of Visipaque was 0.13 mg per dL (11.2 micromol per litre). A transient increase in tubular enzyme excretion was observed after contrast media injection. However, lower or similar effects on the release of enzymes (alkaline phosphatase and N-acetyl-β-glucosaminidase) from the proximal tubular cells were observed for Visipaque in comparison to ioxaglate.
Cardiovascular parameters such as LVEDP, LVSP, heart rate and QT-time as well as femoral blood flow were less influenced after Visipaque than after other contrast media, where measured.

Mechanism of action.

Organic iodine compounds block x-rays as they pass through the body, thereby allowing body structures containing iodine to be delineated in contrast to those structures that do not contain iodine. Iodixanol provides opacification of blood vessels and permits radiographic visualisation until sufficient haemodilution occurs or sufficient contrast material has left the site of injection.

Clinical trials.

The safety and efficacy of Visipaque has been established in the paediatric population for arterial studies, for intravenous procedures and gastrointestinal use. Use of Visipaque in these age groups is supported by evidence from adequate and well controlled studies of Visipaque in adults and additional safety data obtained in paediatric studies.
The clinical development of Visipaque comprised: one pharmacokinetic study in 43 subjects and another ten clinical studies to demonstrate efficacy and safety of Visipaque.
Six studies for intravenous use (two urography studies, four CT studies), two studies for intra-arterial use (two cardioangiography studies) and two studies for gastrointestinal use. In two of these studies there was a pilot part including 3 and 10 patients, respectively. Otherwise, the studies were phase III, randomized, double blind, parallel group comparison between iodixanol (Visipaque) and iohexol (Omnipaque).
A total of 638 infants and children were included in the clinical trials. They aged between birth and up to 17 years, 225 of them were younger than 24 months. Of these 403 received iodixanol and 235 patients received iohexol. The patients were equally distributed concerning age, sex and body weight in all study groups. Neonates were not enrolled in these studies with no child included with body weight < 2 kg.
All the intravascular studies (intravenous and intra-arterial) showed that iodixanol was efficacious. No significant differences were detected between the iodixanol and iohexol groups. Visipaque also gave appropriate contrast in all areas of the gastrointestinal tract and was found to be well suited for gastrointestinal examinations in the paediatric population. Visipaque can also be used safely in the paediatric population.

5.2 Pharmacokinetic Properties

Iodixanol is rapidly distributed in the body with a mean distribution half-life of approximately 21 minutes. The apparent volume of distribution is of the same magnitude as the extracellular fluid (0.26 L/kg b.w.), indicating that iodixanol is distributed in the extra-cellular volume only.
Visipaque displayed no protein binding in vitro (less than 2% detectable limit) at a 1.2 mg I/mL concentration in human plasma. No significant metabolism, deiodination or biotransformation has been detected in animals.
The mean elimination half-life is approximately 2 hours. Iodixanol is excreted mainly through the kidneys by glomerular filtration. Approximately 80% of the administered dose is recovered unmetabolized in the urine within 4 hours and 97% within 24 hours after intravenous injection in healthy volunteers. Only about 1.2% of the injected dose is excreted in faeces within 72 hours. The maximum urinary concentration appears within approximately 1 hour after injection.
No dose dependent kinetics have been observed in the recommended dose range.

Paediatric pharmacokinetics.

Forty three (43) paediatric patients < 12 years old, with renal function that is normal for their age, received multiple intra-arterial administrations of Visipaque Injection in doses of 0.32 to 3.2 g I/kg body weight. The elimination half lives for these patients are derived from the mean terminal elimination rate constants (Kel): 0.185/hr (newborn to 2 months old), 0.256/hr (2 to < 6 months old), 0.299/hr (6 months to < 1 year), 0.322/hr (1 to < 2 years), and 0.307/hr (2 to < 12 years old). The adult mean terminal elimination rate constant is 0.336/hr.
The actual Visipaque clearance and volume of distribution in paediatric patients were not determined. Pharmacodynamic dose adjustments to account for differences in elimination half-life in paediatric patients under 6 months of age have not been studied.

5.3 Preclinical Safety Data

Genotoxicity.

