Omnipaque

Omnipaque injection is supplied ready to use as clear, colourless to pale yellow, sterile aqueous solution. (See Table 1.)

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Iohexol is a non-ionic, monomeric, tri-iodinated, water-soluble X-ray contrast medium. Omnipaque in the concentration of 140 mg I/mL is isotonic with blood and tissue fluid.
The osmolality and viscosity values of Omnipaque are as follows: See Table 2.

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The pH of the product is 6.8-7.6.
Excipients/Inactive Ingredients: Trometamol, sodium calcium edetate, hydrochloric acid (pH adjustment) and water for injections.

Pharmacology: Pharmacodynamics: 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.
Pharmacokinetics: Close to 100 percent 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.
The elimination half-life is approximately 2 hours in patients with normal renal function. No metabolites have been detected. The protein binding of Omnipaque is so low (less than 2%), that it has no clinical relevance and can therefore be neglected.
Toxicology: 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. The cardiovascular and neurotoxicity are low. The histamine release ability and the anticoagulant activity have been shown to be less than for ionic contrast media.

X-ray contrast medium for use in adults and children for cardioangiography, arteriography, urography, phlebography and CT-enhancement. Lumbar, thoracic, cervical myelography and computed tomography of the basal cisterns, following subarachnoid injection. Arthrography, endoscopic retrograde pancreatography (ERP), endoscopic retrograde cholangiopancreatography (ERCP), herniography, hysterosalpingography, sialography and studies of the gastrointestinal tract.

The dosage vary depending on the type of examination, age, weight, cardiac output and general condition of the patient and the technique used. Usually the same iodine concentration and volume is used as with 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 (see Tables 3, 4, 5 and 6).

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Preclinical data indicate a high safety margin for Omnipaque and no fixed upper dose level has been established for routine intravascular use. Symptomatic overdosing is unlikely in patients with normal renal function unless the patient has received an excess of 2000 mg I/kg body-weight over a limited period of time. The duration of the procedure is important for the renal tolerability of high doses of contrast media (t_½~2 hours). Accidental overdosing is most likely following complex angiographic procedures in children, particularly when multiple injections of contrast medium with high-concentration are given.
In cases of overdose, any resulting water or electrolyte imbalance must be corrected. Renal function should be monitored for the next 3 days. If needed, haemodialysis may be used for clearance of excessive contrast medium. There is no specific antidote.

Hypersensitivity to the active substance or to any of the excipients (see Description). Manifest thyrotoxicosis.

Special precautions for use of non-ionic monomeric contrast media in general: 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 Omnipaque is regarded as minor.
However, iodinated contrast media may provoke anaphylactoid reactions or other manifestations of hypersensitivity. Independent of quantity and route of administration, symptoms such as angioedema, 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 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.
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 angioedema, 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. Adequate hydration should be assured before and after contrast media administration.
This applies especially to patients with dys- and paraproteinaemias like multiple myeloma, diabetes mellitus, renal dysfunction, hyperuricaemia as well as to infants, small children, 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.
CNS disturbances: Encephalopathy has been reported with the use of contrast media, such as iohexol (see Adverse Reactions). 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 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, paraproteinaemias (myelomatosis and Waldenström's macroglobulinaemia 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, particular 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 medium and the following precautions undertaken in the following circumstances: Patients with eGFR equal or greater than 60 mL/min/1.73 m² (CKD 1 and 2) can continue to take metformin normally.
Patients with eGFR 30-59 mL/min/1.73 m² (CKD 3): Patients receiving intravenous contrast medium with eGFR equal or greater than 45 mL/min/1.73 m²) 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/1.73 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.
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 iodinated contrast media should be avoided.
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. 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 medium for radiological procedures.
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 Interactions).
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 Use in Children as follows).
Extravasation: Extravasation of contrast medium may on rare occasions give rise to local pain, 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.
Use in Children: Special attention should be paid to paediatric patients below 3 years of age because an incident underactive thyroid during early life may be harmful for motor, hearing, and cognitive development and may require transient T4 replacement therapy.
The incidence of hypothyroidism in patients younger than 3 years of age exposed to iodinated contrast media has been reported between 1.3% and 15% depending on the age of the subjects and the dose of the iodinated contrast agent and is more commonly observed in neonates and premature infants. Neonates may also be exposed through the mother during pregnancy. Thyroid function should be evaluated in all paediatric patients younger than 3 years of age following exposure to iodinated contrast media. If hypothyroidism is detected, the need for treatment should be considered and thyroid function should be monitored until normalized.
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.
Effects on Ability to Drive and Use Machines: It is not advisable to drive a car or use machines during the first 24 hours following intrathecal examination.

