Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use.

Special precautions for use of non-ionic contrast media in general:

Hypersensitivity:
A positive history of allergy, asthma, or untoward reactions to iodinated contrast media indicates a need for special caution. Premedication with corticosteroids or histamine H1 and H2 antagonists might be considered in these cases.
The risk of serious reactions in connection with use of VISIPAQUE is regarded as minor.
However, iodinated contrast media may provoke, anaphylactoid reactions or other manifestations of hypersensitivity.

The possibility of hypersensitivity including serious, life-threatening, fatal anaphylactic/ anaphylactoid reactions should always be considered. The majority of serious undesirable occur within the first 30 minutes. Late onset (that is 1 hour or more after application) hypersensitivity reactions can occur. A course of action should therefore be planned in advance, with necessary drugs and equipment available for immediate treatment, should a serious reaction occur. It is advisable always to use an indwelling cannula or catheter for quick intravenous access throughout the entire X-ray procedure.


The use of beta -adrenergic blocking agents lowers the threshold for and increases the severity of contrast reactions and reduces the responsiveness of treatment of anaphylactoid reactions with adrenaline.
Asthmatic patients are at higher risk on concomitant beta blocker therapy (see section 4.5) Patients should be observed for at least 30 minutes after administration of VISIPAQUE.

Coagulopathy:

Non-ionic, iodinated contrast media inhibit blood coagulation in vitro less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing contrast media including non-ionic media. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting 
Risk for thromboembolism:
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angio-cardiographic procedures with both ionic and non-ionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications, may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended, including close attention to guide wire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing (e.g. with heparinized saline solutions) and minimizing the length of the procedure. Advanced life support facilities should be readily available.

Care should be taken in patients with homocystinuria.

Hydration
Adequate hydration should be assured before and after contrast media administration. This applies especially to patients with multiple myeloma, diabetes mellitus, renal dysfunction, as well as to infants, small children and elderly patients. Young infants (age < 1 year) and especially neonates are susceptible to electrolyte disturbance and haemodynamic alterations.

Cardio-circulatory reactions

Care should also be taken in patients with serious cardiac disease and pulmonary hypertension as they may develop haemodynamic changes or arrhythmias. Rarely severe life-threatening reactions and fatalities of cardiovascular origin such as cardiac-, cardio-respiratory arrest and myocardial infarction have occurred.


CNS disturbances
Encephalopathy has been reported with the use of iodixanol (see section 4.8).
Contrast encephalopathy may manifest with symptoms and signs of neurological dysfunction such as headache, visual disturbance, cortical blindness, confusion, seizures, loss of coordination, hemiparesis, aphasia, unconsciousness, coma and cerebral oedema within minutes to hours after administration of iodixanol, and generally resolves within days. The product should be used with caution in patients with conditions that disrupt the integrity of the blood brain barrier (BBB), Potentially leading to increased permeability of contrast media across the BBB and increasing the risk of encephalopathy
Patients with acute cerebral pathology, tumours or a history of epilepsy are predisposed for seizures and merit particular care. Also alcoholics and drug addicts have an increased risk for seizures and neurological reactions. In regard to intravascular application care should be taken in patients with acute stroke or acute intracranial bleeding, in patients with altered blood brain barrier, cerebral edema or acute demyelinisation.
If contrast encephalopathy is suspected, administration of iodixanol should be discontinued and appropriate medical management should be initiated.

Renal reactions

Major risk factor for contrast medium-induced nephropathy is underlying renal dysfunction.
Diabetes mellitus and the volume of iodinated contrast medium administered are contributing factors in the presence of renal dysfunction. Additional concerns are dehydration, advanced arteriosclerosis, poor renal perfusion and the presence of other factors that may be nephrotoxic, such as certain medications or major surgery.

To prevent acute renal failure following contrast media administration, special care should be exercised in patients with pre-existing renal impairment and diabetes mellitus as they are at risk.
Patients with paraproteinemias (myelomatosis and Waldenström's macroglobulinemia) are also at risk.

Preventive measures include:
• Identification of high risk patients

•   Ensuring adequate hydration. If necessary by maintaining an i.v. infusion from before the procedure until the contrast medium has been cleared by the kidneys.
•   Avoiding additional strain on the kidneys in the form of nephrotoxic drugs, oral cholecystographic agents, arterial clamping, renal arterial angioplasty, or major surgery, until the contrast medium has been cleared.
•   Dose reducing to a minimum.
•   Postponing a repeat contrast medium examination until renal function returns to pre- examination levels.

