1. NAME OF THE MEDICINAL PRODUCT
Lipiodol Ultra Fluid, 480 mg iodine/mL, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Ethyl esters of iodised fatty acids of poppy seed oil — 10 mL
Corresponding to an iodine content of 480 mg/mL

Viscosity at 15°C: 70 cP (centipoise)
Viscosity at 37°C: 25 cP
Relative density at 15°C: 1.280

This product does not contain any excipients.

3. PHARMACEUTICAL FORM
Solution for injection

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
Lipiodol Ultra Fluid is an oily X-ray contrast medium for use in lymphography, hysterosalpingography in women undergoing infertility work-up, and sialography.
On account of its low viscosity, Lipiodol Ultra Fluid is suitable for introduction into narrow channels and may therefore be used in ducts, fistulae, and sinuses.

This medicinal product is for diagnostic use only.

4.2 Posology and method of administration

Posology

Adults
Lymphography:
The volume to be administered depends on the particular requirements of the technique and the size of the patient.

Hysterosalpingography (in women undergoing infertility work-up):
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.

Sialography:
The volume to be administered depends on the particular requirements of the technique and the size of the patient.

Paediatric population
The safety and efficacy of Lipiodol Ultra Fluid in children have not been specifically established for the indications of lymphography and sialography. No data are available.
There is no relevant use of Lipiodol Ultra Fluid in the paediatric population for the indication of hysterosalpingography.

Elderly population
The safety and efficacy of Lipiodol Ultra Fluid in the elderly have not been specifically established. Currently available data are described in section 4.4, but no recommendation on posology can be made.

Method of administration
Lipiodol Ultra Fluid should be administered via a suitable syringe and cannula (see section 6.2, Incompatibilities). The use of a glass syringe is recommended.

• Administration in lymphography is by lymphatic cannulation.
• Administration in hysterosalpingography is by slow injection into the uterine cervical canal via a suitable catheter or cannula. Stop the injection if the patient develops excessive discomfort. The examination should preferably be carried out during the follicular phase of the menstrual cycle.
• Administration in sialography is by cannulation of the salivary duct.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Manifest hyperthyroidism.
• Patients with traumatic injuries, recent haemorrhage or bleeding (risk of extravasation or embolism).
• Hysterosalpingography during pregnancy, in cases of acute pelvic inflammation, marked cervical erosion, endocervicitis, or intrauterine bleeding, and within 30 days following curettage or conisation.
• Bronchography (as the product would rapidly fill the bronchioles and alveoli).

4.4 Special warnings and precautions for use
Lipiodol Ultra Fluid must not be administered by the intravenous, intra-arterial, or intrathecal routes.

There is a risk of hypersensitivity, regardless of the dose administered.

4.4.1 Warnings

4.4.1.1 Lymphography
Pulmonary embolisation occurs in the majority of patients following lymphography with Lipiodol Ultra Fluid, due to a portion of the product temporarily embolising the pulmonary capillaries.
Clinical evidence of such embolisation is infrequent, usually immediate but possibly delayed by a few hours to several days, and is generally transient.

For this reason, the dose should be adjusted—or the examination cancelled—in patients with impaired lung function, cardiorespiratory failure, or pre-existing right-sided cardiac overload, particularly in elderly patients.
Radiological or radioscopic monitoring during injection is recommended.

The occurrence of pulmonary invasion may be minimised if radiographic confirmation of intralymphatic (rather than venous) injection is ensured, and the procedure discontinued once the medium becomes visible in the thoracic duct or if lymphatic obstruction is detected.

4.4.1.2 Hypersensitivity
All iodinated contrast agents can cause minor or major hypersensitivity reactions, which may be life-threatening. These reactions may be allergic (known as anaphylactic reactions when severe) or non-allergic in nature.
They may occur immediately (within 60 minutes) or be delayed (up to 7 days later).
Anaphylactic reactions are immediate, potentially fatal, dose-independent, and may occur upon first exposure. They are often unpredictable.

Because of this risk, equipment for emergency resuscitation must be immediately available.

Patients who have previously experienced a reaction to Lipiodol Ultra Fluid, or who have a history of iodine hypersensitivity, are at increased risk of recurrence upon re-administration and are therefore considered at-risk patients.

Injection of Lipiodol Ultra Fluid may exacerbate symptoms of pre-existing asthma.
In patients with asthma not adequately controlled by treatment, the decision to use Lipiodol Ultra Fluid should be made after a careful evaluation of the risk-benefit ratio.

4.4.1.3 Thyroid
Iodinated contrast media may affect thyroid function due to their free iodine content and can induce hyperthyroidism in predisposed patients.
Those at greatest risk are patients with latent hyperthyroidism or functional thyroid autonomy.

