Special Warning : אזהרת שימוש

4.4.      Special warnings and precautions for use

•     Regardless of the route of administration and dose, there is a risk of allergy.
•     The risk of intolerance is not clear when it comes to medicinal products administered locally for the opacification of body cavities: a) Administration by certain routes (articular, biliary, intrathecal, intrauterine, etc.) leads to fairly significant systemic passage: systemic effects may be observed.
b) Oral or rectal administration normally results in very limited systemic diffusion; If the digestive mucosa is normal, no more than 5% of the administered dose is found in the urine, the remainder being eliminated in faeces. However, in the event of damage to the mucosa, absorption is increased; it is total and rapid in the event of perforation, with passage into the peritoneal cavity, and the drug is eliminated in the urine. The potential occurrence of dose-dependent systemic effects is therefore dependent on the condition of the digestive mucosa.
c) The immunoallergic mechanism is non-dose-dependent and may be observed in any patient, regardless of the route of administration.
The frequency and intensity of adverse reactions therefore differs between the following two groups:
•     Medicinal products administered by the vascular route and certain local routes
•     Medicinal products administered by the digestive route and absorbed very little under normal conditions.


4.4.1. General information applicable to all iodinated contrast agents
4.4.1.1 Warnings
In the absence of specific studies, myelography is not an indication for XENETIX.
All iodinated contrast agents may cause minor or major reactions that can be life- threatening. These reactions can occur immediately (within 60 minutes) or be delayed (within 7 days). They are often unpredictable.

The risk of major reactions means that emergency resuscitation equipment must be immediately available.

Several mechanisms have been discussed:

•   Direct toxicity to the vascular endothelium and tissue proteins.
•   Pharmacological action modifying the concentration of certain endogenous factors (histamine, complement components, inflammatory mediators) is more common with hyperosmolar products.
•   XENETIX contrast agent-dependent immediate IgE allergy (anaphylaxis)
•   Allergic reactions of cellular mechanism (delayed skin reactions) 
Patients who have experienced a reaction with a previous administration of an iodinated contrast agent have an increased risk of a new reaction in the event of re-administration of the same or possibly another iodinated contrast agent and are therefore considered to be at risk.
Iodinated contrast agents and the thyroid (see also Section 4.4.1.2.5.) Prior to administration of iodinated contrast agent, it is important to ensure that the patient is not due to undergo a scintigraphic or biological examination of the thyroid or receive radioactive iodine for therapeutic purposes.
In fact, the administration of any type of iodinated contrast agents interferes with the hormonal doses and iodine uptake by the thyroid or thyroid cancer metastases until normalization of the ioduria.

Other warnings
Extravasation is a non-exceptional complication (0.04% to 0.9%) of intravenous injections of contrast agents. This occurs more frequently with the high osmolar products, most of the injuries are minor, however severe injuries such as skin ulceration, tissue necrosis, and compartment syndrome may occur with any iodinated contrast medium. The risk and/or severity factors are patient-related (poor or fragile vascular conditions), and technique-related (use of a power injector, large volume). It is important to identify these factors, optimise the injection site and technique accordingly, and monitor the injection prior to, during and after the injection of XENETIX.


4.4.1.2. Precautions for use

4.4.1.2.1. Intolerance to iodinated contrast agents:
Prior to the examination:
•   identify at-risk subjects by asking specific questions about their history.
Corticosteroids and H1 antihistamines have been suggested as premedication in patients with the highest risk of intolerance reactions (those with known intolerance to an iodinated contrast agent). However, they do not prevent severe or fatal anaphylactic shock. During the examination, the following measures must be in place:
•   medical surveillance
•   in situ venous access After the examination:
•   After contrast agent administration, the patient must be observed for at least 30 minutes, as the majority of serious adverse reactions occur within this time frame.
•   The patient must be informed of the potential for delayed reactions (up to 7 days) (see Section 4.8 Undesirable effects).
Severe cutaneous adverse reactions
Severe cutaneous adverse reactions (SCARs), such as drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), Lyell’s syndrome (toxic epidermal necrolysis or TEN) and acute generalised exanthematous postulosis (AGEP), potentially life-threatening, have been reported in patients to whom Xenetix had been administered (see section 4.8, Undesirable effects). When initiating the treatment, patients should be informed of the signs and symptoms and should be monitored closely to detect serious adverse skin reactions. Xenetix should be discontinued immediately if a severe hypersensitivity reaction is suspected. In the event of a severe cutaneous adverse reaction in a patient taking Xenetix, Xenetix should never be re-administered to this patient (see Section 4.3).


