Consumer medicine information

Lipiodol Ultra Fluid

Iodised oil

BRAND INFORMATION

Brand name

Lipiodol Ultra Fluid

Active ingredient

Iodised oil

Schedule

Unscheduled

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Lipiodol Ultra Fluid.

What is in this leaflet

Please read this leaflet carefully before you are given an injection of LIPIODOL ULTRA FLUID. It tells you some of the more important points you need to know about this product.

If you have any questions, want to know more about LIPIODOL ULTRA FLUID or are unsure about anything, ask your specialist or radiologist. This leaflet provides only a summary of the information known about LIPIODOL ULTRA FLUID.

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

What is LIPIODOL ULTRA FLUID

LIPIODOL ULTRA FLUID is a diagnostic agent. It belongs to the class of iodinated contrast agents used for radiological examinations.

LIPIODOL ULTRA FLUID is used to enhance the contrast of the images obtained during these radiological examinations, which improves the visualisation and outline of certain body parts. When mixed with certain medicines to treat cancer, LIPIODOL ULTRA FLUID carries and delivers the cancer medicine into the area to be treated.

LIPIODOL ULTRA FLUID is used in radiological examinations of the uterus and Fallopian tubes when searching for causes of infertility.

What LIPIODOL ULTRA FLUID is used for

This medicine is used:

  • during radiological examinations,
  • during surgery.

Before receiving it

When you must not be given it

You must not be given LIPIODOL ULTRA FLUID:

  • If you are allergic to the active substance, iodised oil, also known as ethyl ester of iodised fatty acids of poppy seed oil,
  • If you need to undergo a bronchography, a type of X-ray examination where a dye is directly administered into the lower lungs,
  • If you have or have recently had severe injuries or major bleeding,
  • If you are pregnant or think you are pregnant; or have acute pelvic inflammation, and are due to undergo hysterosalpingography, an examination of the uterus and fallopian tubes,
  • If you have or suspect to have cancer in the reproductive tract,
  • If you have iodine idiosyncrasy,
  • If you have hyperthyroidism, i.e. an overactive thyroid gland,
  • If you have a blood clot in a liver vein.

This medicine must not be injected directly into your arteries or your veins.

Before you are given it
You must tell your doctor if:

  • You are allergic to any other medicines or any foods, dyes or preservatives.
  • You have a history of hypersensitivity to iodine,
  • You are pregnant, intend to become pregnant or breastfeeding or plan to breastfeed. If you receive this medicine whilst pregnant, your newborn should be tested to ensure they are producing the correct amount of thyroid hormone.
  • You have or have had any of the following medical conditions:
    - disease affecting your heart or your blood vessels (heart failure, heart malformation).
    - disease affecting your lungs (respiratory failure),
    - thyroid disorder or history of thyroid disease,
    - you are due to undergo a thyroid examination or treatment with radioactive iodine,
    - disease affecting your liver i.e. cirrhosis,
    - disease affecting your kidneys,
    - dilated veins in the oesophagus,
    - you are diabetic,
    - you have problems with ducts which carry bile,
    - you have a large thyroid or goitre.

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.

These include:

  • Medicines prescribed for heart and high blood pressure disorders i.e. beta-blockers, diuretics,
  • Interleukin-2, a medicine prescribed to treat cancer or to strengthen your immune system.
  • A medicine to treat diabetes (metformin).
  • Medicines you know are toxic to the kidney (i.e. certain antibiotics or antivirals).

How it is given

How much is given

The dose will depend on the particular examination that you need. Your doctor will determine the dose that you will receive and will supervise the injection.

How it is given

Before the examination, a healthcare professional will prepare and administer this medicine to you by injection. Where and how this medicine will be injected depends on the reason for which you are receiving this medicine.

You will be monitored for any side effects for at least 30 minutes after the injection.

You may be given antibiotics to prevent any infections occurring from the procedures.

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

If too much is given (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 LIPIODOL ULTRA FLUID 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 LIPIODOL ULTRA FLUID. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

After receiving it

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

Like all medicines, LIPIODOL ULTRA FLUID can cause side effects, although not everybody gets them.

Tell your doctor immediately if any of these allergic signs occur:

  • Skin redness,
  • Rash,
  • Itching,
  • Hypotension (low blood pressure),
  • Runny nose,
  • Eye irritation,
  • Swelling of the face, eyelids, lips, or throat which may cause you difficulties in breathing or swallowing.

