1 Name of Medicine
2 Qualitative and Quantitative Composition
Optiray (ioversol injection) formulations are sterile, non-pyrogenic, aqueous solutions intended for intravascular administration as diagnostic radiopaque media.
Each millilitre of Optiray 240 (ioversol injection 51% w/v) provides 509 mg of ioversol with 3.6 mg of trometamol as a buffer and 0.2 mg of sodium calcium edetate as a stabiliser. Optiray 240 provides 24% (240 mg/mL) organically bound iodine.
Each millilitre of Optiray 320 (ioversol injection 68% w/v) provides 678 mg of ioversol with 3.6 mg of trometamol as a buffer and 0.2 mg of sodium calcium edetate as a stabiliser. Optiray 320 provides 32% (320 mg/mL) organically bound iodine.
Each millilitre of Optiray 350 (ioversol injection 74% w/v) provides 741 mg of ioversol with 3.6 mg of trometamol as a buffer and 0.2 mg of sodium calcium edetate as a stabiliser. Optiray 350 provides 35% (350 mg/mL) organically bound iodine.
The pH of the Optiray formulations has been adjusted to 6.0 to 7.4 with hydrochloric acid or sodium hydroxide.
Some physical and chemical properties of these formulations are listed in Table 1.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
Solution for injection.
The Optiray formulations are clear, colourless to pale yellow solutions containing no undissolved solids. Crystallisation does not occur at temperatures above 15°C. The products are supplied in containers from which the air has been displaced by nitrogen. Optiray solutions have osmolalities 1.2 to 2.5 times that of plasma (285 mOsm/kg water) as shown in Table 1 and are hypertonic under conditions of use.
4.1 Therapeutic Indications
Optiray is indicated in adults for angiography throughout the cardiovascular system by conventional or digital subtraction techniques. These include cerebral, coronary, peripheral, visceral and renal arteriography, aortography, left ventriculography and venography. Optiray may be used for intravenous excretory urography.
Optiray 320 is indicated in children (excluding neonates) for angiocardiography, contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography.
4.2 Dose and Method of Administration
It is desirable that intravascular administered iodinated contrast media be at, or close to, body temperature when injected.
As with all radiopaque contrast media, only the lowest dose necessary to obtain adequate visualisation should be used.
Under no circumstances should any other therapy be mixed with the contrast media because of the potential for chemical incompatibility.
Withdrawal of contrast media from their containers should be accomplished under strict aseptic conditions using only sterile syringes and transfer devices. Contrast media which have been transferred into other delivery systems should be used immediately.
Parenteral products should be inspected visually for particulate matter and discolouration prior to administration and should not be used if particulates are observed or marked discolouration has occurred.
The Optiray formulations are supplied in single use containers. Discard unused portion.
General angiography. Visualisation of the cardiovascular system may be accomplished by any accepted technique. Since intra-arterial digital subtraction angiography (IA-DSA) requires adjustments in the method of administration, this procedure is described separately.
Additional precautions and adverse reactions. Extreme caution is advised in patients with advanced arteriosclerosis, severe hypertension, cardiac decompensation, senility, recent cerebral thrombosis or embolism and migraine. Cardiovascular reaction that may occur with some frequency are bradycardia and either an increase or decrease in systemic blood pressure.
Dosage and administration (adults). Either Optiray 240 or Optiray 320 is recommended for this procedure. The usual individual injection for visualisation of the carotid or vertebral arteries is 2 to 12 mL, repeated as necessary. Aortic arch injection for a simultaneous four vessel study requires 20 to 50 mL. Total procedural doses should not usually exceed 150 mL.
Additional precautions. Pulsation should be present in the artery to be injected. In thromboangiitis obliterans or ascending infection associated with severe ischaemia, angiography should be performed with extreme caution, if at all.
