Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use.

Special precautions for use of non-ionic monomeric contrast media in general: Hypersensitivity:
A positive history of allergy, asthma, or untoward reactions to iodinated contrast media indicates a need for special caution. Any application of contrast media should, therefore, be preceded by a detailed medical history, in patients with allergic diathesis and in patients with known hypersensitivity reactions a very strict indication is required.
Premedication with corticosteroids or histamine H1 and H2 antagonists might be considered in patients at risk for intolerance, they may, however, not prevent anaphylactic shock, they may actually mask initial symptoms. In patients with bronchial asthma especially the risk for bronchospasm is increased.
The risk of serious reactions in connection with use of Kopaq is regarded as minor. However, iodinated contrast media may provoke serious, life-threatening, fatal anaphylactic/anaphylactoid reactions or other manifestations of hypersensitivity.
Independent of quantity and route of administration, symptoms such as angio-oedema, conjunctivitis, coughing, pruritus, rhinitis, sneezing and urticaria may be indicative of a serious anaphylactoid reaction requiring treatment.
A course of action should therefore be planned in advance, with necessary drugs, equipment, medical experience and skilled personnel available for immediate treatment, should a serious reaction occur. In imminent state of shock, administration of the contrast medium must be terminated immediately and - if necessary - specific intravenous treatment must be initiated. It is advisable to use an indwelling cannula or catheter for quick intravenous access throughout the entire X-ray procedure.
Patients using beta-adrenergic blocking agents, particularly asthmatic patients, may have a lower threshold for bronchospasm and are less responsive to treatment with beta agonists and adrenaline, which may necessitate the use of higher doses. These patients may also present with atypical symptoms of anaphylaxis which may be misinterpreted as vagal reaction.
Usually, hypersensitivity reactions become manifest as minor respiratory or cutaneous symptoms, such as mild difficulties of breathing, skin reddening (erythema), urticaria, pruritus or facial oedema. Severe reactions such as angio-oedema, subglottis oedema, bronchial spasm and shock are rare.

These reactions usually occur within one hour following application of the contrast medium. In rare cases, hypersensitivity may occur delayed (after hours or days), but these cases are rarely life threatening, and mainly affect the skin.
Coagulopathy
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiocardiographic procedures with both ionic and non-ionic contrast media. When performing vascular catheterization procedures one should pay meticulous attention to the angiographic technique and flush the catheter frequently (e.g.: with heparinized saline) so as to minimize the risk of procedure-related thrombosis and embolism.

During catheterization it should be considered that besides the contrast medium numerous other factors may also influence the development of thromboembolic events.
These are: duration of the examination, number of injections, type of catheter and syringe material, existing underlying diseases and concomitant medication.

The examination shall be kept as short as possible.
Care should be taken in patients with homocystinuria. (Risk for thromboembolism).
In vitro, non-ionic contrast media have a weaker coagulation inhibiting effect than ionic contrast media.

Hydration:
Adequate hydration should be assured before and after contrast media administration. If necessary, the patient should be hydrated intravenously until excretion of the contrast medium is complete.
This applies especially to patients with dys- and paraproteinaemias like multiple myeloma, diabetes mellitus, renal dysfunction, hyperuricaemia, as well as to infants, small children and elderly patients and patients in bad general condition. In patients at risk the water and electrolyte metabolism must be controlled and symptoms of a dropping serum calcium level must be taken care of.
Due to the risk of dehydration induced by diuretics, at first, water and electrolyte rehydration is necessary to limit the risk of acute kidney injury .

Cardio-circulatory reactions:
Care should also be taken in patients with serious cardiac disease or cardio-circulatory disease and pulmonary hypertension as they may develop haemodynamic changes or arrhythmias.
This is especially applicable following intracoronary, left and right ventricular application of contrast media (see also section 4.8).
Patients with cardiac insufficiency, severe coronary heart disease, instable angina pectoris, valvular diseases, previous myocardial infarction, coronary bypass and pulmonary hypertension are especially predisposed for cardiac reactions.
In elderly patients and patients with pre-existing cardiac diseases reactions with ischemic changes in the ECG and arrhythmia occur more frequently.
In patients with cardiac insufficiency intravasal injection of contrast media can induce pulmonary oedema.

CNS disturbances:

Encephalopathy has been reported with the use of contrast media, such as iohexol (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. Symptoms usually occur within minutes to hours after administration of iohexol, and generally resolve within days.
Factors which increase blood-brain barrier permeability will ease the transfer of contrast media to brain tissue and may lead to possible CNS reactions for instance encephalopathy.

Caution is advised in intravascular application to patients with acute cerebral infarction or acute intracranial bleeding as well as in patients with diseases causing disturbance of the blood-brain barrier, in patients with cerebral oedema, acute demyelinisation or advanced cerebral atherosclerosis.

If contrast encephalopathy is suspected, administration of iohexol should be discontinued and appropriate medical management should be initiated.


Neurological symptoms caused by metastases, degenerative or inflammatory processes can be aggravated by application of contrast media.

Patients with symptomatic cerebrovascular diseases, previous stroke or frequent transitory ischemic attacks are at increased risk for contrast medium-induced neurological complications following intra-arterial injection. Intra-arterial injection of contrast media may induce vasospasm with resulting cerebral ischaemic phenomena.

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. A few patients have experienced a temporary hearing loss or even deafness after myelography, which is believed to be due to a drop in spinal fluid pressure by the lumbar puncture per se.

Renal reactions:
Use of iodinated contrast media may cause increase in serum creatinine and acute kidney injury. To prevent these conditions following contrast media administration, special care should be exercised in patients with pre-existing renal impairment and diabetes mellitus as they are at risk.
Other predisposing factors are preceding renal failure following application of contrast media, a history of renal disease, age over 60 years, dehydration, advanced arteriosclerosis, decompensated cardiac insufficiency, high doses of contrast media and multiple injections, direct application of contrast media to the renal artery, exposition to further nephrotoxins, severe and chronic hypertension, hyperuricaeia, paraproteinemias (myelomatosis and Waldenström’s macroglobulinemia, plasmocytoma) or dysproteinemias.
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 reduction to a minimum.
-       Postponing a repeat contrast medium examination until renal function returns to pre-examination levels.
Patients on haemodialysis may receive contrast media for radiological procedures.
Correlation of the time of contrast media injection with the haemodialysis session is unnecessary.
Diabetic patients receiving metformin.
There is a risk of the development of lactic acidosis when iodinated contrast agents are administered to diabetic patients treated with metformin, particularly in those with impaired renal function. To reduce the risk of lactic acidosis, serum creatinine level should be measured in diabetic patients treated with metformin prior to intravascular administration of iodinated contrast media and the following precautions undertaken in the following circumstances:
1. Patients with eGFR equal or greater than 60 mL/min/1.73m2 (CKD 1 and 2) can continue to take metformin normally.
2. Patients with eGFR 30-59 mL/min/1.73m2 (CKD 3)
- Patients receiving intravenous contrast medium with eGRF equal or greater than 45 mL/min /1.73m2 can continue to take metformin normally
- In patients receiving intra-arterial contrast medium, and those receiving intravenous contrast medium with an eGFR between 30 and 44 mL/min/1.73m2 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/1.73m2 (CKD 4 and 5) or with an intercurrent illness causing reduced liver function or hypoxia metformin is contraindicated 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.
 patients with disturbance of both hepatic and renal 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.

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.

Disturbed thyroid function
Due to free iodide in the solutions and additional iodide released by deiodination, iodinated contrast media influence thyroid function. This may induce hyperthyroidism or even thyrotoxic crisis in predisposed patients.
Patients with manifest but not yet diagnosed hyperthyroidism are at risk, patients with latent hyperthyroidism (e.g., nodular goitre) and patients with functional autonomy (often e.g. elderly patients, especially in regions with iodine deficiency) should therefore have their thyroid function assessed before examination if such conditions are suspected.
Before administering an iodinated contrast agent, make sure that the patient is not about to undergo thyroid scan or thyroid function tests or treatment with radioactive iodine, as administration of iodinated contrast agents, regardless of the route, interferes with hormone assays and iodine uptake by the thyroid gland or metastases from thyroid cancer until urinary iodine excretion returns to normal. See also section 4.5.
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.



Anxiety conditions
A sedative may be administered in the case of marked anxiety.

Sickle cell disease
Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when injected intravenously and intra-arterially.

Further risk factors
Among patients with autoimmune diseases cases of serious vasculitis or Stevens-Johnson-like syndromes have been observed.
Severe vascular and neurological diseases, especially in elderly patients are risk factors for reactions to contrast media.

Extravasation
Extravasation of contrast media may on rare occasions give rise to local pain, and oedema and erythema, which usually recedes without sequelae. However, inflammation and even tissue necrosis have been seen. Elevating and cooling the affected site is recommended as routine measures. Surgical decompression may be necessary in cases of compartment syndrome.

Observation-time:
Patients must be kept under close observation for 30 minutes following the last injection as the majority of severe reactions occur at this time.
The patient should remain in the hospital environment (but not necessarily the radiology department) for one hour after the last injection, and should return to the radiology department if any symptoms develop.

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.

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.
Especially in infants and small children, adequate hydration should be assured before and after contrast media administration. Nephrotoxic medication should be suspended. The age dependent reduced glomerular filtration rate in infants can also result in delayed excretion of contrast agents.
Young infants (age < 1 year) and especially neonates are susceptible to electrolyte disturbance and haemodynamic alterations.
Cerebral arteriography:
In patients with advanced arteriosclerosis, severe hypertension, cardiac decompensation, old age, and previous cerebral thrombosis or embolism and migraine, cardiovascular reactions such as bradycardia and increases or decreases in blood pressure may occur more often.

Arteriography
In relation to procedure used, injury of the artery, vein, aorta and adjacent organs, pleurocentesis, retroperitoneal bleeding, spinal cord injury and symptoms of paraplegia may occur.
Kopaq contains less than 1 mmol /ml (23 mg/ml) sodium, i.e. practically does not contain sodium.

Effects on Driving

4.7     Effects on ability to drive and use machines
It is not advisable to drive a car or use machines for one hour after the last injection or for 24 hours following intrathecal procedure (see section 4.4). However, individual judgement must be performed if persistent post-myelography symptoms.