The other possible signs of an allergic reaction are:

  • Whistling breathing,
  • Sensation of stuffy nose,
  • Sneezing,
  • Cough,
  • Sensation of throat tightening,
  • Urticaria.

The allergic reaction can be exceptionally serious.

The other side effects you may experience are:

  • High fever during the hours following the examination,
  • Digestive disorders such as nausea, vomiting, diarrhoea,
  • Signs of an overactive thyroid gland such as weight loss, accelerated heart rate and increased intestinal transit rate, anxiety and insomnia,
  • Signs of an underactive thyroid gland such as weight gain, slower heart rate, constipation and tiredness,
  • Increase in size of your thyroid gland
  • Pains and pain in the pelvis (lower abdomen),
  • Blockages of certain blood vessels in lung, brain, liver and retina,
  • Formation of a spherical mass (granuloma) due to the accumulation of oil residue and cells,
  • Light-headedness,
  • Difficult breathing,
  • Inflamed pancreas,
  • Inflamed gall bladder,
  • Stomach pain,
  • Liver damage,
  • Skin damage,
  • Increase in thyroid gland volume,
  • Small amounts of LIPIODOL ULTRA FLUID may leak into the blood supply and end up in other parts of the body, such as blood vessels or arteries,
  • Swelling of various parts of the body (legs, arms),
  • Following hysterosalpingography, a transient fever with pain in the pelvic area is often noted as well as the possibility of salpingitis (inflammation of fallopian tubes) or pelvioperitonitis (inflammation of the abdominal cavity or the pelvic cavity).

Tell your doctor if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet. Other side effects not listed above may also occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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 medicine. 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 stays below 25°C. Keep the ampoule in the carton.

Do not use LIPIODOL ULTRA FLUID 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

LIPIODOL ULTRA FLUID is a clear, pale yellow oily liquid.

It is available in packs of one glass ampoule with 10 mL of solution for injection.

Ingredients

LIPIODOL ULTRA FLUID contains the active substance ethyl esters of iodised fatty acids of poppy seed oil (iodine content: 480 mg/mL). It does not contain any other ingredients.

The Australian Registration number is AUST R 34371.

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 May 2023.

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Lipiodol Ultra Fluid

Active ingredient

Iodised oil

Schedule

Unscheduled

 

1 Name of Medicine

Iodised oil.

2 Qualitative and Quantitative Composition

Lipiodol Ultra Fluid, 480 mg I/mL, solution for injection is an iodinated, non water-soluble contrast agent.
Lipiodol Ultra Fluid is for diagnostic use only.
It is an opaque medium for use in certain radiological investigations, where it is desired to outline a viscus or other structure with directly instilled radio-opaque material. It is slowly absorbed from most sites in the body, but from the peritoneal cavity (after hysterosalpingography) absorption is relatively rapid.
Each ampoule contains 10 mL of the active, ethyl esters of iodised fatty acids of poppy seed oil corresponding to an iodine content of 480 mg/mL. This medicine does not contain any excipients.
Viscosity at 15°C: 70 cP (centipoises).
Viscosity at 37°C: 25 cP.
Relative density at 15°C: 1.280.
ATC code: V08AD01 (V: other).

3 Pharmaceutical Form

Solution for injection.
Lipiodol Ultra Fluid is a clear, bright pale yellow, sterile oil in a glass ampoule.

4 Clinical Particulars

4.1 Therapeutic Indications

In diagnostic radiology.

Hysterosalpingography in women undergoing infertility workup; lymphangiography; urethrography; radiography of the seminal vesicles, vas deferens and epididymis; nasal sinuses (for which purpose dilution to one-half or one-third strength with liquid paraffin or a suitable vegetable oil is generally advised); dacryocystography; sialography and the exploration of sinuses, fistulae, etc.
It has also been used in the form of a 20% emulsion for the X-ray examination of empyema cavities.

In interventional radiology.

As an imaging agent for visualisation and localisation during trans-arterial chemo-embolisation (TACE) of hepatocellular carcinoma (HCC) at intermediate stage in adults (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

4.2 Dose and Method of Administration

Lipiodol Ultra Fluid is for administration using glass syringe or other compatible administration system by slow injection or cannulation (see Section 6.2 Incompatibilities).
After the administration of Lipiodol Ultra Fluid, the patient must be kept under observation for at least 30 minutes.

In diagnostic radiology.

