Guerbet South Africa (Pty) Ltd
LIPIODOL® ULTRA FLUID (Solution for injection)

PROFESSIONAL INFORMATIONSCHEDULING STATUS
S4

1. NAME OF THE MEDICINELIPIODOL® ULTRA FLUID (480 mg I/ml), solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Corresponding to an iodine content of 480 mg/ml in the form of ethyl esters of iodised fatty
acids of poppy seed oil per 1 ml.
One 10 ml ampoule contains 4800 mg of iodine.
Viscosity at 15 °C: 70 cP (centipoise)
Viscosity at 37 °C: 25 cP
Relative density at 15 °C: 1,280
LIPIODOL® ULTRA FLUID does not contain any excipients (see section 6.1)
Sugar free.

3. PHARMACEUTICAL FORM
Solution for injection
A light yellow tinted coloured fluid.

4. CLINICAL PARTICULARS
4.1 Therapeutic indications
In diagnostic radiology:
Hysterosalpingography, lymphangiography, urethrography, radiography of the seminal
vesicles, vas deferens and epididymis; nasal sinuses, dacryocystography, sialography,
exploration of sinuses, fistulae' etc.
In interventional radiology:
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LIPIODOL® ULTRA FLUID (Solution for injection)•

Visualisation, localisation and vectorisation during Trans-Arterial Chemo-Embolisation(TACE) of hepatocellular carcinoma at intermediate stage, in adults.

•

Embolisation with surgical glues.
In association with surgical glues during vascular embolisations.

4.2 Posology and method of administration
LIPIODOL® ULTRA FLUID must be administered by slow injection or by catheter, using anappropriate glass syringe and a catheter (see Section 6.2).

In diagnostic radiology:
Hysterosalpingography
For visualisation of the uterus and fallopian tubes, LIPIODOL® ULTRA FLUID may be used.
Care is needed to avoid the risk of venous intravasation. The injection must therefore not bemade for the first few days after a menstrual period and not 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 subjected
to surgical trauma.
On account of the disadvantages and potential dangers (very rare instance of oil emboli andiodism) associated with the use of LIPIODOL® ULTRA FLUID in hysterosolpingography, etc.,
many radiologists prefer to use water soluble contrast agents such as Diagino Viscous brandsodium acetrizoate 40 % m/v in dextran solution.

Lymphography
LIPIODOL® ULTRA FLUID may be used for the visualisation of the lymph nodes and lymph
vessels. The vessels should first be rendered visible with a subcutaneous injection of patent
blue V; the oily medium is then injected by means of an automatic infusion machine at the rateof 1 ml every 10 minutes. The usual dosage to visualise the lymphatic system of the leg in the
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LIPIODOL® ULTRA FLUID (Solution for injection)

adult patient is 8 ml, in the arm, 3 - 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 paraaortic glands. In children dosage is reduced according to bodyweight using approximately 0,25
ml per kg.
The procedure is usually carried out under local analgesia. Exposure is 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.

Other uses
LIPIODOL® ULTRA FLUID is employed in urethrography, radiography of the seminal vesicles,vas deferens and epididymis, nasal sinuses (for which purpose dilution to one-half or one- third
strengthwith liquidparaffinorasuitablevegetableoil

is generally

advised);dacryocystography; sialography and the exploration of sinuses, fistulae, etc. It has also beenused in the form of a 20 % emulsion for the X-ray examination of empyema cavities.

Paediatric population
The dose must be reduced proportionally in children.

Patients with low weightThe dose must be reduced proportionally in this population.

Elderly
LIPIODOL® ULTRA FLUID must be administered with special care in patients over 65 years ofage with underlying diseases of the cardiovascular, respiratory or nervous systems. Keeping
in mind that part of the product temporarily embolises the pulmonary capillaries, the dose must
be adjusted in elderly patients with cardiorespiratory failure or the examination must be
cancelled.
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LIPIODOL® ULTRA FLUID (Solution for injection)

In interventional radiology:
Trans-Arterial Chemo-Embolisation of hepatocellular carcinoma
The administration is by selective intra-arterial catheterisation of the hepatic artery. The
procedure should be performed within a typical interventional radiology setting with theappropriate equipment. 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.
LIPIODOL® ULTRA FLUID can be mixed with anticancer medicines such as cisplatin,
doxorubicin, epirubicin and mitomycin. Instructions and precautions for use of the anticancer
medicines 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 medicine 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 ahomogeneous mixture. It is recommended to start by pushing the syringe with theanticancer 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, themixture can be re-homogenised as described above.