The safety of Omnipaque for use in human pregnancy has not been established. An evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to reproduction, development of the embryo or fetus, the course of gestation and peri- and postnatal development.
Since whenever possible, radiation exposure should be avoided during pregnancy, the benefits of an X-ray examination, with or without contrast media, should be carefully weighed against the possible risk.
Omnipaque should not be used in pregnancy unless the benefit outweighs risk and it is considered essential by the physician. Contrast media are poorly excreted in human breast milk and minimal amounts are absorbed by the intestine. Harm to the nursing infant is therefore unlikely. In neonates who have been exposed to iodinated contrast media in utero, it is recommended to monitor thyroid function.

General (applies to all uses of iodinated contrast media): As follows are listed as possible general side effects in relation with radiographic procedures which include the use of non-ionic monomeric contrast media. For side effects specific to mode of administration, refer to the specific sections.
The listed frequencies are based on internal clinical documentation and published large scale studies, comprising more than 200,000 patients.
Undesirable effects associated with the use of iodinated contrast media are usually mild to moderate and transient in nature, and less frequent with non-ionic than with ionic contrast media. Serious reactions as well as fatalities are only seen on very rare occasions. The most frequent adverse event is a mild, general sensation such as a feeling of warmth or a transient metallic taste.
Abdominal discomfort/pain is very rare (incidence <1:1000) and gastrointestinal reactions like nausea or vomiting are rare (incidence <1:100, but >1:1000).
Hypersensitivity reactions are rare and usually present as mild respiratory or cutaneous symptoms like dyspnoe, rash, erythema, urticaria, pruritus and angioedema.
They may appear either immediately after the injection or up to a few days later. Severe manifestations such as laryngeal oedema, bronchospasm or pulmonary oedema are very rare. Severe and even toxic skin reactions have been reported.
Anaphylactoid reactions may occur irrespectively of the dose and mode of administration and mild symptoms of hypersensitivity may represent the first signs of a serious reaction. Administration of the contrast medium must be discontinued immediately and, if necessary, specific therapy instituted via the vascular access. Patients using beta blockers may present with atypical symptoms of anaphylaxis which may be misinterpreted as a vagal reaction.
Vagal reactions giving hypotension and bradycardia are seen on very rare occasions. Headache of fever may occur. Episodes of hypertension may also occur. Pyrexia with rigors are seen on rare occasions.
Iodism or "iodide mumps" is a very rare complication of iodinated contrast media resulting in swelling and tenderness of the salivary glands for up to approximately 10 days after the examination.
Intravascular use (Intraarterial and Intravenous use): First read General as previously mentioned. As follows, only undesirable events with frequency during intravascular use of non-ionic monomeric contrast media are described.
The nature of the undesirable effects specifically seen during intraarterial use depend on the site of injection and dose given. Selective arteriographies and other procedures in which the contrast medium reaches a particular organ in high concentrations may be accompanied by complications in that particular organ. Distal pain or heat sensation in peripheral angiography is common (incidence >1:10).
A transient increase in S-creatinine is common after iodinated contrast media, but usually of no clinical relevance. Renal failure is very rare. However, renal failure may occur in high risk patients and among such patients fatalities have been reported.
Arterial spasm may follow injection into coronary, cerebral or renal arteries and result in transient ischaemia.
Neurological reactions are very rare. They may include seizures or transient motor or sensory disturbances. On very rare occasions the contrast medium may cross the blood-brain barrier resulting in uptake of contrast medium in the cerebral cortex being visible on CT-scanning until the day following examination, sometimes associated with transient confusion or cortical blindness.
Serious cardiac complications, including cardiac arrest, arrhythmia, depression or signs of ischaemia, are very rare. Post phlebographic thrombophlebitis or thrombosis is very rare. A very few cases of arthralgia has been reported.
Intrathecal use: First read General as previously mentioned. as follows, only undesirable events with frequency during intrathecal use of non-ionic monomer contrast media are described.
Undesirable effects following intrathecal use may be delayed and present some hours or even days after the procedure. The frequency is similar to lumbar puncture alone.
Headache, nausea, vomiting or dizziness are common and may largely be attributed to pressure loss in the subarachnoid space resulting from leakage at the puncture site. Some of these patients may experience a severe headache lasting for several days. Excessive removal of cerebrospinal fluid should be avoided in order to minimize pressure loss.
Mild local pain, paraesthesia and radicular pain occasionally (incidence <1:10, but >1:100) occur at the site of injection. Cramping and pain in the lower limbs are seen on very rare occasions.
Meningeal irritation giving photophobia and meningism happens occasionally. Frank chemical meningitis appear on very rare occasions. The possibility of an infective meningitis should also be considered. On very rare occasions, manifestations of transient cerebral dysfunction are seen. These include seizures, transient confusion or transient motor or sensory dysfunction. Changes in the EEG may be noted in a few of these patients.
Use in Body Cavities: First read General. As follows, only undesirable events with frequency during use of non-ionic monomeric contrast media in body cavities are described.
Systemic hypersensitivity reactions are rare.
Endoscopic Retrograde Choleangio Pancreatography (ERCP): Some elevation of amylase levels is common. Post ERCP renal opacification is seen on rare occasions and is associated with an increased risk of post ERCP pancreatitis. Rare cases of necrotizing pancreatitis have also been described.
Oral use: Gastrointestinal upset occasionally occur.
Hysterosalpingography (HSG): Transient pain in the lower abdomen is common.
Arthrography: Post procedural pain is common. Frank arthritis is rare. The possibility of infective arthritis should be considered in such cases.
Herniography: Mild postprocedural pain is common.