Hysterosalpingography. In hysterosalpingography (HSG), inject increments of 2 mL of Lipiodol Ultra Fluid into the endometrial cavity under fluoroscopic control until tubal patency is determined.
The total volume to be injected depends on the volume of the uterine cavity, usually not exceeding 15 mL.
The dose of Lipiodol Ultra Fluid for hysterosalpingography should be kept as low as possible to minimise the potential risk of thyroid dysfunction. Nonetheless, thyroid dysfunction may occur at the lower recommended dose during hysterosalpingography.
Administration is by slow injection into the uterine cervical cannula via a suitable catheter or cannula. Stop the injection if the patient develops excessive discomfort. The examination should be preferably carried out during the follicular phase of the menstrual cycle.
Care is needed to avoid the risk of venous intravasation. The injection must therefore not be made either during the first few days after a menstrual period or in the few days before a menstrual period is due. When the injection is made by means of a cannula, direct trauma to the uterine mucosa must be avoided. Excessive pressure should not be used in making the injection, which should be avoided entirely when the endometrium and the cervix have been recently subjected to surgical trauma.
On account of the disadvantages and potential dangers (very rare instances of oil emboli and iodism) associated with the use of Lipiodol Ultra Fluid in hysterosalpingography, etc., many radiologists prefer to use water soluble contrast agents.
Lymphangiography. Administration is by lymphatic cannulation. The lymph vessels should first be rendered visible with a subcutaneous injection of Patent Blue V. Lipiodol Ultra Fluid is then injected by means of an automatic infusion machine at a rate of 1 mL every ten minutes.
The usual dosage to visualise the lymphatic system of the leg in the adult patient is 8 mL; in the arm, 3 to 4 mL is usually adequate to show the axillary glands. For bilateral examinations a total of 15 mL usually gives adequate filling of inguinal, iliac and para-aortic glands.

Paediatric population.

In children, dosage is reduced according to bodyweight using approximately 0.25 mL/kg.
The procedure is usually carried out under local analgesia. Exposures are made at the end of the infusion; further films are taken 24 and 48 hours later.
The lymph glands retain Lipiodol Ultra Fluid for several weeks or months and changes in their appearance may be followed by serial radiographs for example, after a course of chemo- or radiotherapy.

Elderly.

The product must be administered with caution in patients over 65 years of age presenting with underlying pathologies of the cardiovascular, respiratory or neurological system.
In elderly patients with cardiorespiratory failure scheduled for a lymphography, the dose should be adapted or the examination itself cancelled, since a portion of the product will temporarily embolise the pulmonary capillaries.

In interventional radiology.

Trans-arterial chemo-embolisation (TACE). The dose of Lipiodol Ultra Fluid depends on the extent of the lesion but should usually not exceed a total dose of 15 mL in adults.
Procedures involving the use of Lipiodol Ultra Fluid in HCC patients should be conducted by interventional radiologists with prerequisite training and a thorough knowledge of the procedure to be performed.
The administration is by selective intra-arterial catheterisation of the hepatic artery. The procedure should be performed within a typical interventional radiology setting with the appropriate equipment.
Lipiodol Ultra Fluid for TACE can be mixed with anticancer medications for HCC in accordance with the applicable clinical guidelines.
Instructions and precautions for use of the anticancer medications must be strictly followed.
Instructions for preparation of the mixture of Lipiodol Ultra Fluid with an anticancer medicine:
Prepare two syringes large enough to contain the total volume of mixture. The first syringe contains the anticancer solution, the second syringe contains Lipiodol Ultra Fluid.
Connect the two syringes to a 3-way stopcock.
Perform 15 to 20 back and forth movements between the two syringes to obtain a homogeneous mixture. It is recommended to start by pushing the syringe with the anticancer medicine first.
The mixture is to be prepared at the time of use and must be used promptly after preparation (within 3 hours). If necessary during the interventional radiology procedure, the mixture can be re-homogenised as described above.
When the adequate mixture is obtained, use a 1 to 3 mL syringe to inject in the micro-catheter.
The procedure can be repeated every 4 to 8 weeks according to tumour response and patient conditions.

Paediatric population.

The efficacy and safety of the use of Lipiodol Ultra Fluid for trans-arterial chemo-embolisation of hepatocellular carcinoma have not been established in children.

Elderly.

Lipiodol Ultra Fluid must be administered with caution in patients over 65 years of age with underlying diseases of the cardiovascular, respiratory or nervous systems.
Limiting the injected dose may also help prevent non-targeted pulmonary embolism which might occur in the course of a hepatic chemoembolisation.

Renal impairment.

