Optiray 500 ml/100 ml/125 ml Solution

Optiray is for diagnostic use only. Optiray 300 is indicated in adults for cerebral, peripheral and visceral angiography, intravenous urography, intravenous digital subtraction angiography and venography. Optiray 300 is also indicated for contrast enhanced computed tomography of the head and body.

Optiray 300 is indicated in children for cerebral, peripheral and visceral angiography, and for intravenous urography. Optiray 320 is indicated in adults for angiography throughout the cardiovascular system. The uses include cerebral, coronary, peripheral, visceral and renal angiography, in aortography, left ventriculography and intravenous urography. Optiray 320 is also indicated for contrast enhanced computed tomography of the head and body.

Optiray 320 is indicated in children for angiocardiography, contrast enhanced computed tomography of the head and body, and intravenous urography. Optiray 350 is indicated in adults for angiography throughout the cardiovascular system. The uses include coronary, peripheral, visceral and renal angiography, aortography and left ventriculography. Optiray 350 is also indicated for contrast enhanced computed tomography of the head and body, intravenous urography, intravenous digital subtraction angiography and venography.

Please refer to table.

Adult dose: Procedure Product Dosage and administration Maximum total dose Cerebral angiography Carotid or vertebral artery Optiray 320 or Optiray 300 2 - 12 ml 200 ml Aortic arch Optiray 320 or Optiray 300 20 - 50 ml 200 ml Peripheral angiography Aortic-iliac runoff Optiray 350 or Optiray 320 or Optiray 300 10 - 90 ml 60 ml (range 20 to 90 ml) 250 ml Common iliac, femoral Optiray 350 or Optiray 320 or Optiray 300 40 ml (range 10 to 50 ml) 250 ml Subclavian, brachial Optiray 350 or Optiray 320 or Optiray 300 20 ml (range 15 to 30 ml) These doses may be repeated as necessary. 250 ml Venography Optiray 350 or Optiray 300 50 u2013 100 ml per extremity. Following the procedure, the venous system should be flushed with Sodium Chloride Injection USP (United States Pharmacopeia) or 5 % Dextrose in water. Massage and elevation 250 ml Left ventriculography Optiray 350 or Optiray 320 30 u2013 50 ml Left ventricle: 40 ml. May be repeated as necessary. Several minutes should be permitted to elapse between each injection to allow for subsidence of possible haemodynamic disturbance. 250 ml Coronary arteriography Optiray 350 or Optiray 320 1 - 10 ml Left coronary artery: 8 ml (range 2 to 10 ml) Right coronary artery: 6 ml (range 1 to 10 ml) May be repeated as necessary. Several minutes should be permitted to elapse between each injection to allow for subsidence of possible haemodynamic disturbances. 250 ml Visceral angiography Optiray 350 or Optiray 320 or Optiray 300 12 - 60 ml Celiac: 45 ml (range 12 to 60 ml) Superior mesenteric: 45 ml (range 15 to 60 ml) These doses may be repeated as necessary. 250 ml Aortography Optiray 350 or Optiray 320 10 - 80 ml Aorta: 45 ml (range 10 to 80 ml) These doses may be repeated as necessary. 250 ml Renal angiography Optiray 350 or Optiray 320 6 - 15 ml Renal or inferior mesenteric: 9 ml (range 6 to 15 ml) These doses may be repeated as necessary. 250 ml Urography Optiray 350 or Optiray 320 or Optiray 300 50 - 75 ml 50 - 75 ml 50 - 75 ml 150 ml 150 ml 150 ml Computed tomography Head imaging (Head CT) Optiray 350 or Optiray 320 or Optiray 300 50 - 150 ml 50 - 150 ml 50 - 150 ml Scanning may be performed immediately after I.V. administration. 150 ml 150 ml 150 ml Body imaging (Body CT) Optiray 350 or Optiray 320 or Optiray 300 25 - 150 ml 25 - 150 ml 25 - 150 ml 150 ml 150 ml 150 ml Digital subtraction angiography Intra-arterial (IA DSA) Optiray 350 or Optiray 300 5 - 80 ml 250 ml Intravenous (IV DSA) Optiray 350 or Optiray 300 30 - 50 ml Injections may be repeated as necessary. 250 ml Children (older than four weeks): Optiray 300 Recommended dosage schedule Procedure Dosage Maximum total dose Cerebral angiography 1 u2013 3 ml/kg 100 ml Peripheral angiography 1 u2013 3 ml/kg 100 ml Visceral and renal angiography and aortography 1 u2013 3 ml/kg 100 ml Intravenous urography 2 ml/kg (>1 year of age) 3 ml/kg (<1 year of age) 100 ml Children (older than four weeks): Optiray 320 Recommended dosage schedule Procedure Dosage Maximum total dose Computed tomography: Head imaging or Body imaging 1 u2013 3 ml/kg 100 ml Intravenous urography 0,5 u2013 3 ml/kg 100 ml Children (older than four weeks): Optiray 320 Recommended dosage schedule Procedure Dosage Maximum total dose Paediatric: doses of 0,5 to 3 ml/kg have produced diagnostic opacification of the excretory tract. The usual dose is 1 to 1,5 ml/kg. Dosage for infants and children should be administered in proportion to age and body mass. The total administered dose should not exceed 3 ml/kg. Paediatric angiocardiography 1 to 1,5 ml/kg (usual single injection dose - 1,25 ml/kg body mass). When multiple injections are given, total administered dose should not exceed 5 ml/kg. 250 ml Safety and effectiveness of Optiray 300 and Optiray 320 in children of four weeks or less, in any other indication than those listed above have not yet been established. Safety and effectiveness of Optiray 350 in children have not yet been established and should therefore not be used in children until further data becomes available.