Dosage and administration (adults). Optiray 320 or Optiray 350 is recommended for this procedure. The usual individual injection volumes for visualisation of various peripheral arteries are as follows: aorta-iliac runoff - 60 mL (range: 20 to 90 mL); common iliac, femoral - 40 mL (range: 10 to 50 mL); subclavian, brachial - 20 mL (range: 15 to 30 mL).
These doses may be repeated as necessary. Total procedural doses should not usually exceed 150 mL.
Selective visceral and renal arteriography and aortography.
Additional precautions and adverse effects. In aortography, depending on the technique employed, the risks of this procedure also included the following: injury to the aorta and neighbouring organs, pleural puncture, renal damage including infarction and acute tubular necrosis with oliguria and anuria, accidental filling of the renal arteries in the presence of pre-existing renal disease, retroperitoneal haemorrhage, and spinal cord injury and pathology associated with the syndrome of transverse myelitis.
Dosage and administration (adults). Optiray 320 or Optiray 350 is recommended for this procedure. The usual individual injection volumes for visualisation of the aorta and various visceral arteries are as follows: aorta - 45 mL (range: 10 to 80 mL); coeliac - 45 mL (range: 12 to 60 mL); superior mesenteric - 45 mL (range: 15 to 60 mL); renal or inferior mesenteric - 9 mL (range: 6 to 15 mL).
These doses may be repeated as necessary. Total procedural doses should not usually exceed 150 mL.
Coronary arteriography and ventriculography.
Additional precautions and adverse reactions. Selective coronary arteriography should be performed only in selected patients and those in whom the expected benefits outweigh the procedural risk. The inherent risks of angiocardiography in patients with chronic pulmonary emphysema must be weighed against the necessity for performing this procedure.
Cardiac decompensation, serious arrhythmias, myocardial ischaemia, myocardial infarction may occur during coronary arteriography and ventriculography. However, electrocardiographic and haemodynamic changes occur with less frequency and severity with ioversol injection than with conventional ionic media.
Mandatory prerequisites to the procedure are specialised personnel, ECG monitoring apparatus and adequate facilities for immediate resuscitation and cardioversion. Electrocardiograms and vital signs should be routinely monitored throughout the procedure.
When large individual volumes are administered, as in ventriculography and aortography, it has been suggested that several minutes be permitted to elapse between each injection to allow for subsidence of possible hemodynamic disturbances.
Dosage and administration (adults). Optiray 320 or Optiray 350 is recommended for this procedure. The usual individual injection volumes for visualisation of the coronary arteries and left ventricle are: left coronary - 8 mL (range: 2 to 10 mL); right coronary - 6 mL (range: 1 to 10 mL); left ventricle - 40 mL (range: 30 to 50 mL).
These doses may be repeated as necessary. Total procedural dose for the combined procedures should not usually exceed 150 mL.
Additional precautions. Mandatory prerequisites to the procedure are specialised personnel, ECG monitoring apparatus and adequate facilities for immediate resuscitation and cardioversion. Electrocardiograms and vital signs should be routinely monitored throughout the procedure. Paediatric patients are at higher risk of experiencing adverse events during contrast medium administration, these include children having asthma, a sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine greater than 1.5 mg/dL, or those less than 12 months of age.
Dosage and administration. Optiray 320 is recommended for this procedure. The usual single injection dose for Optiray 320 is 1.25 mL/kg of body weight with a range of 1 mL/kg to 1.5 mL/kg. When multiple injections are given, the total administered dose should not exceed 5 mL/kg up to a total volume of 75 mL.
Intra-arterial digital subtraction angiography (IA-DSA). All of the arteriographic procedures described above can be performed using digital subtraction techniques.
Dosage and administration (adults). The recommended doses are similar to those used for conventional arteriography. The flow rate of the vessel being injected should always be considered when selecting the concentration and dose. Total dosage should not usually exceed 150 mL.
Additional precautions. Special care is required when venography is performed in patients with suspected thrombosis, phlebitis, severe ischaemic disease, local infection or a totally obstructed venous system. In order to minimise extravasation during injection, fluoroscopy is recommended.