Lipiodol Ultra Fluid must be administered cautiously in patients with impaired renal function or pre-existing renal failure (see Section 4.4 Special Warnings and Precautions for Use). Dosage adjustment is not recommended for patients with renal impairment.

4.3 Contraindications

Hypersensitivity to Lipiodol Ultra Fluid (ethyl esters of iodised fatty acids of poppy seed oil).
Lipiodol Ultra Fluid is unsuitable for bronchography.
Recent haemorrhage in the region of investigation.
Hysterosalpingography during pregnancy, acute pelvic inflammation, marked cervical erosion, endocervicitis and intrauterine bleeding, within 30 days of curettage or conisation or in patients with known or suspected reproductive tract neoplasia (due to the risk of peritoneal spread of neoplasm).
Iodine idiosyncrasy: it is strongly recommended that the patient be tested for iodine idiosyncrasy before the administration of Lipiodol Ultra Fluid in other than small amounts. Simple and reliable tests can be affected by painting an area of the skin with iodine solution or by giving potassium iodine orally for a few days. Iodism occurs more frequently with Lipiodol Ultra Fluid than with organic salts of iodine.
Documented hyperthyroidism and documented hypothyroidism.
Lipiodol Ultra Fluid must not be administered by systemic intra-arterial (apart for selective catheterisation) or intravenous injection.
To prevent the occurrence of biloma, in the context of TACE procedure, Lipiodol Ultra Fluid must not be administered in liver areas with dilated bile ducts unless drainage has been performed.

4.4 Special Warnings and Precautions for Use

Lipiodol Ultra Fluid must not be administered intravenously, intra-arterially (apart from selective catheterisation) or intrathecally.
There is a risk of hypersensitivity regardless of the dose administered.

Warnings - all indications.

Hypersensitivity.

All iodinated contrast agents can lead to minor or major hypersensitivity reactions, which can be life threatening. These hypersensitivity reactions are of an allergic nature (known as anaphylactic reactions if they are serious) or a non-allergic nature. They can be immediate (occurring within 60 minutes) or delayed (not occurring until up to 7 days later). Anaphylactic reactions are immediate and can be fatal. They are dose-independent, can occur right from the first administration of the product, and are often unforeseeable.
The risk of a major reaction means that the equipment needed for emergency resuscitation must be immediately at hand.
Patients who have already experienced a reaction after a previous administration of Lipiodol Ultra Fluid or who have a history of iodine hypersensitivity are at increased risk of another reaction on re-administration of the product and are thus regarded as at-risk patients (see Section 4.3 Contraindications).
The injection of Lipiodol Ultra Fluid may aggravate symptoms of a pre-existing asthma. In patients with asthma unbalanced by treatment, the decision to use Lipiodol Ultra Fluid requires careful evaluation of the risk/benefit ratio.

Thyroid dysfunction.

Iodinated contrast media can affect thyroid function because of the free iodine content and can cause hypothyroidism, or hyperthyroidism in predisposed patients. Patients at risk are those with latent hyperthyroidism and those presenting with functional thyroid autonomy. Iodism occurs more frequently with Lipiodol Ultra Fluid than with water soluble organic iodine derivatives. Thyroid disorders may be adequately monitored with thyroid function tests after treatment has been initiated.

Embolic and thrombotic complications.

The uncontrolled migration of Lipiodol Ultra Fluid into the arterio-venous system may induce the temporary obliteration of small vessels (oil embolism) in various organs. Evidence of such embolisation is infrequent, usually immediate but can also be delayed, occurring after a few hours or days and is usually transient. Most reported localisations of such an event include pulmonary embolisms, cerebral embolisms (which could lead to cerebral infarction) and skin embolisms (which could lead to skin necrosis). Patients should be warned of the possible signs of embolism and should contact their doctor or hospital if any symptoms emerge.

Specific warning related to lymphography.

Pulmonary embolisation occurs in the majority of patients undergoing lymphography with Lipiodol Ultra Fluid injection, due to a portion of the product temporarily embolising the pulmonary capillaries. The dose should be adapted or the examination cancelled in patients presenting with impaired lung function, cardiorespiratory insufficiency or pre-existing right-side cardiac overload, particularly if the patient is elderly. Lymphography saturates the thyroid with iodine for several months and any thyroid function tests should therefore be conducted prior to the radiological examination.

Specific warnings related to trans-arterial chemo-embolisation.

