Visipaque

Iodixanol (Visipaque) is supplied ready to use as clear, colourless to pale yellow aqueous solutions. (See Table 1.)

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Iodixanol (Visipaque) is a non-ionic, dimeric, hexaiodinated, water-soluble X-ray contrast medium. Pure aqueous solutions of Iodixanol (Visipaque) in all clinical relevant concentrations have a lower osmolality than whole blood and the corresponding strengths of the non-ionic monomeric contrast media. Iodixanol (Visipaque) is made isotonic with normal body fluids by addition of electrolytes. The osmolality and viscosity values of Iodixanol (Visipaque) are as follows: See Table 2.

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320 mg l/mL: This medicinal product contains 0.45 mg (0.02 mmol) sodium per mL. To be taken into consideration by patient on a controlled sodium diet.
The pH of the product is 6.8-7.6.
Excipients/Inactive Ingredients: Trometamol, Sodium chloride, Calcium chloride dihydrate, Sodium calcium edetate, Hydrochloric acid (pH adjustment), Water for injection.

Pharmacotherapeutic Group: X-ray contrast medium, iodinated. ATC Code: V08A B09.
Pharmacology: Pharmacodynamics: The organically bound iodine absorbs radiation in the blood vessels/tissues when it is injected.
For most of the haemodynamic, clinical-chemical and coagulation parameters examined following intravenous injection of iodixanol 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.
Iodixanol (Visipaque) induces only minor effects on renal function in patients. In diabetic patients with serum creatinine levels of 1.3-3.5 mg/dL, Iodixanol (Visipaque) use resulted in 3% of patients experiencing a rise in creatinine of ≥0.5 mg/dL and 0% of patients with a rise of ≥1.0 mg/dL. The release of enzymes (alkaline phosphatase and N-acetyl-β-glucosaminidase) from the proximal tubular cells is less than after injections of non-ionic monomeric contrast media and the same trend is seen compared to ionic dimeric contrast media. Iodixanol (Visipaque) is also well tolerated by the kidney.
Cardiovascular parameters such as LVEDP, LVSP, heart rate and QT-time as well as femoral blood flow were less influenced after Iodixanol (Visipaque) than after other contrast media, where measured.
Pharmacokinetics: Iodixanol (Visipaque) is rapidly distributed in the body with a mean distribution half-life of approximately 21 minutes. The apparent volume of distribution is of the same magnitude as the extracellular fluid (0.26 L/kg b.w.), indicating that iodixanol is distributed in the extra-cellular volume only. No metabolites have been detected. The protein binding is less than 2%.
The mean elimination half-life is approximately 2 hours. Iodixanol (Visipaque) is excreted mainly through the kidneys by glomerular filtration. Approximately 80% of the administered dose is recovered unmetabolized in the urine within 4 hours and 97% within 24 hours after intravenous injection in healthy volunteers. Only about 1.2% of the injected dose is excreted in faeces within 72 hours. The maximum urinary concentration appears within approximately 1 hour after injection.
No dose dependent kinetics has been observed in the recommended dose range.
No specific pharmacokinetic studies have been performed for use in body cavities.
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and toxicity to reproduction.

This medicinal product is for diagnostic use only. X-ray contrast medium for use in adults for cardioangiography, cerebral angiography (conventional), peripheral angiography, (conventional), abdominal angiography (i.a. DSA), urography, venography, CT-enhancement and studies of the gastrointestinal tract, and for use in children for cardioangiography, urography, CT-enhancement and studies of the gastrointestinal tract. Lumbar, thoracic and cervical myelography. Arthrography and hysterosalpingography (HSG).

The dosage may vary depending on the type of examination, the age, weight, cardiac output and general condition of the patient and the technique used. Usually approximately the same iodine concentration and volume is used as with other iodinated X-ray contrast media in current use, but adequate diagnostic information has also been obtained in some studies with iodixanol (Visipaque) injection with somewhat lower iodine concentration. Adequate hydration should be assured before and after administration as for other contrast media. The product is for intravenous, intra-arterial and intrathecal use, and for use in body cavities.
The following dosages may serve as a guide. The doses given for intra-arterial use are for single injections that may be repeated (see Tables 3 and 4).

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For elderly patients, patients with hepatic and/or renal impairments, the usual/proposed doses for adults can be used.

Overdosage is unlikely in patients with a normal renal function. The duration of the procedure is important for the renal tolerability of high doses of contrast media (t½ ~ 2 hours). In the event of accidental overdosing, the water and electrolyte losses must be compensated by infusion. Renal function should be monitored for at least the next 3 days. If needed, haemodialysis may be used to remove iodixanol from the patient's system. There is no specific antidote.

Hypersensitivity to the active substance or to any of the excipients. Manifest thyrotoxicosis.