Dosage and administration (adults). Either Optiray 240, Optiray 320 or Optiray 350 is recommended for this procedure. The usual dose is 50 to 100 mL per extremity. Total dosage should not usually exceed 150 mL.
Following the procedure, the venous system should be flushed with Sodium Chloride Injection USP or 5% glucose in water (D5W). Massage and elevation are also helpful in clearing the contrast media from the extremity.
Computed tomography. Optiray 320 or Optiray 350 is recommended for these procedures in adults and Optiray 320 in children.
Dosage and administration. Adults: The usual dosage is 50 to 150 mL of Optiray 320 or Optiray 350. Scanning may be performed immediately after completion of the intravenous administration. Total dosage should not usually exceed 150 mL.
Children: The usual dosage for use in children is 1.9 mL/kg (range: 1.3 to 2.4 mL/kg) of Optiray 320.
Dosage and administration. Optiray 320 or Optiray 350 may be administered by bolus injection, by rapid infusion, or by a combination of both. The usual dose for bolus injection is 25 to 75 mL.
Adults: The usual dose for infusion is 50 to 150 mL. Total dosage should not usually exceed 150 mL.
Children: The usual dosage for use in children is 2 mL/kg (range: 1.7 to 2.4 mL/kg) of Optiray 320.
Dosage and administration. Optiray 320 or Optiray 350 is recommended for routine and high dose excretory urography.
Adults: The usual dose for routine excretory urography in adults is 50 to 75 mL of Optiray 320 or Optiray 350. Higher doses may be indicated to achieve optimum results where poor visualisation is anticipated (e.g. elderly patients or patients with impaired renal function). In these patients, high dose urography may be preferred, using Optiray 320 at a dose of 1.5 to 2 mL/kg (maximum 150 mL).
Children: Optiray 320 at doses of 0.5 mL/kg to 3 mL/kg of body weight has produced diagnostic opacification of the excretory tract. The usual dose for children is 1 mL/kg to 1.5 mL/kg of Optiray 320. Dosage for infants and children (on a mL/kg basis) gradually decreases with age. In one study, mean dose (mL/kg) decreased from 2.7 in infants to 1.0 in children 12-18 years of age. The total administered dose should not exceed 3 mL/kg.
Known hypersensitivity to ioversol (Optiray) or any of the excipients.
Decompensated cardiac insufficiency.
Certain specific procedures and situations, e.g. carotid artery angiography during the progressive period of stroke, coronary arteriography in the first four weeks after myocardial infarction, and the presence of infection or open injury in or near the region to be examined.
4.4 Special Warnings and Precautions for Use
(Precautions for specific procedures receive comment, see Section 4.2 Dose and Method of Administration.)
Serious or fatal reactions have been associated with the administration of iodine containing radiopaque media. It is of utmost importance to be completely prepared to treat any contrast medium reactions.
Reports of thyroid storm following the intravascular use of iodinated radiopaque agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of any contrast media.
Serious thromboembolic events have been observed during catheterisation procedures with iodinated X-ray contrast media, and clotting has been reported when blood remains in contact with syringes containing nonionic contrast media. Optiray like all non-ionic compounds, does not have any significant anticoagulant effect. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and non-ionic contrast media.
Meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimise 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 guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinised saline solutions and minimising the length of the procedure. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.
As with any contrast media, serious neurologic sequelae, including permanent paralysis, can occur following cardiac catheterisation, cerebral arteriography, selective spinal arteriography and arteriography of vessels supplying the spinal cord. A cause effect relationship to the contrast media has not been established since the patients' pre-existing condition and procedural technique are causative factors in themselves. The arterial injection of a contrast media should never be made following the administration of vasopressor since they strongly potentiate neurologic effects.