Trans-arterial chemo-embolisation is not recommended in patients with decompensated liver cirrhosis (Child-Pugh score ≥ 8), advanced liver dysfunction, macroscopic invasion and/or extrahepatic spread of the tumour.
The uncontrolled migration of Lipiodol Ultra Fluid into the arterio-venous system may induce the temporary obliteration of small vessels (oil embolism) in various organs. Evidence of such embolisation is infrequent, usually immediate but can also be delayed occurring after a few hours or days and is usually transient. Most reported localizations of such an event include pulmonary embolisms, cerebral embolisms and skin embolisms (which could lead to skin necrosis). Patients should be warned of the possible signs of embolism and should contact their doctor or hospital if any symptoms emerge.
Hepatic intra-arterial procedures can cause an irreversible liver insufficiency in patients with serious liver malfunction and/or undergoing close multiple sessions. More than 50% liver replacement with tumour, bilirubin level greater than 2 mg/dL, lactate dehydrogenase level greater than 425 mg/dL, aspartate aminotransferase (AST) level greater than 100 units/L and decompensated cirrhosis have been described as associated with increased post-procedural mortality.
Oesophageal varices must be carefully monitored as they can rupture immediately after treatment. If a risk of rupture is demonstrated, endoscope sclerotherapy/ligature should be performed before the trans-arterial chemo-embolisation procedure.
Iodinated contrast agent induced renal insufficiency must be systematically prevented by correct rehydration before and after the procedure.
The risk of superinfection in the treated area is normally prevented by administration of antibiotics.

Specific warnings related to hysterosalpingography.

Intravasation of Lipiodol Ultra Fluid may occur in the course of a hysterosalpingography procedure and may result in serious pulmonary or cerebral embolic complications (see Embolic and thrombotic complications) in the next hours following the procedure. The hysterosalpingography procedure should be immediately interrupted in case of suspected or confirmed intravasation of Lipiodol Ultra Fluid. The patient should be closely monitored for embolic complication in a care setting deemed appropriate by the treating clinician.
When used in hysterosalpingography in patients considered at risk for hypothyroidism, close monitoring of thyroid function and follow-up of hypothyroidism should be monitored closely for several months after the examination to observe potential development of hypothyroidism. The dose of Lipiodol Ultra Fluid should be kept as low as possible to minimise the potential risk of thyroid dysfunction.

Precautions for use.

Hypersensitivity.

Before the examination: identify patients at risk through precise questioning about their history.
Throughout the examination, it is necessary to ensure the following: medical monitoring; maintenance of venous access.
After the examination:
After administration of a contrast agent, the patient must be kept under observation for at least 30 min, as most of the serious adverse reactions occur within this period.
The patient must be warned of the possibility of delayed reactions (occurring up to 7 days after administration) (see Section 4.8 Adverse Effects (Undesirable Effects)).

Thyroid dysfunction.

To prevent any metabolic disorder, possible thyroid risk factors must be determined. If administration of an iodised contrast agent is planned in such patients at risk, thyroid function must be determined before the examination.

Chemoembolisation.

Iodinated contrast agents can induce a transient alteration in renal function or worsening pre-existing renal insufficiency. Preventive measures include:
Identify patients at risk, i.e. patients who are dehydrated or who have renal insufficiency, diabetes, severe heart failure, monoclonal gammopathy (multiple myeloma, Waldenstrom's macroglobulinemia), a history of renal failure after administration of iodinated contrast agents, children under one year of age and elderly patients with atheroma.
Hydrate the patient before and after the examination.
Avoid combinations with nephrotoxic medicines. If this cannot be avoided, laboratory monitoring of renal function must be intensified. The medicines concerned include aminoglycosides, organoplatinum compounds, high doses of methotrexate, pentamidine, foscarnet and certain antiviral agents [aciclovir, ganciclovir, valaciclovir, adefovir, cidofovir, tenofovir], vancomycin, amphotericin B, immunosuppressants such as ciclosporin or tacrolimus, ifosfamide.
Allow at least 48 hours between two radiological examinations or procedures with iodinated contrast agent, or delay further examinations or procedures until renal function returns to baseline.
Prevent for lactic acidosis in diabetics treated with metformin, by monitoring serum creatinine levels. Normal renal function: discontinue metformin before and for at least 48 hours after contrast agent administration or until renal function returns to baseline. Abnormal renal function: metformin is contraindicated. In case of emergency, if the examination is mandatory, precautions must be taken, i.e. discontinue metformin, hydrate the patient, monitor renal function and test for signs of lactic acidosis.
Cardiovascular and/or pulmonary co-morbidities should be assessed before initiation of a transarterial chemo-embolisation procedure.