Use of iodinated contrast media may result in a transient impairment of renal function and this may precipitate lactic acidosis in diabetics who are taking metformin (see Precautions).
Patients treated with interleukin-2 less than two weeks previously have been associated with an increased risk for delayed reactions (erythema, flu-like symptoms or skin reactions).
All iodinated contrast media may interfere with tests on thyroid function, thus the iodine binding capacity of the thyroid may be reduced for up to several weeks.
High concentrations of contrast media in serum and urine can interfere with laboratory tests for bilirubin, proteins or inorganic substances (e.g. iron, copper, calcium and phosphate). These substances should therefore not be assayed on the day of examination.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. A separate syringe should be used.
Instructions for Use/Handling: Like all parenteral products, Omnipaque should be inspected visually for particulate contamination, discolouration and the integrity of the container prior to use.
As the product does not contain a preservative, it should be drawn into the syringe immediately before use. Any unused product or waste material should be disposed of in accordance with local requirements.
Omnipaque may be warmed to body temperature (37°C) before administration.
Additional instruction for auto injector/pump: The 500 mL contrast medium bottles should only be used in connection with auto injectors/pumps approved for this volume. A single piercing procedure should be used.
The line running from this auto injector/pump to the patient must be exchanged after each patient. Any unused portions of the contrast medium remaining in the bottle and all connecting tubes must be discarded at the end of the day. When convenient, smaller bottles can also be used. Instructions from the manufacturer of the auto injector/pump must be followed.

Store below 30°C. Protect from light.

Radiographic & Diagnostic Agents

V08AB02 - iohexol ; Belongs to the class of watersoluble, nephrotropic, low osmolar preparations used as X-ray contrast media.

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