LIPIODOL ULTRA FLUID

The format of this leaflet has been defined by the MOH and its content has been checked and approved,

July 2013

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

LIPIODOL 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 iodized 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

This medicinal product does not contain any excipients.

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

In diagnostic radiology

Lymphography

4.2. Posology and method of administration

LIPIODOL ULTRA-FLUID must be administered by slow injection or by catheter, using an appropriate

glass syringe and a catheter (see Section 6.2 – Incompatibilities).

In diagnostic radiology:

Lymphography

Administer via a catheter inserted into a lymph duct. A dye can first be injected to locate the lymph

ducts.

The usual dose is 5 to 7 mL via the strict lymphatic route to enhance contrast in an extremity

(depending on the height of the subject), i.e. 10 to 14 mL for bilateral lymphography of the feet.

Patients with low weight

The dose must be reduced proportionally in this population.

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. 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.

4.3. Contraindications

This product must not be administered by intra-arterial, intravenous or intrathecal injection.

Hypersensitivity to LIPIODOL ULTRA-FLUID (ethyl esters of iodised fatty acids of poppyseed oil).

Confirmed hyperthyroidism.

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

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

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 whatever the dose administered.

4.4.1 Warnings

4.4.1.1. 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, the signs are immediate (though they

may appear several hours or even several days after administration) and are usually transient. For this

reason, doses must be adjusted or the examination cancelled in subjects with impaired respiratory

function, cardiorespiratory failure or 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 or endoscopic guidance. Pulmonary invasion can be reduced to the minimum by intra-

arterial, confirming radiologically that the injection is strictly intralymphatic (and not intravenous or

intrathecal injection) and by discontinuing the examination as soon as the contrast agent becomes

visible in the thoracic duct or as soon as lymphatic obstruction is observed.

4.4.1.2. Hypersensitivity

All iodinated contrast agents may cause minor or major hypersensitivity reactions that may be life-

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 are often 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 another reaction 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.

4.4.1.3. 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 with latent 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.

4.4.1.4. 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 and the glue must be

tested in vitro.

4.4.2 Precautions for use

4.4.2.1. 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 at greatest

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) (see Section

4.8 - Undesirable effects).

4.4.2.2. Thyroid

Possible thyroid risk factors must be investigated to prevent metabolic disorders. If iodinated contrast

agents are to be administered to patients at risk, thyroid function tests must be carried out before the

examination.

4.4.2.3. 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.

Avoid combinations with nephrotoxic medicines. If such a combination is necessary, laboratory

monitoring of renal function must be intensified. The medicines concerned are in 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 iodinated contrast

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.

4.4.2.4. Other

Injection into certain fistulas 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 medicinal products 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, metformin must be

discontinued 48 hours before the examination and resumed no earlier than two days after the

examination.

Combinations requiring caution

+

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

angiotensin receptor antagonists.

These medicinal products reduce the efficacy of cardiovascular compensation mechanisms for blood

pressure disorders. The physician must be aware of this before administering LIPIODOL ULTRA-

FLUID 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 ULTRA-FLUID for

embolisation.

+

Interleukin 2

Reactions to contrast agents may be increased if the patient has recently been treated with interleukin

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. Pregnancy and lactation

Pregnancy

The safety of LIPIODOL ULTRA-FLUID has not been demonstrated in pregnant women. The use of

LIPIODOL ULTRA-FLUID during pregnancy increases the transplacental transfer of iodine, which

probably interferes with thyroid function in the fœtus. Although transient, this abnormality may involve

a risk of cerebral lesions and permanent hypothyroidism, calling for monitoring of thyroid function and

close medical follow-up of the neonate.

Consequently, LIPIODOL ULTRA-FLUID should not be used in pregnant women unless it is absolutely

necessary, and only with strict medical monitoring.

Breastfeeding

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, or else thyroid function should monitored more frequently in the neonate.

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 of macrophages

and foreign-body giant cells and the occurrence of sinus catarrh, plasmacytosis and subsequently

changes in lymph node connective tissue. Healthy lymph nodes tolerate the resulting decrease in

transport capacity. In patients with lymph node lesions or hypoplasia, these changes may exacerbate

lymph stasis.

Hypersensitivity reactions are possible.

A sharp increase in temperature followed by a fever of 38 to 39°C may occur within 24 hours following

the examination.

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 are

particularly at risk for fat micro-embolisms in the brain.

Adverse reactions are given in the following table according to system organ class and frequency,

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).

System organ class

Frequency: adverse reactions

Immune system disorders

Undetermined frequency: hypersensitivity, anaphylactic reaction.

Endocrine disorders

Undetermined frequency: hyperthyroidism.

Nervous system disorders

Undetermined frequency: cerebral embolism.

Respiratory, thoracic and

mediastinal disorders

Undetermined frequency: pulmonary embolism.

Gastrointestinal disorders

Undetermined frequency: vomiting, diarrhoea, nausea.

General disorders and

administration site conditions

Undetermined frequency: fever, pain.

Injury, poisoning and

procedural complications

Rare: spinal cord injury.

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.

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.

The total dose of LIPIODOL ULTRA-FLUID must not exceed 20 mL.

The treatment of an overdose involves immediate symptomatic treatment and maintenance of vital

functions. Establishments performing examinations with contrast agents must have emergency

medicines and equipment available.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

NON-WATER-SOLUBLE CONTRAST AGENTS, Code ATC: V08AD01

(V: Other)

5.2. Pharmacokinetic properties

After intralymphatic injection

Lipiodol is released into the blood, taken up by the liver and lungs where 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 occurs over a period

lasting from a few days to several months or years. This is continuous and regular and the presence of

iodides in the urine can be detected as long as contrast material is visible on the images.

A portion of the oil accumulates in the muscle and adjacent tissues. Another portion is deiodinated via

the metabolic route, the iodine being used to compensate for the iodine losses of 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. The iodinated contrast agent is significantly more

concentrated in the tumour than in the surrounding tissue, especially in the case of hepatocellular

carcinomas.

5.3. Preclinical safety data

Preclinical data from conventional studies on pharmacological safety, single- and repeated-dose

toxicology, genotoxicity and reproductive and developmental functions showed no particular risks for

human subjects

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

This medicinal product contains no excipients.

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 below 25ºC, protected from light.

6.5. Nature and contents of container

10 mL glass (type 1) ampoules.

6.6. Special precautions for disposal and other handling

Any unused product or waste material should be discarded in accordance with current regulations.

7. MARKETING AUTHORISATION NUMBERS

056-03-21367-00

056-03-21367-01

8. MANUFACTURER

Guerbet

BP 57400

F-95943 Roissy CdG cedex

FRANCE

9. MARKETING AUTHORISATION HOLDER

Promedico Ltd

6 Hashiloach St.

Petach- Tikva