Miscellaneous.

The injection of Lipiodol Ultra Fluid into certain fistulae should be conducted with great care in order to avoid penetration of vascular channels and the possibility of oil emboli.
Care should be taken not to inject the product into an area affected by haemorrhage or trauma.
Indications for the use of Lipiodol Ultra Fluid must be carefully assessed in patients with primary lymph oedema, as the oedema can be exacerbated.
Lipiodol Ultra Fluid has been shown to dissolve polystyrene. Disposable syringes made from the latter must not be used. The product should be administered using a glass syringe or other administration system proven to be compatible with it.

Effects on laboratory tests.

As Lipiodol Ultra Fluid remains in the body for several months, the results of thyroid diagnostic results can be incorrect for up to 2 years after lymphography.

Paediatric use.

Infants.

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.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Elderly.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Interactions with other medicines.

Metformin.

In diabetic patients, intra-arterial administration of Lipiodol Ultra Fluid may cause lactic acidosis induced by diminished renal function. For patients scheduled to undergo embolisation or a trans-arterial chemo-embolisation, metformin must be discontinued 48 hours before the procedure and resumed no earlier than two days after the procedure.

Combinations requiring caution.

Beta-blockers, vasoactive substances, angiotensin converting enzyme inhibitors, angiotensin receptor blockers.

These medicines reduce the effectiveness of the cardiovascular mechanisms that compensate for blood pressure disturbances. The doctor should be informed about these prior to the administration of Lipiodol Ultra Fluid and have resuscitation equipment at hand.

Interleukin II (IV).

There is an increased risk of reaction to contrast agent in the event of recent interleukin II administration (IV route): skin rash or more rarely hypotension, oliguria or even renal failure.

Diuretics.

There is an increased risk of acute renal failure with diuretics as these may cause dehydration, particularly when high doses of iodinated contrast agents are used.
Precautions for use: rehydration before intra-arterial administration of Lipiodol Ultra Fluid for embolisation or chemoembolisation.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In women who underwent hysterosalpingography with Lipiodol Ultra Fluid for infertility workup, a significantly higher rate of pregnancy has been observed, compared to women who did not undergo any hysterosalpingography or who underwent hysterosalpingography with water-soluble iodinated contrast agents (see Section 5.1 Pharmacodynamic Properties).
No effects on fertility were observed in female rats treated with a single intra-uterine dose of 440 mg iodine/kg Lipiodol Ultra Fluid (approx. 3-fold higher than the maximum recommended clinical dose on a mg/kg basis).
(Category C)
The safety of Lipiodol Ultra Fluid during pregnancy has not been demonstrated and, therefore, should only be used in pregnancy if absolutely necessary and under strict medical supervision.
It must not be used for hysterosalpingography when pregnancy is suspected or confirmed.
The use of Lipiodol Ultra Fluid during pregnancy causes iodine transfer which probably interferes with the thyroid function of the foetus. It produces the potential risk of brain damage and permanent hypothyroidism and, therefore, requires supervision of thyroid function and careful medical monitoring of the neonate.
The occurrence of maternal hypothyroidism after hysterosalpingography procedure (see Section 4.4 Special Warnings and Precautions for Use, Specific warnings related to hysterosalpingography) and the possible long half-life of the product in the event of a successful pregnancy requires a surveillance of the newborn's thyroid function.
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. See Section 4.4 Special Warnings and Precautions for Use, Paediatric use.
Lipiodol Ultra Fluid did not affect embryofetal and postnatal development in rats after a single intrauterine dose of 440 mg iodine/kg (approx. 3-fold higher than the maximum recommended clinical dose on a mg/kg basis). Lipiodol Ultra Fluid was not embryotoxic or teratogenic in rats after oral administration of 50 mg iodine/kg/day during gestation days 6 to 17, or in rabbits after 4-5 intermittent (once every three days) oral administration of 12.5 mg iodine/kg during gestation days 6 to 18. In rats, increased incidences of dilated renal pelvis and ureter were observed at oral doses of 110 and 250 mg iodine/kg/day and increased incidence of kinked ureter at 250 mg/kg/day.
 Pharmacokinetic studies have shown significant secretion of iodine in breast milk after intramuscular administration of Lipiodol Ultra Fluid. It has been demonstrated that the iodine enters the vascular system of the breastfed infant via the gastrointestinal tract and this could interfere with thyroid function. Consequently, breastfeeding should be discontinued if Lipiodol Ultra Fluid must be used.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Lipiodol Ultra Fluid on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects not related to a specific indication.