Administration of the contrast medium and the investigation must be interrupted if pronounced side effects or allergic reactions occur during the administration and appropriate treatment should be instituted. If, despite this, the reactions do not disappear, or even grow worse, the investigation must be terminated. Even relatively minor symptoms, such as itching of the skin, sneezing, violent yawning, tickling in the throat, hoarseness, coughing fits, may be initial signs of a severe reaction (including shock), so careful attention should be paid to them.
In patients with severe impairment of hepatic or renal function, cardiac and circulatory insufficiency, pulmonary emphysema, poor general health, cerebral arteriosclerosis, juvenile-type diabetes or diabetes of long standing, cerebral spasmodic conditions and latent thyroid hyperfunction, the need for examination merits particularly careful consideration. Diabetics with serum creatinine above 500 micromol/L should not be examined unless the possibility of benefit clearly outweighs the additional risk.
In patients with renal impairment the maximum dose should not be exceeded (see Section 4.2 Dose and Method of Administration). Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, renal and hepatic disease, multiple myeloma or other paraproteinemia or anuria, particularly when large doses are administered. Myeloma occurs most commonly in persons over age 40. Although neither the contrast medium nor dehydration has been proved separately to be the cause of renal failure, it has been speculated that the combination of both may be causative. The risk in patients with impaired renal function is not a contraindication to the procedure, however, special precautions, including maintenance of normal hydration and close monitoring are required. Partial dehydration in the preparation of these patients prior to injection maybe harmful and is not recommended, especially in myelomatous patients, since this may predispose the patient to precipitation of the myeloma protein.
Administration of radiopaque materials to patients known or suspected of having pheochromocytoma should be performed with extreme caution. If, in the opinion of the physician, the possible benefits of such procedures outweigh the considered risks, the procedures may be performed, however the amount of radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for treatment of a hypertensive crisis should be available.
Contrast media may promote sickling in individuals who are homozygous for sickle cell disease when administered intravascularly.
General. Diagnostic procedure which involve the use of iodinated intravascular contrast media should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognising and treating adverse reactions of all types should always be available. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes after administration.
Preparatory dehydration is dangerous and may contribute to acute renal failure in patients with advanced vascular disease, diabetics and in susceptible nondiabetics (often elderly with pre-existing renal disease). Fluid intake should not be restricted before the use of Optiray, especially in patients with multiple myeloma, juvenile-type diabetes or diabetes of long standing, polyuria, oliguria, gout in babies or small children, elderly or in debilitated patients. Patients should be well hydrated prior to and following the administration of Optiray. The possibility that a reaction, including serious life-threatening, fatal, anaphylactoid or cardiovascular reactions, may occur should always be considered (see Section 4.8 Adverse Effects (Undesirable Effects)). Severe, life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in patients administered Optiray. Early or late manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately.
Increased risk is associated with a history of previous reaction to contrast media, a known sensitivity to iodine and known allergies (including bronchial asthma, hay fever and food allergies) or hypersensitivities. However, while this implies the need for extra caution it does not necessarily contraindicate the use of the contrast media.
The occurrence of severe idiosyncratic reactions has prompted the use of several pretesting methods. However, pretesting cannot be relied upon to predict severe reactions and may itself be hazardous to the patient. It is suggested that a thorough medical history with emphasis on allergy and hypersensitivity, prior to the injection of any contrast media, may be more accurate than pretesting in predicting potential adverse reactions.
A positive history of allergies or hypersensitivity does not arbitrarily contraindicate the use of contrast media when a diagnostic procedure is thought essential, but caution should be exercised. Premedication with antihistamines or corticosteroids to avoid or minimise possible allergic reactions in such patients should be considered. Reports indicate that such pretreatment does not prevent serious life threatening reactions, but may reduce both their incidence and severity.
General anaesthesia may be indicated in the performance of some procedures in selected patients, however, a higher incidence of adverse reactions has been reported in these patients, and may be attributed to the inability of the patient to identify untoward symptoms or to the hypotensive effect of anaesthesia which can prolong the circulation time and increase the duration of exposure to the contrast agent.