Iodism occurs more frequently with Lipiodol Ultra Fluid than with water-soluble organic iodine derivatives.
Lymphography saturates the thyroid with iodine for several months; therefore, any thyroid exploration should be performed before the radiological examination.

When Lipiodol Ultra Fluid is used for hysterosalpingography in patients at risk of hypothyroidism, thyroid function should be closely monitored for several months after the procedure to detect any 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.

4.4.1.4 Hysterosalpingography
Intravasation of Lipiodol may occur during hysterosalpingography and may lead to serious pulmonary or cerebral embolic complications within hours following the procedure.

The procedure must be immediately discontinued if intravasation of Lipiodol is suspected or confirmed.
Patients should be closely monitored for embolic complications in an appropriate care setting as determined by the treating clinician.

4.4.2 Precautions for use

4.4.2.1 Hypersensitivity

Before the examination:

• Identify at-risk patients through thorough questioning about their medical history.
• Corticosteroids and H₁ antihistamines may be considered as premedication in patients at high risk of intolerance reactions (e.g. those known to be intolerant to contrast agents). However, these measures do not prevent severe or fatal anaphylactic shock.

During the examination:

• Ensure continuous medical supervision.
• Maintain venous access at all times.

After the examination:

• Following administration of a contrast agent, the patient should remain under observation for at least 30 minutes, as most serious adverse reactions occur within this period.
• Patients should be informed about the possibility of delayed reactions (up to 7 days post-administration) (see section 4.8 Undesirable effects).

4.4.2.2 Thyroid
To prevent any metabolic disorder, potential thyroid risk factors must be identified.
If administration of an iodised contrast agent is planned in patients at risk, thyroid function must be assessed prior to the examination.

4.4.2.3 Miscellaneous
When injected into certain fistulae, great care must be taken to avoid penetration of vascular channels, as this may lead to oil embolism.
Care should also be taken to avoid injecting the product into areas affected by haemorrhage or trauma.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations that need to be taken into account

• Beta-blockers, vasoactive substances, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs):
  These medicines reduce the effectiveness of the cardiovascular compensatory mechanisms that respond to blood pressure disturbances.
  The physician should be informed of such treatments before administration of Lipiodol Ultra Fluid, and resuscitation equipment should be readily available.

• Interleukin II:
  The risk of hypersensitivity reactions to contrast agents is increased in patients previously treated with interleukin II (intravenous route).
  Reactions may include skin rash or, more rarely, hypotension, oliguria, or renal failure.

Interference with diagnostic tests
As Lipiodol Ultra Fluid may remain in the body for several months, thyroid diagnostic results can be affected for up to two years following lymphography.

4.6 Fertility, pregnancy and lactation

Pregnancy
The safety of Lipiodol Ultra Fluid during pregnancy has not been established.
Use of Lipiodol Ultra Fluid during pregnancy results in iodine transfer, which may interfere with foetal thyroid function.
Although this dysfunction is usually transient, it carries a potential risk of brain damage and permanent hypothyroidism. Therefore, neonatal thyroid function must be carefully monitored, and appropriate medical supervision is required.

Consequently, Lipiodol Ultra Fluid should only be used during pregnancy when absolutely necessary and under strict medical supervision.
Lipiodol Ultra Fluid must not be used for hysterosalpingography when pregnancy is suspected or confirmed.

Breast-feeding
Pharmacokinetic studies have shown significant excretion of iodine in breast milk following intramuscular administration of Lipiodol Ultra Fluid.
Iodine may pass into the vascular system of breast-fed infants via the digestive tract and may interfere with their thyroid function.

Therefore, if use of Lipiodol Ultra Fluid is considered necessary, breast-feeding should be interrupted temporarily, or the neonate’s thyroid function should be closely monitored.

Fertility
In women who have undergone hysterosalpingography with Lipiodol Ultra Fluid as part of an infertility work-up, a higher rate of subsequent pregnancy has been observed compared with women who did not undergo hysterosalpingography or who underwent hysterosalpingography with water-soluble iodinated contrast agents.

4.7 Effects on ability to drive and use machines
The effects of Lipiodol Ultra Fluid on the ability to drive and use machines have not been investigated.

4.8 Undesirable effects
Most adverse reactions are dose-dependent; therefore, the dose should be kept as low as possible.

Use of Lipiodol Ultra Fluid may cause a foreign body reaction, characterised by the formation of macrophages and foreign body giant cells, accompanied by sinus catarrh, plasmacytosis, and subsequent connective tissue changes in the lymph nodes.
Healthy lymph nodes generally tolerate the resulting reduction in transport capacity. However, in previously damaged or hypoplastic lymph nodes, these changes may exacerbate pre-existing lymphostasis.