•

When the adequate mixture is obtained, use a 1 to 3 ml syringe to inject in the microcatheter.

•

The procedure can be repeated every 4 to 8 weeks according to tumour response andpatient conditions.

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LIPIODOL® ULTRA FLUID (Solution for injection)

Paediatric population
The efficacy and safety of the use of LIPIODOL® ULTRA FLUID for Trans-Arterial ChemoEmbolisation of hepatocellular carcinoma have not been established in children.

Elderly
The product must be administered with special care in patients over 65 years of age with
underlying diseases of the cardiovascular, respiratory or nervous systems.

Embolisation with surgical glues
Exclusive selective arterial catheterisation.
The dose of LIPIODOL® ULTRA FLUID per embolisation session is determined depending on
the size of the lesions.

The proportion of LIPIODOL® ULTRA FLUID versus the liquid

embolising agent can vary from 20 to 80 % but is usually a 50/50 mixture.
The injection volume must not exceed 15 ml.

4.3 Contraindications•

Hypersensitivity to LIPIODOL® ULTRA FLUID (ethyl esters of iodised fatty acids of poppy
seed oil) or iodine•

Traumatic lesions, haemorrhage or recent bleeding (risk of extravasation or embolism)•

Pregnant women•

Confirmed hyperthyroidism•

Bronchography (the product rapidly inundates the bronchioles and alveoli).

Contraindications specific to the use in interventional radiology:•

Trans-Arterial Chemo-Embolisation
Administration in liver areas with dilated bile ducts unless drainage has been performed.

•

Embolisation with surgical glues
Patients with portal vein thrombosis.

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4.4 Special warnings and precautions for use
LIPIODOL® ULTRA FLUID must not be administered intravenously, intra-arterially (apart fromselective catheterisation) or intrathecally.
There is a risk of hypersensitivity whatever the dose administered.

Iodine idiosyncrasy
It is strongly recommended that the patient be tested for iodine idiosyncrasy before theadministration of LIPIODOL® ULTRA FLUID. Simple and reliable tests can be affected bypainting an area of the skin with iodine solution or by giving potassium iodide orally for a few
days.
Care should be taken in those subjects presenting a history of previous allergic manifestations
or of thyroid dysfunction.
If marked side effects or suspected allergic reactions occur during administration, it is possiblethat the patient has such a hypersensitivity, and the administration must be abandoned.

Lymphography
Pulmonary embolism occurs in most patients undergoing lymphography with injection of
LIPIODOL® ULTRA FLUID, as part of the product temporarily embolises the pulmonary
capillaries. It is uncommon for this embolism to be manifested clinically; should this occur, thesigns are immediate (though they may appear several hours or even several days afteradministration) and are usually transient. For this reason, doses must be adjusted or theexamination cancelled in subjects with impaired respiratory function, cardiorespiratory failureor right ventricular overload, particularly if the patient is elderly. Doses must also be reduced
after antineoplastic chemotherapy or radiotherapy because lymph nodes shrink significantly
and retain very little contrast agent. The injection should be carried out with radiological orendoscopic guidance. Pulmonary invasion can be reduced to the minimum by confirming
radiologically that the injection is strictly intralymphatic (and not intravenous) and by
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discontinuing the examination as soon as the contrast agent becomes visible in the thoracic
duct or as soon as lymphatic obstruction is observed.

Hypersensitivity
All iodinated contrast agents may cause minor or major hypersensitivity reactions that may belife-threatening.

These hypersensitivity reactions may be either allergic (described as

anaphylactic reactions when serious) or non-allergic. They may be immediate (within 60
minutes) or delayed (up to 7 days). Anaphylactic reactions occur immediately and can be fatal.
They are independent of the dose, can occur after even the first dose of the product, and areoften unpredictable.
Emergency resuscitation equipment must be immediately available due to the risk of a major
reaction.
Patients who have previously experienced a reaction during administration of LIPIODOL®
ULTRA FLUID or who have a history of hypersensitivity to iodine are at higher risk for anotherreaction if the product is again administered. They are thus considered to be patients at risk.
Injection of LIPIODOL® ULTRA FLUID may exacerbate symptoms of asthma. In patients
whose asthma is not controlled by treatment, the decision to use LIPIODOL® ULTRA FLUID
must be based on a careful consideration of the benefit-to-risk ratio.