In angiographic procedures, the risk of dislodging plaques or damaging or perforating the vessel wall should be considered during catheter manipulations and contrast medium injection. Test injections to ensure proper catheter placement are suggested.
The inhibitory effects of nonionic contrast media on mechanisms of haemostasis have been shown, in vitro, to be less than conventional ionic contrast media at comparable concentrations. For this reason, standard angiographic procedures should always be followed, e.g. angiographic catheters should be flushed frequently and prolonged contact of blood with the contrast medium in syringes and catheters should be avoided.
Angiography should be avoided whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
Patients with congestive heart failure should be observed for several hours following the procedure to detect delayed haemodynamic disturbances which may be associated with a transitory increase in the circulating osmotic load.
Any contrast medium solution left over from the examination must be discarded. The potential risk of seizures may be increased under the following conditions: large dose of contrast medium, renal failure, blood-brain barrier disruption.
Optiray in prefilled syringes must only be used with administration devices (e.g. infusion pumps or dual-head injectors), which are provided with reliable connecting tubes. The manufacturer's instructions for use for these devices must be followed.
Optiray 500 mL vials. The transmission of viral infections and bacterial contamination are recognised but rare complications of multi-use vials and administration devices. The following measures should be strictly adhered to when using Optiray 500 mL vial.
The use of the specific automatic injector with Optiray 500 mL vial should only be carried out by the healthcare professionals who have received adequate training on the use of the device and aseptic technique.
The multiple withdrawal must be performed utilising an administration device approved for this use, such as dual-head injectors which are provided with reliable connecting tubes.
The rubber stopper of the vial can only be pierced once to prevent large amounts of microparticles from the stopper getting into the solution.
Optiray 500 mL vials must be administered by means of an automatic injector, or by other approved procedures which ensure sterility of the contrast medium.
Aseptic technique practices and routine checks for visible contamination with blood should be adhered to when changing connections.
The Instructions for Use from the device manufacturer must be followed, including connecting tubes and all disposable parts of the injector system.
Any Optiray injection solution in the 500 mL vial which is unused at the end of the day must be discarded.
Other. Other precautions which apply to the various radiographic contrast procedures are the same for Optiray as they are for conventional ionic media.
The risk of the procedure itself should be carefully evaluated in each patient. Such precautions include:
Cerebral angiography. Used with caution in patients with extreme senility, advanced atherosclerosis or severe hypotension.
The procedure may be hazardous in subarachnoid haemorrhage and in migraine (because of ischaemic complications).
Peripheral angiography. Pulsation should be present in the artery to be injected.
In thromboangiitis obliterans (Buerger's disease) or ischaemia associated with ascending infection, angiography should be performed with extreme caution, if at all.
Cardioangiography. Caution is advised in the administration of large volumes to patients with incipient heart failure because of the possibility of aggravating the pre-existing condition. Hypotension should be corrected promptly since it may induce serious arrhythmias.
Caution is advised with dosage in patients with right ventricular failure, pulmonary hypertension or stenotic pulmonary vascular beds because of the haemodynamic changes which may occur after injection into the right heart outflow tract.
Urography. It is advisable to allow an interval of at least 48 hours before repeating excretory urography.
Dehydration should be avoided in the elderly, particularly those with polyuria, oliguria, advanced vascular disease or pre-existing dehydration (see Section 4.4 Special Warnings and Precautions for Use).
Myelomatosis (see Section 4.4 Special Warnings and Precautions for Use).
Use in the elderly. The tolerance of elderly patients to drugs in general is diminished. These patients may have reduced renal reserve, impaired general health and may be taking medication (e.g. adrenergic β-blockers) which make them more susceptible to the potentially harmful effects of procedures involving the use of contrast media. The need for and the expected benefits of the procedure have to be carefully evaluated and dosage should be very conservative.