Hypersensitivity to ioversol or to any of the ingredients, including excipients. Proven hypersensitivity to iodine-containing contrast media. Manifest hyperthyroidism. Pregnancy and lactation (see section 4.6 Fertility, Pregnancy and Lactation).

Diagnostic procedures which involve the use of iodinated intravascular contrast agents such as Optiray 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 healthcare professional competent in recognising and treating adverse reactions of all types, should always be available. Fatal reactions have been associated with the administration of water-soluble contrast media including Optiray. It is, therefore of the utmost importance that a course of action is carefully planned, in advance, for the treatment of serious reactions, and that appropriate and adequate facilities and personnel be readily available in case of a severe reaction. Patients should be observed for a possible severe reaction, during, and for at least 30 to 60 minutes after administration of Optiray. Patients with known or suspected hypersensitivity to iodinated contrast media should be closely observed.

The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following Optiray administration. This may precipitate lactic acidosis in patients who are taking biguanides, such as metformin. As a precaution, biguanides should be stopped prior to the time of the Optiray examination for 48 hours and reinstated only after control of renal function has been regained.

Patients should be informed that allergic reactions may develop up to several days post administration; in which case a medical practitioner should be consulted immediately. Pre-testing cannot be relied on to confidently predict severe allergic reactions. The thorough assessment of the medical history of the specific patient may be more accurate in predicting potential adverse reactions. A positive history of allergies is not a contraindication but does require caution (see section 4.3 Contraindications). Pre-medication with antihistamines and corticosteroids to avoid or minimise allergic reactions should be considered. However, this pre-medication does not always prevent the occurrence, but may reduce both the incidence and severity of severe adverse events.

Optiray may cause anaphylaxis or other manifestations of allergy, including nausea, vomiting, dyspnoea, erythema, urticaria and hypotension. An increased risk of such reactions is associated with patients who have a history of increased sensitivity to iodine, or known allergies, asthma or hypersensitivity. In such patients, the benefit should clearly outweigh the risk (see section 4.3 Contraindications).

Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of a contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering Optiray to patients with a history of a severe cutaneous adverse reaction to ioversol.

The anticoagulant effect of non-ionic X-ray contrast media, such as Optiray has been shown, in vitro, to be less than that of conventional ionic agents at comparable concentrations. Similar results were found in some in vivo studies. Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiographic procedures with both ionic and non-ionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimise thromboembolic events. For this reason, standard angiographic catheters should be flushed frequently and prolonged contact of blood with contrast agent in syringes and catheters should be avoided.

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 the additional risk be evaluated in such patients before use of Optiray (see section 4.3 Contraindications).

In angiographic procedures, the possibility of dislodging plaques or damaging or perforating the vessel wall should be considered during catheter manipulations and Optiray injection. Test injections to ensure proper catheter placement are recommended. 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.

In patients with advanced atherosclerosis, serious uncontrolled/severe hypertension, cardiac decompensation, senility, preceding cerebral thrombosis or embolism, special caution should be exercised. Cardiovascular reactions as bradycardia, rising or falling of blood pressure may occur more often.