Thyroid
Because of the free iodine content in iodinated contrast agents, they may modify thyroid
function and cause hyperthyroidism in predisposed patients. Patients at risk are those withlatent hyperthyroidism or thyroid autonomy. Iodism occurs more commonly with LIPIODOL®
ULTRA FLUID than with water-soluble organic iodine derivatives.
Lymphography saturates the thyroid with iodine for several months and consequently thyroid
function tests must be carried out before the radiological examination.

Other
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LIPIODOL® ULTRA FLUID has been shown to dissolve polystyrene; for this reason, disposable
syringes made from the latter must not be used to administer these preparations.

Trans-Arterial Chemo-Embolisation
Trans-Arterial Chemo-Embolisation is not recommended in patients with decompensated livercirrhosis (Child-Pugh ≥ 8), advanced liver dysfunction, macroscopic invasion and/or extrahepatic spread of the tumour.
Hepatic intra-arterial procedures can cause an irreversible liver insufficiency in patients withserious 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 level greater than 100 IU/L anddecompensated 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 bycorrect rehydration before and after the procedure.
The risk of superinfection in the treated area is normally prevented by administration of
antibiotics.

Embolisation with surgical glues
An early polymerisation reaction may exceptionally occur between LIPIODOL® ULTRA FLUID
and certain surgical glues, or even certain batches of glue. Before using new batches of
LIPIODOL® ULTRA FLUID or surgical glue, the compatibility of LIPIODOL® ULTRA FLUID andthe glue must be tested in vitro.

Precautions for use
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Hypersensitivity
Before the examination:
Identify patients at risk in a detailed interview on their history.
Corticosteroids and H1 antihistamines have been proposed as premedication in patients atgreatest risk for hypersensitivity reactions (patients with known hypersensitivity to a contrast
agent). However, they do not prevent the occurrence of serious or fatal anaphylactic shock.
Throughout the examination, maintain:•

medical monitoring•

an indwelling intravenous catheter.

After the examination:
After contrast agent administration, the patient must be monitored for at least 30 minutes, as
most serious adverse reactions occur within this time period.
The patient must be warned of the possibility of delayed reactions (for up to seven days) (seeSection 4.8).

Thyroid
Possible thyroid risk factors must be investigated to prevent metabolic disorders. If iodinatedcontrast agents are to be administered to patients at risk, thyroid function tests must be carriedout before the examination.

Trans-Arterial Chemo-Embolisation / Embolisation
Iodinated contrast agents can induce a transient deterioration of renal function or exacerbate
pre-existing renal failure. The preventive measures are as follows:•

Identify patients at risk, i.e. patients who are dehydrated or who have renal failure,
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 atheromatous subjects.

•

Hydrate the patient before and after the examination.

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LIPIODOL® ULTRA FLUID (Solution for injection)•

Avoid combinations with nephrotoxic medicines. If such a combination is necessary,laboratory monitoring of renal function must be intensified. The medicines concerned arein particular the aminoglycosides, organoplatinums, high doses of methotrexate,
pentamidine, foscarnet and certain antiviral agents [aciclovir, ganciclovir, valaciclovir,
adefovir, cidofovir, tenofovir], vancomycin, amphotericin B, immunosuppressors such as
cyclosporine or tacrolimus, ifosfamide)•

Allow at least 48 hours between radiological examinations or interventions with iodinatedcontrast agent injections or delay further examinations or interventions until renal function
returns to baseline.

•

Check for lactic acidosis in diabetics treated with metformin, by monitoring serum
creatinine. 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 emergencies, if the examination is required,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 aTrans-Arterial Chemo-Embolisation procedure.

Other
Injection into certain fistulae requires the utmost caution to avoid any vascular penetration,
taking into account the risk of fat embolisms.
Care should be taken not to inject the product into areas of bleeding or trauma.

4.5 Interaction with other medicines and other forms of interaction
Interactions with other medicines+Metformin
In diabetic patients, intra-arterial administration LIPIODOL® ULTRA FLUID may cause lactic
acidosis induced by diminished renal function. In patients undergoing embolisation or a TransVersion: 8.1
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Arterial Chemo-Embolisation, metformin must be discontinued 48 hours before the procedureand resumed no earlier than two days after the procedure.