Iodinated contrast agents can be used by patients on haemodialysis as the agents are removed by the dialysis process.

Diabetic patients receiving metformin:
Intravascular contrast studies with iodinated contrast media can lead to acute alteration of renal function and have been associated with lactic acidosis in patients with impaired renal function receiving metformin.
To prevent lactic acidosis, the serum creatinine level should be measured in diabetic patients treated with metformin prior to intravascular administration of iodinated contrast medium.
1. Patients with eGFR equal or greater than 60 ml/min/1.73 m2 (CKD 1 and 2) can continue to take metformin normally.
2. Patients with eGFR 30‐59 ml/min/1.73 m2 (CKD 3): a. Patients receiving intravenous contrast medium with eGRF equal or greater than 45 ml/min /1.73 m2 can continue to take metformin normally.
b. In patients receiving intra‐arterial contrast medium, and those receiving intravenous contrast medium with an eGFR between 30 and 44 ml/min/1.73 m2 metformin should be discontinued 48 hours before contrast medium and should only be restarted 48 hours after contrast medium if renal function has not deteriorated.
3. In patients with eGFR less than 30 ml/min/1.73 m2 (CKD 4 and 5) or with an intercurrent illness causing reduced liver function or hypoxia, metformin is contraindicated and iodinated contrast media should be avoided.
4. In emergency patients in whom renal function is either impaired or unknown, the physician shall weigh out risk and benefit of an examination with a contrast medium.
Metformin should be stopped from the time of contrast medium administration. After the procedure, the patient should be monitored for signs of lactic acidosis. Metformin should be restarted 48 hours after contrast medium if serum creatinine/eGFR is unchanged from the pre‐imaging level.

Impaired renal and hepatic function

Particular care is required in patients with severe disturbance of both renal and hepatic function as they may have significantly delayed contrast medium clearance. Patients on haemodialysis may receive contrast media for radiological procedures. Correlation of the time of contrast media injection with the haemodialysis session is unnecessary because there is no evidencee that haemodialysis protects patients with impaired renal function from contrast medium induced nephropathy.

Myasthenia gravis

The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis.
Phaeochromocytoma

In patients with phaeochromocytoma undergoing interventional procedures, alpha blockers should be given as prophylaxis to avoid a hypertensive crisis.

Disturbances in thyroid function
Patients with manifest but not yet diagnosed hyperthyroidism, patients with latent hyperthyroidism (e.g., nodular goitre) and patients with functional autonomy (often e.g. elderly patients, especially in regions with iodine deficiency) are at higher risk of acute thyrotoxicosis after use of iodinated contrast media. The additional risk should be evaluated in such patients before use of an iodinated contrast medium. Testing of thyroid function prior to contrast medium administration and/or preventative thyreostatic medication may be considered in patients with suspected hyperthyroidism. The patients at risk of should be monitored for the development of thyrotoxicosis in the weeks following the injection.
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

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.

Extravasation:
VISIPAQUE due to its isotonicity gives rise to less local pain and extravascular oedema than hyperosmolar contrast media. In case of extravasation, elevating and cooling the affected site is recommended as routine measures. Surgical decompression may be necessary in cases of compartment syndrome.
Visipaque may, dependent on the indication, contain more than 23 mg sodium per dose. This must be taken into consideration in patients on a controlled sodium diet 
Observation-time:
After contrast medium administration the patient should be observed for at least 30 minutes, since the majority of serious side effects occur within this time. However, experience shows that hypersensitivity reactions may appear up to several hours or days post injection.

Intrathecal use:
Following myelography the patient should rest with the head and thorax elevated by 20° for one hour. Thereafter he/she may ambulate carefully but bending down must be avoided. The head and thorax should be kept elevated for the first 6 hours if remaining in bed. Patients suspected of having a low seizure threshold should be observed during this period. Outpatients should not be completely alone for the first 24 hours.

Effects on Driving

4.7    Effects on ability to drive and use machines

No studies on the ability to drive or use machines have been performed. However, it is not advisable to drive a car or use machines during the first 24 hours following intrathecal examination .