Most adverse reactions are dose related and consequently the dose should be as low as possible.
The use of Lipiodol Ultra Fluid causes a foreign body reaction with the formation of macrophages and foreign-body giant cells and the occurrence of sinus catarrh, plasmacytosis and subsequent connective tissue changes in the lymph nodes. Healthy lymph nodes tolerate the resulting reduced transport capacity. In previously damaged or hypoplastic lymph nodes, these changes can exacerbate the existing lymphostasis.
Hypersensitivity reactions are possible. These reactions may involve one or more effects, occurring concomitantly or successively, and usually including cutaneous, respiratory and/or cardiovascular manifestations, each of which can be a warning sign of incipient shock and, in very rare instances, can even prove fatal.
Severe allergic reactions have occurred in patients with a hypersensitivity to iodine so adrenaline and oxygen should be available at the time of administration and the patient pretested for allergy. Other dangers include oil embolism and venous intravasation.

Adverse effects related to a specific indication.

In diagnostic radiology.

Lymphography.

A large increase in temperature followed by a fever of 38 to 39°C may occur within 24 hours following the examination.
Oil microemboli can occur, with or without clinical symptoms. In very rare cases, they may resemble emboli in appearance and size. They appear as punctiform opacities on radiographic images of the lungs. Transient increases in temperature are possible.
Oil microemboli usually occur following an overdose of contrast agent or excessively rapid infusion. They are favoured by anatomic abnormalities such as lymphovenous fistulas or decreased lymph node uptake capacity (e.g. in elderly patients or after radiotherapy or cytostatic therapy).
Patients with a right-to-left cardiac shunts and those with a massive pulmonary embolism are particularly at risk of oil micro-emboli.

Hysterosalpingography.

Transitory fever reactions usually below 38°C accompanied by pelvic pain are frequent. Episodes of salpingitis or pelvic peritonitis have been reported after the procedure in case of latent infection. Granuloma type tissue reactions are rare but could be serious during the procedure as they produce a risk of perforation.
Hypothyroidism may also occur especially in patients with subclinical hypothyroidism. Following maternal exposure with Lipiodol Ultra Fluid, foetal thyroid disorders including foetal goitre were also reported.
Intravasation of Lipiodol Ultra Fluid may occur in the course of hysterosalpingography procedure and may result in serious pulmonary or cerebral embolic complications.
In interventional radiology.

Trans-arterial chemo-embolisation.

Most adverse reactions are not caused by Lipiodol Ultra Fluid but are due to anticancer medications or the embolisation itself. Procedural risks associated with catheterisation include vascular complications and infections.
The most frequent adverse reactions associated with Lipiodol Ultra Fluid in the context of trans-arterial chemo-embolisation are part of the postembolisation syndrome (fever, abdominal pain, nausea, vomiting and transitory changes in liver function). These reactions may also be induced by the anticancer medications or by the procedure itself.
The worsening of a pre-existing hepatocellular insufficiency can occur following the use of Lipiodol Ultra Fluid in the context of trans-arterial chemo-embolisation and may exceptionally lead to the occurrence of serious and potentially fatal complications such as hepatic encephalopathy, liver abscess, hepatic infarction, ascites, pancreatitis, or even necrotising pancreatitis.
Further serious adverse events associated with uncontrolled dissemination of Lipiodol Ultra Fluid in various organs includes pulmonary, cerebral (which could lead to cerebral infarction) or skin embolisms (which could lead to skin necrosis) may also occur. Massive pulmonary embolism has been associated with serious complications including dyspnoea, pulmonary oedema, plural effusion, acute respiratory distress syndrome, and pneumonitis.

Frequencies adverse effects.

The adverse effects (regardless of indication) are presented in Table 1, by system organ class and by frequency using 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), unknown (cannot be estimated from the available data).

Undesirable effects in paediatrics.

The expected nature of the undesirable effects connected with Lipiodol Ultra Fluid is the same as that of the effects reported in adults. Their frequency cannot be estimated from the available data.

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

Overdose may lead to respiratory, cardiac or cerebral complications, which can potentially be fatal. Microembolisms may occur more frequently in the context of overdose.
Management of overdose consists in initiating symptomatic treatment and maintaining vital functions in the shortest possible timeframe.
Sites performing contrast medium examinations must be equipped with medicines and equipment for emergency aid.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Clinical trials.