Paediatric use. Some paediatric patients have a higher risk of adverse reactions to contrast media. Such patients may include those with sensitivity to allergens, including other medicines, those with asthma, congestive heart failure, a serum creatinine > 1.5 mg/dL, or ages under 12 months.
Infants. Thyroid function in infants exposed to iodinated contrast media (ICM) should be evaluated and monitored. Decreased levels of thyroxine (T4) and triiodothyronine (T3) and increased level of thyroid stimulating hormone (TSH) were reported after exposure to ICM in infants, especially preterm infants, which remained for up to a few weeks or more than a month. Thyroid function in infants exposed to ICM should therefore be evaluated and monitored until thyroid function is normalised. Some patients were treated for hypothyroidism.
Effects on laboratory tests. The results of protein-bound iodine (PBI) and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for up to sixteen (16) days following administration of iodinated contrast media. However, thyroid function tests not depending on iodine estimations e.g. T3 resin uptake and total or free thyroxine (T4) assays are not likely to be affected.
Information for patients. Patients receiving iodinated intravascular contrast media should be instructed to:
1. Inform your physician if you are pregnant.
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease or known thyroid disorder (see Section 4.4 Special Warnings and Precautions for Use).
3. Inform your physician if you are allergic to any medicines or food, or if you had any reactions to previous injections of dyes used for X-ray procedures (see Section 4.4 Special Warnings and Precautions for Use).
4.5 Interactions with Other Medicines and Other Forms of Interactions
Cholecystographic agents. Renal toxicity has been reported in a few patients with liver dysfunction who were given oral cholecystographic agents followed by intravascular contrast media. Administration of any intravascular contrast medium should therefore be postponed in patients who have recently received a cholecystographic contrast agent.
Metformin. Acute renal failure has been associated with lactic acidosis in patients receiving metformin at the time of an x-ray examination involving parenteral administration of iodinated contrast media. Therefore, in diabetic patients taking metformin, the examination should be performed, and intake of metformin stopped from the time of the examination. The use of metformin should not be resumed for 48 hours and should only be restarted if renal function/serum creatinine remains within the normal range.
Vasopressors. The arterial injection of a contrast media should not be made following the administration of vasopressors since they strongly potentiate neurologic effects.
Other medicines should not be mixed with Optiray injection.
4.6 Fertility, Pregnancy and Lactation
Effects on fertility. No long term animal studies have been performed to evaluate carcinogenic potential. However, animal studies suggest that this drug is not mutagenic and does not affect fertility in males or females.
No teratogenic effects attributable to ioversol have been observed in teratology studies performed on animals using doses up to 3.2 gL/kg. There are, however, no adequate and well controlled studies in pregnant women. It is not known whether Optiray crosses the placental barrier or reaches foetal tissues. However, many injectable contrast media cross the placental barrier in humans and appears to enter foetal tissue passively. Because animal teratology studies are not always predictive of human response, Optiray should be used during pregnancy only if clearly needed. X-ray procedures involve a certain risk related to the exposure of the foetus.
Infants born to women who received iodinated contrast media while pregnant should have testing for hypothyroidism in the neonatal period. Some patients were treated for hypothyroidism (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
It is not known whether ioversol is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast media are administered to nursing women because of potential adverse reactions, and considerations should be given to temporarily discontinuing nursing (see Section 4.4 Special Warnings and Precautions for Use, Paediatric use).
4.7 Effects on Ability to Drive and Use Machines
There is no known effect of Optiray on the ability to drive and operate machines, however, because of the risk of early reactions, driving or operating machinery is not advisable for 30 to 60 minutes following Optiray administration.
4.8 Adverse Effects (Undesirable Effects)
Adverse reactions following the use of Optiray formulations are generally independent of the dose administered. They are usually mild to moderate, of short duration and generally resolve spontaneously (without treatment). However, even mild adverse reactions may be the first indication of a serious, generalised reaction that can occur rarely after iodinated contrast media. Such serious reactions may be life-threatening and fatal and will mostly affect the cardiovascular system.