Hypersensitivity reactions are possible. These may involve one or more manifestations, occurring concomitantly or sequentially, and may include cutaneous, respiratory, and/or cardiovascular symptoms. Each of these can serve as a warning sign of incipient shock and, in very rare cases, may be fatal.

In lymphography
An increase in body temperature, sometimes followed by fever of 38–39°C, may occur within 24 hours after the procedure.

Oil microemboli may develop, with or without clinical symptoms. In very rare cases, these may resemble organic emboli in size and appearance, presenting as punctiform or flat opacities on chest X-rays.
Transient pyrexia may also occur.

Oil microemboli are more likely to occur following overdose of the contrast medium or excessively rapid injection. They are also favoured by anatomical abnormalities such as lymphovenous fistulae or decreased lymph node uptake capacity (as seen in elderly patients or following radiotherapy or cytostatic therapy).

Patients with a cardiac right-to-left shunt or those with massive pulmonary embolism are particularly at risk of cerebral oil microemboli.

In hysterosalpingography
Transient febrile reactions (usually below 38°C) accompanied by pelvic pain are common.
Episodes of salpingitis or pelvic peritonitis have been reported following the procedure in cases of latent infection.
Granulomatous tissue reactions are rare but may be serious, as they carry a risk of perforation during the procedure.
Hypothyroidism may also occur, particularly in patients with subclinical hypothyroidism.

In sialography
A transient inflammatory reaction may occur, occasionally accompanied by temporary functional glandular paralysis (salivary duct inflammation), which generally resolves within 48 hours.

Tabulated summary of adverse reactions
The undesirable effects reported with Lipiodol Ultra Fluid are presented in the table below by system organ class (SOC) and by frequency, using the following convention:

• Very common (≥ 1/10)
• Common (≥ 1/100 to < 1/10)
• Uncommon (≥ 1/1,000 to < 1/100)
• Rare (≥ 1/10,000 to < 1/1,000)
• Very rare (< 1/10,000)
• Not known (cannot be estimated from the available data)

​

* In the context of hysterosalpingography.

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or by searching for “MHRA Yellow Card” in the Google Play or Apple App Store.

4.9 Overdose
Overdose may lead to respiratory, cardiac, or cerebral complications, which can potentially be fatal. Microembolisms may occur more frequently in the event of overdose.

The total dose of Lipiodol Ultra-Fluid administered must not exceed 20 mL.

The management of overdose should focus on the prompt initiation of symptomatic treatment and the support of all vital functions. Facilities performing contrast medium examinations must be equipped with the necessary medicines and equipment for emergency assistance.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Non-water-soluble contrast agents
ATC code: V08AD01

Lipiodol Ultra-Fluid is an X-ray contrast medium.

5.2 Pharmacokinetic properties

Distribution
Following intralymphatic administration, Lipiodol Ultra-Fluid is transported via the bloodstream to the liver, the lungs—where the lipid droplets are rapidly dispersed within the pulmonary alveoli—the spleen, and adipose tissue.

Elimination
The disappearance of droplets from the lungs and other tissues occurs slowly. During metabolism, iodine is released and eliminated in the urine as inorganic iodine. Lipiodol Ultra-Fluid may remain in the body for several weeks or months after lymphography.

5.3 Preclinical safety data

After intrauterine injection in rats, Lipiodol Ultra-Fluid migrates through the Fallopian tubes to the peritoneal cavity, from which it is resorbed. The Tmax in plasma is reached approximately 8 hours post-administration. The plasma half-life is about 18 hours. After 7 days, 48% of the administered dose was eliminated (37% in urine, 11% in faeces).

There are no additional findings from preclinical testing of Lipiodol Ultra-Fluid that are of relevance to the prescriber in evaluating the safety of this product for its authorised indications, beyond those already described in other sections of this Summary of Product Characteristics.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.
Each ampoule contains 100% iodised ethyl esters of the fatty acids of poppy seed oil.

6.2 Incompatibilities

Lipiodol Ultra-Fluid has been shown to dissolve polystyrene. For this reason, disposable syringes made from this material must not be used to administer the preparation.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Protect from light.
If the product becomes opaque or dark amber in colour, it should not be used.
Store below 25°C.

6.5 Nature and contents of container

Clear glass ampoules containing 10 mL.

6.6 Special precautions for disposal

If the product becomes opaque or dark amber in colour, it should not be used.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Guerbet
BP 57400
95943 Roissy CdG Cedex
France

8. MARKETING AUTHORISATION NUMBER(S)

PL 12308/0022

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20 November 2002

10. DATE OF REVISION OF THE TEXT

22 September 2020