Trans-arterial chemo-embolisation.

Used in trans-arterial chemo-embolisation (TACE) by selective intra-arterial hepatic injection, Lipiodol Ultra Fluid allows visualisation and control of the procedure due to its opacifying properties. In literature reports, after close-arterial injection to the liver, selective retention of Lipiodol Ultra Fluid within HCC nodules has been shown for up to 6 to 12 months on computed tomography scans.

Hysterosalpingography.

Used in hysterosalpingography, in women with infertility for more than 1 year, randomly assigned to hysterosalpingography with Lipiodol Ultra Fluid (n=73) or no hysterosalpingography (n=85), the pregnancy rate at 6 months follow-up was 38.4% (28/73) and 16.5% (14/85), respectively (p=0.002) and the live birth rate was 31.5% (23/73) and 12.9% (11/85), respectively (p=0.005). In women with infertility for more than 1 year, randomly assigned to hysterosalpingography with Lipiodol Ultra Fluid (n=554) or hysterosalpingography with water soluble iodinated contrast agent (n=554), the pregnancy rate at 6 months follow-up was 39.7% (220/554) and 29.1% (161/554), respectively (p < 0.001) and the live birth rate was 38.8% (214/552) and 28.1% (155/552), respectively (p=0.005). A meta-analysis of randomised controlled trials showed an overall odds ratio (OR) for pregnancy within 6 months after the procedure significantly in favour of hysterosalpingography with Lipiodol Ultra Fluid: OR of 3.47 [95% CI: 1.98; 6.08] when compared to no hysterosalpingography (p < 0.001, 3 studies, 382 women) and OR of 1.59 [95% CI: 1.28; 1.98] when compared to hysterosalpingography with water soluble iodinated contrast agent (p < 0.001, 4 studies, 1510 women).
The mechanisms underlying these differences are not well characterised. The following hypotheses have been proposed:
mechanical effect: tubal flushing of debris out of the fallopian tubes;
endometrial bathing effect;
immunologic effect: inhibition of peritoneal macrophages.

5.2 Pharmacokinetic Properties

After selective intra-arterial injection.

The iodine is eliminated mainly in the urine. After selective intra-arterial injection into the hepatic artery for the diagnosis of hepatic lesions or in trans-arterial chemo-embolisation of hepatocellular carcinoma, Lipiodol Ultra Fluid is significantly more concentrated in the tumour than in the healthy liver tissue.
Following intra-arterial administration of Lipiodol Ultra Fluid, iodised oil retained in normal hepatic parenchyma is phagocytised by the Kupffer cells of the liver and washed out via the hepatic lymphatic system in about 2 to 4 weeks. In HCC, retention in the liver tumour is prolonged, allowing re-imaging of the tumour for four weeks or longer.

After intrauterine injection.

After intrauterine injection in rats, Lipiodol Ultra Fluid migrates through the fallopian tubes to the ovaries and peritoneal cavity from which it is resorbed. The Tmax in plasma is reached around 8 hours post-administration. Half-life in plasma was about 18 hours. After 7 days, 48% of injected dose was eliminated (37% in urine, 11% in faeces). The two most exposed organs/tissues, distant from the administration site, were the thyroid and brown fat. The elimination from ovaries was fast, but was very slow from thyroid and brown fat.

5.3 Preclinical Safety Data

Genotoxicity.

Lipiodol Ultra Fluid is non-genotoxic based on negative results in a bacterial reverse mutation assay (in vitro), a mouse lymphoma forward mutation assay (in vitro), and an in vivo micronucleus bone marrow assay in rats after intravenous injection of Lipiodol at 479 mg iodine/kg.

Carcinogenicity.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Lipiodol Ultra Fluid.

6 Pharmaceutical Particulars

6.1 List of Excipients

None.
See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Lipiodol Ultra Fluid does not keep well in plastic containers. Therefore, Lipiodol Ultra Fluid must be administered using glass syringes or other administration system proven to be compatible with it.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.
If the product becomes opaque or dark amber in colour (approximately the colour of a 1% solution of potassium dichromate), it should not be used.

6.5 Nature and Contents of Container

10 mL Type I glass ampoule. Pack size of 1.

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

The drug substance is a mixture of ethyl esters of iodised and non-iodised fatty acids.

CAS number.

8002-46-8.

7 Medicine Schedule (Poisons Standard)

Unscheduled.

Summary Table of Changes