Most adverse drug reactions to Optiray occur within minutes after administration. However, contrast related hypersensitivity reactions may occur with a delay of some hours up to several days. Injections of contrast media are very commonly associated with sensations of warmth and commonly associated with pain, especially in peripheral arteriography. When compared with ionic contrast media, warmth and pain occurred less frequently and were less severe with ioversol injection.
Adverse drug reactions may be classified as follows:
Hypersensitivity or anaphylactoid reactions are mostly mild to moderate with symptoms like rash, pruritus, urticaria, rhinitis and blister. These symptoms may occur independent of dose and route of administration and may be the first signs of an evolving shock with symptoms like pronounced decrease in blood pressure, tachycardia, dyspnoea, pallor and decrease in consciousness. Fatal cases reported.
Vasovagal reactions with symptoms ranging from dizziness and hypotension to syncope. Vasovagal reactions may be caused either by the contrast media or by the procedure.
Cardiologic side effects during cardiac catheterisation may include ECG changes, arrhythmia, conductivity disorders as well as coronary spasm. Such reactions may be caused by the contrast media or by the procedure.
Nephrotoxic reactions with acute renal failure may occur in patients with pre-existing renal damage.
Neurotoxic reactions after intra-arterial injection of the contrast media like confusion, visual disorders, convulsions or fits. The symptoms are generally transient and abate spontaneously within several hours.
Local reactions at the injection site may occur and include rashes, swelling, inflammation and oedema. Such reactions occur probably in most cases due to extravasation of the contrast media. Extended paravasation may necessitate surgical treatment.
Regardless of the contrast media employed, the overall incidence of serious adverse reaction is higher with coronary arteriography than with other procedures. Cardiac decompensation, serious arrhythmias, myocardial ischaemia or myocardial infarction may occur during coronary arteriography and left ventriculography. In coronary arteriography clinical studies with ioversol, the only adverse reaction with an incidence of greater than one percent was angina (1.6%).
Following coronary artery and left ventricular injection, electrocardiograms and cardiovascular and haemodynamic functions were affected less frequently with Optiray than with the comparative ionic contrast agents. These changes included the following parameters: bradycardia, tachycardia, T wave amplitude, ST depression and ST elevation.
Optiray has also been shown to cause fewer changes in cardiac function and systemic blood pressure. These include cardiac output, left ventricular systolic and end diastolic pressure, right ventricular systolic and pulmonary artery systolic pressures and decreases in systolic and diastolic blood pressure.
For adverse reactions for specific procedures and for serious or life-threatening reactions see Section 4.4 Special Warnings and Precautions for Use.
Clinical trial experience. Table 2 incidence of reactions is based upon clinical trials with Optiray formulations in over 1000 adult patients. This listing includes all adverse reactions which were coincidental to the administration of ioversol regardless of their direct attributability to the drug or the procedure. Adverse reactions are listed by organ system and in decreasing order of occurrence. Significantly more severe reactions are listed before others in a system regardless of frequency.
Paediatrics. In clinical trials involving 128 patients for paediatric angiocardiography, contrast enhanced computed tomographic imaging of the head and body, or intravenous excretory urography, adverse reactions following the use of Optiray 320 were generally similar to adults.
Post-marketing experience. The following adverse reactions have been reported during the post-approval use of Optiray. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency. See Table 3.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
Activated charcoal may reduce absorption of Optiray if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Whole bowel irrigation (e.g. 1 or 2 litres of polyethylene glycol solution orally per hour until rectal effluent is clear) may be useful for gut decontamination.
The adverse effects of overdosage are life threatening and affect mainly the pulmonary and cardiovascular system. Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.
Ioversol does not bind significantly to plasma or serum protein and is, therefore, dialyzable.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
No data available.