Visipaque did not induce gene mutation in bacteria or Chinese hamster ovary (CHO) cells in vitro. It was not clastogenic in CHO cells in vitro or in mice in vivo.

Carcinogenicity.

No long term animal studies have been performed to evaluate the carcinogenic potential of Visipaque.

6 Pharmaceutical Particulars

6.1 List of Excipients

Trometamol, sodium chloride, calcium chloride dihydrate, sodium calcium edetate, sodium hydroxide, hydrochloric acid (pH adjustment), water for injections.
The pH of the product is 6.8 - 7.6.

6.2 Incompatibilities

No incompatibility has been found. However, Visipaque should not be directly mixed with other drugs. A separate syringe should be used.

6.3 Shelf Life

The shelf lives are:

Glass vials.

3 years in all climatic zones.

Polypropylene bottles.

3 years in climatic zone I and II.
In climatic zone III and IV the shelf life is shorter, depending on volume and storage conditions.

6.4 Special Precautions for Storage

Protect Visipaque from light. Store below 30°C. Do not freeze.
The product in glass containers and in polypropylene bottles may be stored at 37°C for up to one month prior to use, in a contrast agent warmer utilising circulating warm air. 10 and 20 mL polypropylene ampoules may be stored at 37°C for up to one week prior to use.
Like all parenteral products, Visipaque should be inspected visually for particulate matter, discolouration and the integrity of the container prior to use.
The product should be drawn into the syringe immediately before use. Vials are intended for single use only, any unused portions must be discarded.

6.5 Nature and Contents of Container

Glass vials and bottles.

The product is filled in injection vials (20 mL) and infusion bottles (50, 75, 100, 150, 200 and 500 mL). Both containers are made of colourless highly resistant borosilicate glass (Ph. Eur. Type I), closed with halobutyl rubber stoppers (Ph. Eur. Type I), and sealed with complete tear off caps with coloured plastic 'flip-off' tops.

Polypropylene bottles.

The product is filled in polypropylene bottles. The bottles of 10, 20, 40 and 50 mL are rigid stand-up bottles with a twist-off top. The bottles of 50, 75, 100, 150, 175, 200 and 500 mL are closed with halobutyl rubber stoppers (Ph. Eur. Type I), and supplied with a plastic screw cap which is provided with a tamper proof ring.
Presentations:*
Visipaque (iodixanol) injection 270 mg I/mL.
20 mL glass vials, boxes of 10;
50 mL glass and PPE bottles, boxes of 10;
100 mL glass and PPE bottles, boxes of 10;
150 mL glass and PPE bottles, boxes of 10;
200 mL glass bottles, boxes of 6;
200 mL PPE bottles, boxes of 10;
10 mL PPE ampoules, boxes of 10;
20 mL PPE ampoules, boxes of 10;
40 mL PPE ampoules, boxes of 10;
50 mL PPE ampoules, boxes of 10;
100 mL bag, 150 mL bag and 200 mL bag.
Visipaque (iodixanol) injection 320 mg I/mL.
20 mL glass vials, boxes of 10;
50 mL glass and PPE bottles, boxes of 10;
100 mL glass and PPE bottles, boxes of 10;
150 mL glass and PPE bottles, boxes of 10;
200 mL glass bottles, boxes of 6;
200 mL PPE bottles, boxes of 10;
10 mL PPE ampoules, boxes of 10;
20 mL PPE ampoules, boxes of 10;
40 mL PPE ampoules, boxes of 10;
50 mL PPE ampoules, boxes of 10;
100 mL bag, 150 mL bag and 200 mL bag;
* Some presentations may not be marketed in Australia.

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.

Visipaque (C35H44I6N6O15) has the following chemical structure:

CAS number.

92339-11-2.
Visipaque (iodixanol) Injection, 5,5-[(2-hydroxy- 1,3-propanediyl) bis(acetylimino)] bis(N,N'-bis(2,3- dihydroxypropyl)- 2,4,8-triiodo-1,3- benzenedicarboxamide), is a dimeric, nonionic, water soluble, radiographic contrast medium with a molecular weight of 1550.20 (iodine content 49.1%). It is administered by intravascular injection.
The osmolality, viscosity and density values of Visipaque are listed in Table 5.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes