Summary of medicine characteristics - IOHEXOL 300 MG I/ML SOLUTION FOR INJECTION
1 NAME OF THE MEDICINAL PRODUCT
Iohexol 300 mg I/ml solution for injection
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
| Active substance | Concentration | Content per ml. |
| lohexol (INN) lohexol (INN) | 300 mg I/ml 350 mg I/ml | 647 mg equivalent 300 mg I 755 mg equivalent 350 mg I |
For the full list of excipients see section 6.1.
Iohexol is a non-ionic, monomeric, tri-iodinated, water-soluble X-ray contrast agent (Iohexol in a concentration of 140 mg I/ml is isotonic with blood and tissue fluid). The pH is 6.8 to 7.6 for all solutions.
The osmolality and viscosity of Iohexol are as follows:
| Concentration | Osmolality | Viscosity (mPa s) |
| (mOsm/kg H20 37°C) | 20°C | |
| 300 mg I/ml | 709 | 11.8 |
| 350 mg I/ml | 887 | 23.1 |
Method: vapour pressure osmometry
3 PHARMACEUTICAL FORM
Solution for injection
Iohexol is supplied ready for use as a clear, colourless to pale yellow, sterile aqueous solution.
4.1 Therapeutic indications
This medicinal product is for diagnostic use only.
X-ray contrast medium for use in adults and children for urography, phlebography, i.v. DSA, CT, arteriography, cardioangiography and i.a. DSA. Myelography.
For use in body cavities: Arthrography, ERP/ERCP, herniography, hysterosalpingography, sialography and use in the G-I tract.
4.2 Posology and method of administration
The dosage depends on the type of investigation and the technique used. Usually the same iodine concentration and volume is used as for other iodinated X-ray contrast media in current use.
Adequate hydration should be assured before and after administration as for other contrast media.
For intravenous, intra-arterial and intrathecal use, and use in body cavities.
The following dosages may serve as a guide:
Guidelines for intravenous use
| Indication | Concentration | Volume | Comments |
| Urography | |||
| Adults | 300 mg I/ml or 350 mg I/ml | 40–80 ml 40–80 ml | |
| Children < 7 kg | 240 mg I/ml or 300 mg I/ml | 4 ml/kg b.w. 3 ml/kg b.w. | |
| Children > 7 kg | 240 mg I/ml or 300 mg I/ml | 3 ml/kg b.w. 2 ml/kg b.w. | |
| Phlebography (leg) | 240 mg I/ml or 300 mg I/ml | 20–100 ml/leg |
| Digital subtraction angiography | 140 mg I/ml | Up to 3 ml per kg body weight | |
| Adults | 300 mg I/ml | 20 – 60 ml/inj. | |
| or 350 mg I/ml | 20 – 60 ml/inj. | ||
| Children | 140 mg I/ml | Dependent upon age, weight and pathology | |
| CT enhancement | 140 mg I/ml | 100 –400 ml | |
| Adults | or 240 mg I/ml | 100–250 ml | |
| or 300 mg I/ml | 100–200 ml | ||
| or 350 mg I/ml | 100–150 ml |
Guidelines for intraarterial use:
| Indication | Concentration | Volume | Comments |
| Arteriographies Arch aortography Selective cerebral Aortography Femoral Various | 300 mg I/ml 300 mg I/ml 350 mg I/ml 300 mg I/ml or 350 mg I/ml 300 mg I/ml | 30–40 ml/inj. 5–10 ml/inj. 40–60 ml/inj. 30–50 ml/inj. depending on type of avnminnti on------- | |
| Cardioangi ography Adults Left ventricle and aortic root inj. Selective coronary arteriography Children | 350 mg I/ml 350 mg I/ml 300 mg I/ml or 350 mg I/ml | 30–60 ml/inj. 4–8 ml/inj. depending on age, weight and pathology (max 8____ | |
| Digital subtraction angiography Adults Children | 140 mg I/ml or 240 mg I/ml or 300 mg I/ml 140 mg I/ml | 4 – 10 ml/inj. 1 – 15 ml/inj. 1 – 15 ml/inj. Dependent upon age, weight and |
Guidelines for intrathecal use:
| Indication | Concentration | Volume | Comments |
| Lumbar and thoracic myelography | 240 mg I/ml | 8 – 12 ml |
| (lumbar injection) Cervical myelography (lumbar injection) | 240 mg I/ml or 300 mg I/ml | 10–12 ml 7 – 10 ml | |
| Cervical myelography (lateral cervical injection) | 240 mg I/ml or 300 mg I/ml | 6 – 10 ml 6 – 8 ml | |
| CT cisternography (lumbar injection) | 240 mg I/ml | 4 – 12 ml |
To minimize possible adverse reactions a total dose of 3 g iodine should not be exceeded.
Guidelines for body cavities:
| Indication | Concentration | Volume | Comments |
| Arthrography | 240 mg I/ml or 300 mg I/ml or 350 mg I/ml | 5 – 20 ml 5 – 15 ml 5 – 10 ml | |
| ERP/ERCP | 240 mg I/ml | 20 – 50 ml | |
| Hemiography | 240 mg I/ml | 50 ml | |
| Hysterosalpingograph y | 240 mg I/ml or 300 mg I/ml | 15 – 50 ml 15 – 25 ml | |
| Sialography | 240 mg I/ml or 300 mg I/ml | 0.5 – 2 ml 0.5 – 2 ml | |
| Gastrointestinal studies | 350 mg I/ml | 10–20 ml |
1 The recommended dose is not possible using this product, however there are other products available with Iohexol dosages lower than 300 mg I/ml 647 mg/ml.
For elderly patients, patients with hepatic and/or renal impairments, the usual/proposed doses for adults can be used.
4.3 Contraindications
Hypersensitivity to the active ingredient, other iodine X-ray media, or to any of the excipients listed in section 6.1.
Manifest thyrotoxicosis.
There are no clear, absolute contraindications for the use of non-ionic uro-angiographic contrast media.
4.4 Special warnings and precautions for use
Special precautions for using non-ionic contrast media in general:
Sensitivity
A history of allergy, asthma or untoward reactions to iodinated radiographic contrast media calls for extra caution. Each application of contrast media should therefore be preceded by a detailed medical history, for 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 blockers may be considered in these cases, for patients with an increased risk of intolerance. However, they cannot prevent anaphylactic shock. They may even mask first symptoms. In patients with bronchial asthma mainly the risk of bronchospasm is increased.
The risk of adverse effects when using Iohexol is considered to be minimal. Iodinated X-ray contrast media can, however, cause serious, life-threatening anaphylactic reactions or other signs of hypersensitivity.
Independent of the amount and the method of administration, symptoms such as angioedema, conjunctivitis, cough, pruritus, rhinitis, sneezing and urticaria may be an indication of a severe anaphylactic reaction requiring treatment.
In the event that adverse effects occur, a treatment plan as well as necessary medication, equipment, medical experience and educated staff should be present in advance, to allow for immediate action if necessary.
In threatening shock, administration of the contrast medium must be discontinued immediately and if necessary a specific intravenous treatment started.
In connection with this it is recommended that an indwelling catheter or needle be used for intravenous or intraarterial contrast medium administration.
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 exhibit atypical symptoms of anaphylaxis. These could be misconstrued as a vagal reaction.
Hypersensitivity reactions usually manifest themselves as minor respiratory or cutaneous symptoms such as mild breathing difficulties, redness of the skin (erythema), urticaria, pruritus or facial edema. Severe reactions such as angioedema, subglottic edema, bronchial spasms and shock are rare. These reactions usually occur within one hour after administration of the contrast agent. In rare cases delayed hypersensitivity may occur (after hours or days), but these cases are rarely life threatening, and mainly affect the skin.
Observation period:
Patients should generally remain under medical supervision for at least one hour after administration since the majority of side effects occurs within this period. Delayed reactions may be observed. The observation period especially applies to patients with impaired renal function. For patients with congestive heart failure, a period of observation of several hours is indicated.
Coagulopathy
Catheter angiography with contrast media bears a risk to induce thrombo-embolic diseases. In vitro, non-ionic contrast media have a weaker coagulation-inhibitory effect than ionic contrast media. During catheterization it must be considered that in addition to the contrast medium numerous other factors may also have an influence on the development of thrombo-embolic events. These include: the duration of the study, the number of injections, catheter and syringe material type, existing underlying diseases and concomitant medications. In conducting vascular catheterisation care must be put into a precise angiographic technique. To minimise the risk of procedure-related thrombosis and embolism, the catheter must be regularly rinsed (e.g., with heparinized physiologic saline). The investigation should be kept as short as possible.
In patients with homocystinuria, there is the risk that an angiographic procedure may cause thrombosis or embolism.
Caution is indicated in patients in whom thrombosis, phlebitis, embolism, local infection or total occlusion of the venous system is suspected. In order to prevent extravasation, administration under fluoroscopy is recommended.
When the contrast medium is administered intra-arterially, pulsations must be perceived at all times.
In the presence of thromboangiitis obliterans (M. Buerger), or ascending infections with ischemia, a clear indication for angiography must exist. Otherwise such a study is contra-indicated in these cases.
Hydration
Before and after contrast administration it must be guaranteed that the patient is adequately hydrated. If necessary, the patient must be hydrated intravenously until excretion of the contrast medium is complete. This applies particularly for patients with multiple myeloma, diabetes mellitus, renal insufficiency, hyperuricemia as well as for (young) children, the elderly and patients with a poor general condition. In risk patients the water and electrolyte metabolism should be monitored and symptoms of a sudden fall in serum calcium level should be managed. Due to the risk of dehydration, induced by diuretics, first water and electrolytes rehydration is necessary to reduce the risk of acute renal failure. In particular children under the age of 1 year and newborns are susceptible to disturbances in hemodynamics and electrolytes.
Cardio-circular reactions
Special attention should be paid to patients with severe heart disease/heartcirculation and pulmonary hypertension, since in these patients hemodynamic changes or cardiac arrhythmias may occur. This must particularly be done after administration of contrast medium in the coronary arteries, the left and right ventricle (see also section 4.8).
Patients with cardiac insufficiency, severe coronary heart disease, unstable angina pectoris, valvular diseases, previous myocardial infarction, coronary artery bypass graft and pulmonary hypertension are specially predisposed to cardiac reactions.
In elderly patients and patients with pre-existing cardiac diseases, reactions with ischemic ECG changes and arrhythmias occur more often.
In patients with heart failure intravascular injection of contrast media may cause pulmonary edema.
CNS disorders
In connection with the potential risk of seizure, caution is indicated in patients with acute cerebral pathology, tumors or epilepsy. Alcoholics and drug addicts also have an increased risk for seizures and neurological reactions.
Encephalopathy has been reported with the use of 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 and in patients with cerebral edema, acute demyelinisation or advanced cerebral atherosclerosis. If contrast encephalophy is suspected, appropriate medical management should be initiated and iohexol must not be readministered.
Neurological symptoms caused by metastases, degenerative or inflammatory processes may be exacerbated by the use of contrast media. Intra- arterial injection of contrast media may induce vasospasms, resulting in cerebral ischemic events. Patients with symptomatic cerebrovascular disease, previous stroke or frequent transient ischemic attacks have an increased risk of contrast medium-induced neurological complications after an intra-arterial injection.
Some patients experience a temporary hearing loss or even deafness after myelography. It is assumed that this is caused by a drop in spinal fluid pressure as a consequence of the lumbar puncture.
Renal reactions
The use of iodinated radiological contrast media can lead to contrast-induced nephropathy, worsening of renal function or acute renal failure. In order to prevent the occurrence of these side effects after the administration of contrast media, particular caution should be exercised in patients with already existing compromised renal function or diabetes mellitus, since these patients demonstrate an increased risk for this. Other predisposing factors precede kidney failure after application of contrast media, a history of kidney disease, age over 60 years, dehydration, advanced arteriosclerosis, decompensated heart failure, high doses of contrast media and multiple injections, direct administration of contrast agents to the renal artery, exposure to further nephrotoxins, severe and chronic hypertension, hyperuricemia, paraproteinemias (myelomatosis and Waldenstrom's macroglobulinemia plasmacytoma) or dysproteinemias.
Preventive measures:
– Identify patients with a high risk
– Ensure sufficient hydration. If necessary, administer IV hydration prior to the administration until the contrast medium is excreted by the kidneys.
– Avoid additional stress on the kidneys by postponing the use of nephrotoxic medication, cholecystographic media, arterial stenosis, renal arterial angioplasty or extensive surgery until the contrast medium has been excreted by the kidneys.
– Dose reduction to a minimum
– Postpone repeated study using contrast media until renal function has been restored to baseline values.
X-ray examination with contrast media is permitted in haemodialysis patients. The time interval between injection of the contrast medium and the haemodialysis is not important.
Diabetic patients being treated with metformin:
Diabetic patients being treated with metformin run the risk of developing lactic acidosis when iodinated radiologic contrast media are administered to them. This is particularly true of patients with compromised renal function. To reduce the risk of lactic acidosis, the concentration of creatinine in the serum must be determined before these patients are administered intravascular iodinated radiologic contrast media, and the following precautionary measures must be taken under the following circumstances.
With a normal serum creatinine level (<130^mol/liter)/normal renal function:
The use of metformin should be discontinued when the study using contrast media commences. The use of metformin can be recommenced 48 hours after the study if the serum creatinine level is normal.
With an abnormal serum creatinine level (>130p,mol/liter)/decreased renal function:
The use of metformin should be discontinued 48 hours before commencement of the study using a contrast medium. The use of metformin can be recommenced 48 hours after the study if the serum creatinine level is normal (<130 pmol/l).
In emergencies
If in urgent cases the renal function is abnormal or unknown, the physician should weigh the advantages and disadvantages of the administration of contrast media against each other. Alternative imaging techniques should be considered.
If use of the contrast medium is necessary, the following precautionary measures should be taken:
The use of metformin should be stopped. It is particularly important that the patient be fully hydrated before administration of the contrast medium as well as during the 24 hours after administration. The renal function (e.g. serum creatinine), serum lactic acid and pH of the blood must be monitored, and the hospital personnel should be especially alert to the occurrence of symptoms of lactic acidosis.
Hepatic reactions
A potential risk of transient renal function disorder exists. Particular caution is indicated in patients with serious disturbances in both renal and hepatic function because in these patients the excretion of the contrast medium is significantly delayed.
Myasthenia gravis
Administration of iodinated radiological contrast media can worsen the symptoms of myasthenia gravis.
Pheochromocytoma
In patients with pheochromocytoma that are undergoing interventional procedures, alpha blockers should be given as prophylaxis to prevent hypertensive crisis.
Disturbed thyroidfunction
Because of the free iodide in the solutions and the additional iodide released by deiodination, iodinated contrast media affect the thyroid function. This may induce hyperthyroidism or even thyrotoxic crisis in predisposed patients. If necessary, research must be carried out under the protection of anti-thyroid drugs (see section 4.3). Special attention should be exercised in patients with hyperthyroidism. Patients with a manifest, but not yet diagnosed hyperthyroidism are a risk, patients with latent hyperthyroidism (e.g. nodular goiter) and patients with functional autonomy (often e.g. elderly patients, especially in areas with iodine deficiency) should therefore have their thyroid function tested before the research if such conditions are expected.
Ensure that prior to administration of an iodinated contrast medium the patient must not undergo a thyroid scan nor thyroid function tests nor treatment with radioactive iodine, since administration of iodinated contrast media, regardless of the route, interferes with hormone analysis and iodine uptake by the thyroid or metastases of thyroid cancer until urinary iodine excretion returns to normal. See also section 4.5.
After injection of an iodinated contrast medium, there is also a risk of induction of hypothyroidism.
In premature infants receiving contrast media, consideration must be taken of the possibility that transient hyperthyroidism may be induced.
Anxiety disorders
A sedative may be administered in marked anxiety.
Sickle cell disease
Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when they are injected intravenously and intra-arterially.
Other risk factors
In patients with autoimmune disorders cases of severe vasculitis or Stevens-Johnson-like syndromes have been observed.
Severe vascular and neurological disorders, which are in particular present in elderly patients, are risk factors for contrast medium reactions.
Extravasation
Extravasation of contrast medium can sometimes cause pain, edema and erythema, usually without permanent sequelae. Inflammatory symptoms and even tissue necrosis have been observed. If this occurs, elevation and the application of ice are recommended. If compartmental syndrome occurs, surgical decompression may be required. When the contrast medium is administered intra-arterially, pulsations must be perceived at all times.
Pediatric population:
Transient hypothyroidism has been reported after the administration of iodinated radiological contrast media in premature infants, neonates and other children. Premature infants are particularly sensitive to the effect of iodine. It is recommended to monitor thyroid function. Thyroid function should be monitored in neonates during the first week of life, after administration of iodinated contrast media to the mother during pregnancy. Repeated tests of thyroid function are recommended for 2 to 6 weeks of age, particularly in premature infants with low birth weight or preterm infants. See also section 4.6.
In particular, infants and small children must be kept sufficiently hydrated before and after the administration of the contrast medium. Nephrotoxic medication should be suspended. The age-related accelerated glomerular filtration rate in infants can also lead to delayed excretion of contrast media.
Young children (age <1 year) and especially newborns are sensitive to electrolyte disturbances and hemodynamic changes.
Intrathecal use:
It is recommended to let the patient rest for one hour after myelography with an elevated head and chest at an angle of 20°. Walking is permitted after that period, though bending forward must be avoided. If the patient is in bed, his head and chest should be kept elevated for 6 hours. It is recommended that patients with a low seizure threshold be observed during this period. It is recommended that outpatients not be left entirely let alone for the first 24 hours.
Important information about the ingredients of Iohexol:
This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially ‘sodium-free.
4.5 Interaction with other medicinal products and other forms of interaction
Iodinated radiological contrast media can cause transient decreased renal function, which in combination with metformin may lead to lactic acidosis in diabetics (see section 4.4).
To reduce the risk of possible incompatibilities, it is recommended that the contrast medium not be mixed with other medicines.
Patients treated with interleukin-2 and interferons less than 2 weeks before the study are associated with an increased risk of later reactions (erythema, flu-like symptoms and/or skin reactions).
The concomitant use of certain neuroleptics or tricyclic antidepressants may reduce the seizure threshold and thus increase the risk of contrast medium-induced seizures.
Treatment with P-blockers may lower the threshold for allergic reactions, as well as require a higher dose of P- agonists if hypersensitivity reactions are treated.
Beta-blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists may reduce the efficacy of the cardiovascular compensation mechanisms of changes in blood pressure.
All iodinated radiological contrast media can affect thyroid function tests, with the binding capacity of iodine of the thyroid being decreased for a few weeks after treatment.
Thyroid function tests which are not based on iodine determinations, e.g. T3-resin-uptake or direct thyroxin tests are not affected.
High concentrations of contrast medium in the serum and urine can affect laboratory tests for bilirubin, protein or inorganic substances (such as iron, copper, calcium and phosphate). These substances should therefore not be tested on the day of the study.
The literature gives no indications of interactions between renally excreted contrast media and oral contrast media for cholecystography.
During the concomitant use of contrast media and medicines that can cause vasoconstriction, neurological adverse effects may be intensified.
4.6 Fertility, pregnancy and lactation
Pregnancy:
The safety of Iohexol for use during pregnancy has not been established. An evaluation of animal experiments did not demonstrate direct or indirect harmful effects with regard to reproduction, the development of the embryo or the fetus, the course of the pregnancy and peri- and postnatal development. As far as possible exposure to radiation should be avoided during pregnancy. Therefore, the benefits of radiological studies, with or without contrast, should be weighed carefully versus the possible risks. Iohexol must not be used during pregnancy unless the benefits outweigh the risks and the physician considers the treatment to be essential. In addition to avoiding exposure to radiation, the sensitivity of the fetal thyroid for iodine should be taken into account when assessing the risks and benefits.
Thyroid function should be monitored in all newborns during the first week of life after administration of iodinated contrast agents to the mother during pregnancy. It’s recommended to repeatedly test the thyroid function for 2 to 6 weeks of age, particularly in premature infants with low birth weight or preterm infants.
Breastfeeding:
Contrast media are only minimally excreted in the mother’s milk, and only minimal quantities are absorbed by the intestine. Breastfeeding can be continued normally if iodinated radiological contrast media are administered to the mother. The amount of iohexol excreted in the mother’s milk within 24 hours after injection was 0.5% of the weight-adjusted dosage in a clinical study. The amount of iohexol ingested by the baby in the first 24 hours after injection corresponds with only 0.2% of the pediatric dosage.
4.7 Effects on ability to drive and use machines
It is advised not to drive vehicles or operate machinery during one hour after the last injection or for 24 hours after an intrathecal procedure (see section 4.4). However, individual assessment should be performed if there are persistent post-myelographic symptoms.
Outpatients that leave the hospital after a brief observation period should bear in mind the possible occurrence of dizziness.
4.8 Undesirable effects
GENERAL (applies to all forms of use of iodinated radiological contrast media)
Below are listed the possible general side effects in connection with radiological studies that may occur in (the use of) non-iodinated monomer radiological contrast media. For the side effects that are specific to the respective mode of administration, please refer to the relevant sections.
Hypersensitivity reactions can occur irrespective of the dosage and mode of administration. Mild symptoms can represent the first signs of serious anaphylactic reaction/shock. Administration of the contrast medium should be discontinued immediately and, if necessary, specific therapy commenced via the vascular route.
A transient increase in S-creatinine after administration of iodinated radiological contrast medium occurs frequently.
Contrast-induced encephalopathy may occur after intravascular and intrathecal use of Iohexol. This is caused by extravasation of the contrast agent, which can manifest as sensory, motor or general neurological dysfunction.
Contrast-induced nephropathy may occur.
Iodinism or ‘iodine mumps’ is a very rare complication of iodinated radiological contrast media whereby swelling and sensitivity occurs of the salivary glands up to approximately 10 days after the study.
The stated frequencies are based on internal clinical documentation and published large-scale studies involving more than 90,000 patients.
Frequencies of undesirable side effects are defined as follows:
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) and not known (cannot be estimated from the available data).
Rare: hypersensitivity (including dyspnoea, skin rash, erythema, urticaria, pruritus, skin reaction, conjunctivitis, cough, rhinitis, sneezing, vasculitis, angioneurotic edema, laryngeal edema, laryngospasm, bronchospasm or non-cardiogenic bronchial edema). They can occur either immediately after the injection or up to a few days later and can be an indication of the beginning of a state of shock. Hypersensitivity-related skin reactions may occur up to several days after injection
Not known: Anaphylactic/anaphylactoid reactions, anaphylactic/anaphylactoid shock
Rare: headache
Very rare: dysgeusia (transient metallic taste), seizures
Not known: vasovagal syncope (sudden loss of consciousness)
Rare: bradycardia
Very rare: hypertension, hypotension
Uncommon: nausea Rare:
vomiting
Very rare: diarrhea, abdominal pain /discomfort
Not known: swelling and sensitivity of the salivary glands
General disorders and administration site
disturbances: Common: pain, warm feeling, transient
creatinine increase Uncommon: hyperhidrosis, cold
feeling, vasovagal reactions Rare: fever
Very rare: chills
INTRAVASCULAR USE (INTRA-ARTERIAL AND INTRAVENOUS USE):
First read the section ‘GENERAL’. Below we mention all side effects and their frequencies related to intravascular use of non-iodinated monomer radiological contrast media.
The nature of the side effects that have occurred mainly during intra-arterial administration depends upon the site of the injection and the dosage administered. Selective arteriography and other procedures in which the contrast medium reaches a particular organ in high concentrations may be associated with complications in that particular organ.
Not known: thrombocytopenia
Not known: thyrotoxicosis, transient hypothyroidism
Not known: confusion, agitation, restlessness, anxiety
Rare: dizziness, paresis, palsy, photophobia, sleepiness Very rare: Seizures, disturbance of consciousness, cerebrovascular accident, sensory abnormalities (including hypoaesthesia), paraesthesia, tremor
Not known: transient memory loss, disorientation, transient motor dysfunction (including speech disturbances, aphasia, dysarthria), brain oedema, transient contrast-induced encephalopathy (including transient memory loss, coma, stupor, retrograde amnesia).
Rare: visual impairment
Not known: transient cortical blindness
Not known: Transient hearing loss
Rare: arrhythmia (including bradycardia, tachycardia).
Very rare: myocardial infarction.
Not known: Severe cardiac complications (including cardiac arrest, cardiac/respiratory arrest), cardiac failure, spasm of the coronary arteries, cyanosis, chest pain.
Very rare: sudden facial or neck redness
Not known: shock, arteriospasm, thrombophlebitis, venous thrombosis
Common: transient changes in respiratory rate, respiratory distress
Rare: cough, respiratory arrest
Very rare: dyspnea, asthma attack ()
Not known: severe respiratory symptoms and signs, pulmonary edema, acute respiratory distress syndrome, bronchospasm, laryngospasm, apnoea, aspiration, asthmatic attack
The side effect was not observed in clinical trials
Rare: Diarrhoea
Not known: worsening of pancreatitis, acute pancreatitis
Rare: skin rash, pruritus, urticaria
Very rare: generalized acute pustular rash ()
Not known: Bullous dermatitis, Stevens-Johnson syndrome, erythema multiformae, toxic epidermal necrolysis, acute generalised exanthematous pustulosis (), medication rash with eosinophilia and systemic symptoms, induced psoriasis, erythema, drug eruption, skin exfoliation
* The side effect was not observed in clinical trials
Not known: arthralgia, muscular weakness, muscle spasm
Rare: worsening of renal function including acute renal failure
Uncommon: pain and discomfort
Rare: asthenic conditions (such as feeling unwell, fatigue) Not known: administration site reactions, back pain
Not known: iodine poisoning
INTRATHECAL USE:
First read the section ‘GENERAL’. Below we mention all side effects and their frequencies related to the intrathecal use of non-iodinated monomer radiological contrast media.
Undesirable effects following intrathecal use may be delayed and it may be several hours or even days after the procedure that they occur. The frequency of the side effects is comparable to that of lumbar puncture.
Headache, nausea, vomiting or dizziness can be attributed largely to pressure loss in the subarachnoid space as a consequence of leakage at the puncture site. Excessive withdrawal of cerebrospinal fluid should be avoided in order to minimise pressure loss.
Not known: confusion, agitation
Very common: headache (may be severe and prolonged)
Uncommon: Aseptic meningitis (including chemical meningitis)
Rare: Seizures, dizziness
Not known: abnormal electro-encephalogram, meningism, status epilepticus, motor skills disorders (including speech disorders, aphasia, dysarthria), paraesthesia, hypesthesia, sensory disorder, transient contrast-induced encephalopathy (including transient memory loss, coma, stupor, retrograde amnesia).
Not known: transient cortical blindness, photophobia
Unknown: transient hearing loss
Common: nausea, vomiting
Rare: neck pain, back pain
Not known: muscle spasm
Rare: pain in the limbs
Not known: administration site reactions,
USE IN BODY CAVITIES:
First read the section ‘GENERAL’. Below we mention all side effects and their frequencies related to the use of non-iodinated monomer radiological contrast media in body cavities.
ORAL USE:
Gastrointestinal
disorders: Very common:
diarrhea Common: Nausea,
vomiting Uncommon:
abdominal pain
HYSTEROSALPINGOGRAPHY (HSG):
Very common: lower abdominal pain
ARTHROGRAPHY:
Not known: arthritis
Very common: pain
Description of selected side effects
Thromboembolic complications have been reported in association with contrast-enhanced angiography of coronary, cerebral, renal and peripheral arteries. The contrast medium may have contributed to the complications (see section 4.4).
Cardiac complications including acute myocardial infarction have been reported during or after contrast-enhanced coronary angiography. Elderly patients or patients with severe coronary disease, unstable angina pectoris and left ventricular dysfunction had a higher risk (see section 4.4).
In very rare cases, the contrast medium can pass the blood-brain barrier resulting in absorption of the contrast medium in the cerebral cortex that can lead to neurological reactions such as: seizures, transient motor or sensory disorders, transient confusion, transient memory loss, and encephalopathy (see section 4.4).
Anaphylactic reaction and anaphylactoid shock can lead to: serious hypotension and related symptoms such as hypotoxic encephalopathy, renal and hepatic failure (see section 4.4).
In some cases, extravasation of contrast medium has caused local pain and edema, which usually disappeared again without sequelae. Inflammation, tissue necrosis and compartmental syndrome have occurred (see section 4.4).
Pediatric patients:
Transient hypothyroidism has been reported after the administration of iodinated radiological contrast medium in premature infants, newborns and other children. Premature infants are particularly sensitive to the effect of iodine. Transient hypothyroidism in a premature infant that was breastfed was reported. The mother was repeatedly exposed to Iohexol (see section 4.4).
Sufficient hydration must be ensured particularly in infants and small children both before and after the administration of contrast medium. Nephrotoxic medication should be discontinued. The age-related decreased glomerular filtration rate in infants can also lead to delayed excretion of contrast media.
Reporting suspected side effects
It is important to report suspected side effects after the authorisation of the drug. In this way the relationship between benefits and risks of the drug can be constantly monitored. Healthcare professionals are asked to report any suspected side effects via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Symptoms
The maximum dose of iohexol that can be administered intravascularly is not known. Particularly in patients with decreased renal or cardiac function, consideration should be taken of the occurrence of overdose. On overdose mainly symptoms of circulation disorders of the lungs and heart occur. Iohexol is only minimally neurotoxic.
Preclinical data indicate a high safety margin for Iohexol and no fixed upper limit dose has been established for routine intravascular use. Symptomatic overdose is unlikely in patients with normal renal function, unless the patient receives an excess of 2000 mg I/kg body weight during a limited period of time. The duration of the procedure is important for the renal tolerability of high doses of contrast medium (t^ 2 hours). An overdose that has been administered by mistake is most probably a consequence of complex angiographic procedures in children, in particular when earlier injections of contrast medium with a high concentration have been given.
Treatment
The treatment is symptomatic.
Haemodialysis may be required for patients with decreased renal function.
The water or electrolyte imbalance must be corrected. Renal function should be monitored for 3 days. If necessary, haemodialysis may be used to clear the excess of contrast medium. There is no specific antidote.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: X-ray contrast media, iodinated. ATC code: V08AB02
For most of the haemodynamic, clinical-chemical and coagulation parameters examined following intravenous injection of iohexol in healthy volunteers, no significant deviation from preinjection values has been found. The few changes observed in the laboratory parameters were minor and considered to be of no clinical importance.
5.2 Pharmacokinetic properties
Close to 100 per cent of the intravenously injected iohexol is excreted unchanged through the kidneys within 24 hours in patients with normal renal function. The maximum urinary concentration of iohexol appears within approximately 1 hour after injection. No metabolites have been detected. The protein binding of Omnipaque is very low (less than 2 %).
5.3 Preclinical safety data
Iohexol has a very low acute intravenous toxicity in mice and rats. Animal studies have shown that iohexol has a very low protein binding, and is well tolerated by the kidneys.
6.1 List of excipients
Sodium calcium edetate Trometamol
Hydrochloric acid Sodium hydroxide Water for injection
6.2 Incompatibilities
In the absence of compatibility studies, Iohexol must not be mixed with other medicinal products. A separate syringe should be used.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Keep the container in the outer carton in order to protect from light.
6.5 Nature and contents of container
The product is packed in glass vials (50 and 100 ml). Both vials are made of type I glass. The containers are sealed with chlorobutyl rubber stoppers and sealed with a 32 mm cap with an aluminum/plastic flip-off seal (green or brown).
The vials of this product are available in packs of 10.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The solution of contrast medium should be drawn into the syringe or infusion bottle connected to the equipment only immediately before the test.
The vials containing the solutions of contrast media are intended for single use only. The rubber stoppers should not be pierced more than once.
Any portions contrast medium solution not used in examination must be discarded.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Zentiva Pharma UK Limited
12 New Fetter Lane
London EC4A 1JP
United Kingdom
PL 17780/0900
25/01/2019
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