5.2 Pharmacokinetic Properties
The pharmacokinetics of ioversol in normal adult subjects conform to an open two compartment model with first order elimination (a rapid alpha phase for drug distribution and a slower beta phase for drug elimination). Based on the blood clearance curves for twelve healthy adult volunteers (six receiving 50 mL and six receiving 150 mL of Optiray 320), the biological half-life was 1.5 hours for both dose levels and there was no evidence of any dose related difference in the rate of elimination.
Ioversol is excreted mainly through the kidneys following intravascular administration. In patients with impaired renal function, the elimination half-life is prolonged. In the absence of renal dysfunction, the mean half-life for urinary excretion following a 50 mL dose was 118 minutes (105 to 156) and following a 150 mL dose was 105 minutes (74 to 141). Faecal elimination was negligible.
Ioversol is bound to serum or plasma proteins to the extent of 9 to 13% only and no significant metabolism or biotransformation occurs.
Intravascular injection of ioversol opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualisation of the internal structures until significant haemodilution occurs.
Ioversol may be visualised in the renal parenchyma within 30 to 60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal functions becomes apparent within 1 to 3 minutes, with optimum contrast occurring within 5 to 15 minutes.
Pharmacokinetics of ioversol in children has not been established.
5.3 Preclinical Safety Data
Animal studies indicate that ioversol does not cross the blood-brain barrier or cause endothelial damage to any significant extent.
6 Pharmaceutical Particulars
6.1 List of Excipients
Trometamol; trometamol hydrochloride; sodium hydroxide; hydrochloric acid; sodium calcium edetate; water for injections.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
6.3 Shelf Life
Vials and pre-filled syringes: 36 months.
The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store below 25°C, protect from light and secondary X-rays. Do not freeze.
Optiray in 500 mL vials is suitable for use over 24 hours in connection with a multi-dispensing device.
6.5 Nature and Contents of Container
Optiray vials are packaged in type I clear glass, closed with a bromobutyl stopper and sealed with an aluminium cap.
Optiray prefilled syringes are packaged in polypropylene syringes, coated with silicone. Pistons and tip caps are moulded from a natural/synthetic rubber blend, coated with silicon.
Optiray 240 (ioversol injection 51% w/v). 30 mL, 50 mL glass vial;
50 mL Ultraject prefilled plastic syringe hand-held;
125 mL Ultraject prefilled plastic syringe power injector.
Optiray 320 (ioversol injection 68% w/v). 20 mL, 30 mL, 50 mL, 100 mL, 150 mL, 200 mL glass vial;
50 mL Ultraject prefilled plastic syringe hand-held;
50 mL, 75 mL, 125 mL Ultraject prefilled plastic syringe power injector.
Optiray 350 (ioversol injection 74% w/v). 20 mL, 30 mL, 50 mL, 75 mL, 100 mL, 150 mL, 200 mL, 500 mL glass vial;
30 mL, 50 mL Ultraject prefilled plastic syringe hand-held;
50 mL, 75 mL, 100 mL, 125 mL Ultraject prefilled plastic syringe power injector.
Optiray prefilled syringes are packed in boxes of 1, 10 or 20 units.
Optiray glass vials are packed in boxes of 10, 12 or 25 units.
Optiray 350 in 500 mL glass vials are packed in boxes of 5 or 6 units.
Note. Not all presentations and pack sizes may be available.
6.6 Special Precautions for Disposal
In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
6.7 Physicochemical Properties
Chemical structure. Ioversol is designated chemically as N, N'-bis (2, 3-dihydroxypropyl)-5-[N-(2-hydroxyethyl) glycolamido]-2, 4, 6-triiodoisopthalamide and has the following structural formula:
Chemical formula: C18H24I3N3O9.
The molecular weight of ioversol is 807.13 and the organically bound iodine content is 47.2%. Ioversol is non-ionic and does not dissociate in solution.
CAS number. 87771-40-2.
7 Medicine Schedule (Poisons Standard)
Summary Table of Changes