Special precautions for use of non-ionic 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 Iodixanol (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 may lower the threshold for bronchospasm in asthmatic patients after contrast medium administration, and reduce the responsiveness of treatment with adrenaline.
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.
Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiocardiographic 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 so as to minimise the risk of procedure. Advanced life support facilities should be readily available.
Care should be taken in patients with homocystinuria.
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.
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-, cardiorespiratory arrest and myocardial infarction have occurred.
Encephalopathy has been reported with the use of iodixanol. 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.
If contrast encephalopathy is suspected, administration of iodixanol should be discontinued and appropriate medical management should be initiated.
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, 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 Waldenstrom'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.
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.
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, serum creatinine level should be measured in diabetic patients treated with Metformin prior to intravascular administration of iodinated contrast medium.
Normal serum creatinine/renal function: 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 media for radiological procedures. Correlation of the time of contrast media injection with the haemodialysis session is unnecessary because there is no evidence that haemodialysis protects patients with impaired renal function from contrast medium induced nephropathy.
The administration of iodinated contrast media may aggravate the symptoms of myasthenia gravis. In patients with phaeochromocytoma undergoing interventional procedures, alpha blockers should be given as prophylaxis to avoid a hypertensive crisis.
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 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.
Special attention should be paid to pediatric 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 pediatric 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.
In case of extravasation of Visipaque conservative management is adequate in most cases.
Administration of an iodinated contrast medium to patients known or suspected of having phaeochromocytoma should be performed with caution.
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.
Hysterosalpingography: Hysterosalpingography should not be performed during pregnancy or in the presence of acute pelvic inflammatory disease (PID).
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.

The safety of Iodixanol (Visipaque) 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, wherever possible, radiation exposure should be avoided during pregnancy, the benefits of any X-ray examination, with or without contrast media, should be carefully weighed against the possible risk. The product should not be used in pregnancy unless benefit outweighs risk and it is considered essential by the physician.
In neonates who have been exposed to iodinated contrast media in utero, it is recommended to monitor thyroid function.
The degree of excretion into human milk is not known, although expected to be low. Breast feeding may be continued normally when iodinated contrast media are given to the mother.
The effect of VISIPAQUE on human reproduction has not been established. An evaluation of experimental animal studies does not indicate direct or indirect harmful effects with respect to reproduction.

Listed as follows are possible side effects in relation with radiographic procedures which include the use of Visipaque.
Undesirable effects associated with VISIPAQUE are usually mild to moderate and transient in nature. Serious reactions as well as fatalities are only seen on very rare occasions, these may include acute-on-chronic renal failure, acute renal failure, anaphylactic or anaphylactoid shock, hypersensitivity reaction followed by cardiac reactions (Kounis' syndrome), cardiac or cardio-respiratory arrest and myocardial infarction. Cardiac reaction may be promoted by the underlying disease or the procedure.
Hypersensitivity reactions may present as respiratory or cutaneous symptoms like dyspnoea, rash, erythema, urticaria, pruritus, severe skin reactions, angioneurotic oedema, hypotension, fever, laryngeal oedema, bronchospasm or pulmonary oedema. In patients with autoimmune diseases cases of vasculitis and SJS-like syndrome were observed.
They may appear either immediately after the injection or up to a few days later. Hypersensitivity reactions may occur irrespectively of the dose and mode of administration and mild symptoms may represent the first signs of a serious anaphylactoid reaction/shock.
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 hypersensitivity which may be misinterpreted as a vagal reaction.
A minor transient increase in serum creatinine is common after iodinated contrast media, but is usually of no clinical relevance.
The frequencies of undesirable 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).
The listed frequencies are based on internal clinical documentation and published studies, comprising more than 57,705 patients.
The following undesirable effects are recognised for VISIPAQUE: See Tables 5, 6, 7, 8 and 9.

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Description of selected adverse reactions: Transient contrast-induced encephalopathy: In unknown occasions the contrast medium may cross the blood-brain barrier resulting in uptake of contrast medium in the cerebral cortex that may cause contrast-induced encephalopathy. The symptoms may include agitation, transient cortical blindness, amnesia, hallucination, paralysis, paresis, disorientation, transient speech disorder, aphasia, dysarthria.

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.
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.
Patients treated with interleukin-2 less than two weeks previous to an iodinated contrast medium injection have been associated with an increased risk for delayed reactions (flu-like symptoms or skin reactions).

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. A separate syringe should be used.
Special Precautions for Disposal and Other Handling: Vials are intended for single use only; any unused portions must be discarded.
Like all parenteral products, Iodixanol (Visipaque) should be inspected visually for particulate matter, discolouration and the integrity of the container prior to use.
The product should be drawn into the syringe immediately before use.
Iodixanol (Visipaque) may be warmed to body temperature 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 the 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.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store below 30°C. Keep the container in the outer carton in order to protect this medicine from light and from secondary x-ray.
Polypropylene containers: The product can be stored for up to 1 month at 37°C.
Shelf-Life: 3 years. The product must be used immediately after opening.

Radiographic & Diagnostic Agents

V08AB09 - iodixanol ; Belongs to the class of watersoluble, nephrotropic, low osmolar preparations used as X-ray contrast media.

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