Combinations requiring caution+Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors,
angiotensin receptor antagonists
These medicines reduce the efficacy of cardiovascular compensation mechanisms for bloodpressure disorders. The doctor must be aware of this before administering LIPIODOL® ULTRAFLUID and emergency measures must be available.
+Diuretics
As diuretics may cause dehydration, the risk of acute renal failure is increased, particularly
when high doses of contrast agents are administered.
Precautions for use: rehydration before intra-arterial administration of LIPIODOL® ULTRAFLUID for embolisation.
+Interleukin 2
Reactions to contrast agents may be increased if the patient has recently been treated withinterleukin 2 (i.v.), i.e. skin eruptions or more rarely hypotension, oliguria, or renal failure.

Interference with laboratory tests
As LIPIODOL® ULTRA FLUID remains in the body for several months, thyroid laboratory tests
may be falsified for as long as two years after lymphography.

4.6 Fertility, pregnancy and lactation
Pregnancy
LIPIODOL® ULTRA FLUID must not be used in pregnant women because of the transplacental transfer of iodine, over a long period of time, which interferes probably with the thyroid
function of the foetus, with a potential risk of cerebral lesions and permanent hypothyroidism.

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Breastfeeding
Pharmacokinetic studies have shown significant secretion of iodine in breast milk after
intramuscular administration of LIPIODOL® ULTRA FLUID. It has been demonstrated that theiodine 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 Undesirable effects
Most of the adverse reactions are dose-related and consequently the dose should be as low
as possible.
Use of LIPIODOL® ULTRA FLUID causes a foreign body reaction, with the formation ofmacrophages and foreign-body giant cells and the occurrence of sinus catarrh, plasmacytosis
and subsequently changes in lymph node connective tissue. Healthy lymph nodes tolerate theresulting decrease in transport capacity. In patients with lymph node lesions or hypoplasia,
these changes may exacerbate lymph stasis.
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, invery rare instances, can even prove fatal.

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.
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Fat micro-embolisms may occur, with or without symptoms. In very rare cases, they may
resemble embolisms originating in the body, in terms of their appearance and size. They
usually appear as punctiform opacities on radiographic images of the lungs. Transient
increases in temperature are possible. Fat micro-embolisms usually occur following an
overdose of contrast agent or excessively rapid infusion. Anatomic anomalies such as
lymphovenous fistulas or a decrease in the capacity of lymph nodes to retain the contrast agent(in elderly patients or after radiotherapy or cytostatic therapy) favour their occurrence.
Patients with a right-to-left cardiac shunt and those with a massive pulmonary embolism areparticularly at risk for fat micro-embolisms in the brain.
•

Diagnosis of hepatic lesions

A temperature increase is often observed. Other more rare complications may occur, i.e.
nausea, vomiting and diarrhoea.

In interventional radiology:•

In Trans-Arterial Chemo-Embolisation

Most of the adverse reactions are not caused by LIPIODOL® ULTRA FLUID itself but are due
to anticancer medicines or the embolisation itself.
The most frequent adverse reactions of the TACE treatment are post embolisation syndrome(fever, abdominal pain, nausea, vomiting) and transitory changes in liver function tests.
•

Embolisation with surgical glues

Specific adverse reactions directly related to LIPIODOL® ULTRA FLUID have not beenreported.

Adverse reactions are given in the following table according to system organ class andfrequency, using the following classification: 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),undetermined frequency (cannot be estimated on the basis of available data).

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LIPIODOL® ULTRA FLUID (Solution for injection)

System organ classFrequency: adverse reactions

Immune system disorders

Undeterminedfrequency:

hypersensitivity,

anaphylactic reaction.
Endocrine disorders

Undetermined frequency: hyperthyroidism.

Nervous system disorders

Undetermined frequency: cerebral embolism.

Respiratory, thoracic and mediastinal Undetermined frequency: pulmonary embolism.
disorders
Gastrointestinal disorders

Undetermined frequency: vomiting, diarrhoea,
nausea.

General disorders and administration Undetermined frequency: fever, pain.
site conditions
Injury, poisoning and procedural Rare: spinal cord injury.
complications

Undetermined frequency: fat embolism.