4.4.1.2.2. Renal impairment
Iodinated contrast agents may cause temporary changes in renal function or worsen pre- existing renal impairment. Preventive measures are as follows:

•   Identify at-risk patients, i.e., with dehydration, renal insufficiency, diabetes, severe heart failure, monoclonal gammapathy (multiple myeloma, Waldenstrom's macroglobulinemia), history of renal failure after contrast agent administration; infants below the age of one year and elderly subjects with atheroma.
•   Hydrate as necessary using an appropriate quantity of saline solution.
•   Avoid combinations with nephrotoxic medicinal products. If this combination is necessary, increase biological renal monitoring. The medicines products concerned include aminosides, organoplatinum compounds, high dose methotrexate, pentamidine, foscarnet and certain antivirals (aciclovir, ganciclovir, valaciclovir, adefovir, cidofovir, tenofovir), vancomycin, amphotericin B, immunosuppressants such as ciclosporin, tacrolimus and ifosfamide.
•   Allow at least 48 hours between radiological examinations with contrast agent injections or delay further examinations until renal function returns to baseline.
•   Prevent lactic acidosis in diabetics treated with metformin, by monitoring serum creatinine levels. Normal renal function: metformin is discontinued when the contrast agent is administered, for a period of at least 48 hours or until normal renal function is restored. Abnormal renal function: metformin is contraindicated. In an emergency: if the examination cannot be avoided, precautions must be taken: discontinuation of metformin, hydration, renal function monitoring and monitoring for signs of lactic acidosis.
Haemodialysis patients can receive iodinated contrast agents, as these products are dialysable. Consult with the haemodialysis department prior to administration.

4.4.1.2.3. Hepatic insufficiency
Particular attention is required when a patient presents with both hepatic and renal insufficiency since, in this situation, the risk for retention of contrast agent is increased.
Care should be taken in renal or hepatic impairment, diabetes or in patients with sickle cell disease.

Adequate hydration should be ensured in all patients before and after contrast media administration and particularly in patients with renal impairment or diabetes where it is important to maintain hydration to minimise deterioration in renal function.

4.4.1.2.4. Asthma
It is recommended that asthma be brought under control before the injection of an iodinated contrast agent.
Due to an increased risk of bronchospasm, special caution should be taken in patients who suffered an asthmatic attack within 8 days prior to the examination.

4.4.1.2.5. Disturbed thyroid function

Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration to adult and paediatric patients, including infants. Some patients were treated for hypothyroidism. See also section on Paediatric population.
Paediatric population:
Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age
Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media (ICM) in pediatric patients 0 to 3 years of age.
Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after ICM exposure. Pediatric patients with congenital cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures.


An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to ICM, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.



4.4.1.2.6. Cardiovascular diseases (see Section 4.8 Undesirable effects)
In patients with cardiovascular disease (such as early or patent heart failure, coronaropathy, pulmonary hypertension, valvular heart disease, cardiac arrhythmias), the risk of cardiovascular reactions is increased after administration of an iodinated contrast agent. Intravasal injection of the contrast medium may cause pulmonary oedema in patients with manifest or incipient heart failure, whereas administration in pulmonary hypertension and heart valve disorders may result in marked changes in haemodynamics.
The frequency and degree of severity appear to be related to the severity of the cardiac disorders. In case of severe and chronic hypertension, the risk of renal damage secondary to the administration of the contrast medium and also due to the catheterization itself may be increased. Careful evaluation of the risk-benefit ratio is necessary in these patients.

4.4.1.2.7. Central nervous system disorders
The benefit-to-risk ratio must be evaluated in each case:
•   due to the risk of aggravation of neurological symptoms in patients with transient ischaemic attack, acute cerebral infarction, recent intracranial haemorrhage, cerebral oedema, or idiopathic or secondary (tumour, scar) epilepsy.
•   if the case of intra-arterial use in alcoholics (acute or chronic alcoholism) and in people addicted to other substances.

4.4.1.2.8. Phaeochromocytoma
Patients with phaeochromocytoma may develop a hypertensive crisis after intravascular administration of a contrast agent and require appropriate management prior to the examination.

4.4.1.2.9. Myasthenia gravis
Administration of a contrast agent may worsen the symptoms of myasthenia gravis.
4.4.1.2.10. Increased adverse reactions
Undesirable effects linked to iodinated contrast agent administration may be intensified in patients showing pronounced agitation, anxiety and pain. Appropriate management may be necessary, up to and including sedation.

4.4.1.2.11. Excipients
This medicine contains sodium. It contains less than 1 mmol sodium per 100 mL i.e., it is essentially “sodium-free”.




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