Adverse reactions in children
The types of adverse reactions to LIPIODOL® ULTRA FLUID are the same as those reported
in adults. Their frequency cannot be estimated on the basis of available data.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers
are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug
Reactions

Reporting

Form”

found

onlineunder

SAHPRA’s

publications:

https://www.sahpra.org.za/Publications/Index/8.

4.9. Overdose
Overdose can cause respiratory, cardiac or cerebral complications, which can be fatal. The
frequency of micro-embolisms may be increased after an overdose.
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The total dose of LIPIODOL® ULTRA FLUID must not exceed 20 ml.
The treatment of an overdose involves immediate symptomatic treatment and maintenance ofvital functions.

Establishments performing examinations with contrast agents must haveemergency medicines and equipment available.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Non-water-soluble contrast agents, ATC Code: V08AD01 (V: Other)
LIPIODOL® ULTRA FLUID is used as an opaque medium in certain radiological investigations,where it is desired to outline a viscus or other structure with directly instilled radiopaquematerial. From most sites in the body, it is slowly absorbed, but from the peritoneal cavity(after hysterosalpinography) absorption is relatively rapid. On account of its low viscosity,
LIPIODOL® ULTRA FLUID is suitable for introduction into narrow channels and may therefore
be used in ducts and sinuses.
Used in Trans-Arterial Chemo-Embolisation by selective intra-arterial hepatic injection,
LIPIODOL® ULTRA FLUID allows, as an oily contrast agent, the visualisation and control ofthe procedure thanks to its opacifying properties. As a vehicle, it carries and elutes anticancer
medicines into hepatocellular carcinoma nodules and, as a transient embolic agent, it
contributes to the vascular embolisation induced during the procedure.
As a selective intra-arterial hepatic injection procedure, Trans-Arterial Chemo-Embolisation
combines the effect of a loco-regional targeted anticancer medicine with the effect of anischemic necrosis induced by dual arterio-portal embolisation. LIPIODOL® ULTRA FLUID’s
opacifying properties and tropism for hepatic tumours continues for several months, so postprocedure imaging can be performed for an effective patient follow-up.

5.2. Pharmacokinetic properties
After intralymphatic injection
LIPIODOL® ULTRA FLUID is released into the blood, taken up by the liver and lungs where
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the oily droplets are degraded in the pulmonary alveoli, spleen and adipose tissue.
After being taken up by the tissues and storage organs, reabsorption of LIPIODOL ULTRAFLUID occurs over a period lasting from a few days to several months or years. This iscontinuous and regular and the presence of iodides in the urine can be detected as long as
contrast material is visible on the images.

After intramuscular injection
A portion of the oil accumulates in the muscle and adjacent tissues. Another portion isdeiodinated via the metabolic route, the iodine being used to compensate for the iodine lossesof the thyroid.
Urinary iodine excretion is massive and occurs rapidly (within the first few hours after the
injection) but continues over the following months.
Urinary iodine excretion falls to 50 μg/day in adults within 3 to 5 years.

After selective intra-arterial injection
The iodine is eliminated mainly in the urine. After selective intra-arterial injection into thehepatic artery for the diagnostic of hepatic lesions or in Trans-Arterial Chemo-Embolisation ofhepatocellular carcinoma, LIPIODOL® ULTRA FLUID is significantly more concentrated in thetumour than in the healthy liver tissue.

5.3. Preclinical safety data
Preclinical data from conventional studies on pharmacological safety, single- and repeateddose toxicology, genotoxicity and reproductive and developmental functions showed no
particular risks for human subjects.

6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
LIPIODOL® ULTRA FLUID contains no excipients.
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6.2. Incompatibilities
Plastic is not suitable for the storage of LIPIODOL® ULTRA-FLUID. In the absence of any
specific compatibility studies, plastic containers and syringes should not be used.

6.3. Shelf life
3 years

6.4. Special precautions for storage
Store at or below 25 °C in the original package. Protect from light.

6.5. Nature and contents of container
Pack of 1 x 10 ml ampoule6.6. Special precautions for disposal and other handlingNo special requirements.

7. HOLDER OF CERTIFICATE OF REGISTRATION
Guerbet South Africa (Pty) Ltd
Hertford Office Park, Building I
90 Bekker Road, Vorna Valley
Midrand, Gauteng, 1682

8. REGISTRATION NUMBER(S)H2829 (Act 101/1965)

9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

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10. DATE OF REVISION OF THE TEXT
9 March 2021

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