Serious neurological events, including permanent paralysis, have been observed following direct injection into cerebral arteries or vessels supplying the spinal cord, or in angiocardiography. A cause-effect relationship to the contrast medium has not been established since the patientsu2019 pre-existing condition and procedural technique are causative factors in themselves. Encephalopathy has been reported with the use of Optiray (see section 4.8). Contrast-induced 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 ioversol and generally resolve within days. Factors which increase blood-brain barrier permeability facilitate the passage of the contrast medium into cerebral tissue, which can lead to central nervous system reactions, e.g. encephalopathy. If contrast encephalopathy is suspected, appropriate medical management should be initiated, and administration of Optiray must not be repeated.

Combinations with nephrotoxic medicines should be avoided. If this cannot be avoided, laboratory monitoring of renal function must be intensified. Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, or anuria, diabetes mellitus, homozygous sickle cell disease, multiple myeloma or other paraproteinaemia, particularly when large doses are administered. Serious renal effects, including acute renal failure, may occur in these patients. Effective hydration prior to the administration of Optiray is essential and may decrease the risk of renal injury. Preparatory dehydration is dangerous and may contribute to acute renal failure especially in myelomatous patients since this may predispose the patient to precipitation of the myeloma protein.

Administration of Optiray to patients known or suspected of having phaeochromocytoma should be performed with extreme caution. If, in the opinion of the medical practitioner the possible benefits of such procedures outweigh the considered risks, the procedure may be performed; however, the amount of Optiray 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. Due to risk of a hypertensive crisis, a premedication with u03b1 - and fl-blockers is advisable when Optiray is administered intravascularly.

In patients with homozygous sickle cell disease, hyperosmolar agents such as X-ray contrast media, including Optiray, may affect sickling of the erythrocytes. Hence, there is a need for careful consideration before the intra-arterial administration of such agents to patients with homozygous sickle cell disease.

Optiray should be injected with caution to avoid perivascular application. This is especially important in patients with severe arterial or venous disease. However, significant extravasation of Optiray may occur, especially during the use of power injectors. Generally, it is tolerated without substantial tissue injury applying conservative treatment. However, serious tissue damage (e.g. ulceration) has been reported in isolated cases requiring surgical treatment.

General anaesthesia may be indicated in selected patients. However, a slightly higher incidence of adverse reactions has been reported in these patients, probably due to the hypotensive effect of the anaesthetic.

In patients with suspected phlebitis, serious ischaemia, local infections or complete occlusion of the venous system special caution should be exercised. There should be pulsation in the artery, into which the Optiray will be injected. In patients with thromboangiitis obliterans or ascending infections in combination with serious ischaemia the angiography should only be performed with special caution, if at all. In these procedures cardiac decompensation, serious dysrhythmias, ischaemia and myocardial infarction may occur.

Paediatric patients at higher risk of experiencing adverse events during Optiray administration may include those having asthma, a sensitivity to medication and/or allergies, congestive heart failure, a serum creatinine greater than 132,6 u03bcmol/L or those less than 12 months of age.

Hypothyroidism or transient thyroid suppression may be observed after exposure to iodinated contrast media. This adverse reaction should also be observed in newborns whose mothers have received an iodinated contrast medium during pregnancy (see section 4.6). The incidence of hypothyroidism in patients younger than 3 years of age exposed to iodinated contrast media ranges between 1 % and 15 % depending on the age of the subjects and the dose of the iodinated contrast agent. Younger age, very low birth weight, prematurity, and the presence of other conditions, such as, admission to neonatal or paediatric intensive care units, and cardiac conditions are associated with an increased risk. Paediatric patients with cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures, such as catheterization, and computed tomography (CT). 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 thyroxin (T4) replacement therapy. Thyroid function should be evaluated in all paediatric patients younger than 3 years of age within 3 weeks following exposure to iodinated contrast media. In neonates and particularly in premature neonates, it is recommended to control TSH level and T4, 7-10 days and 1 month after the administration of iodinated contrast media. If hypothyroidism is detected, thyroid function should be monitored as appropriate even when replacement treatment is given.

The following interactions have been reported after the administration of other iodinated contrast media. They are generally accepted as being attributable to this class of contrast media. No interaction studies have been performed.

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 before 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 or has returned to baseline.

Patients treated with interleukin may develop a higher rate of adverse reactions. The reason has not yet been clarified. An increased or delayed occurrence of these reactions within a period of 2 weeks was observed after administration of interleukin.

In case of diuretic-induced dehydration, patients are at increased risk of acute renal failure when using iodinated contrast media. Close monitoring is required to ensure adequate hydration before administration of Optiray. The lowest necessary dose of Optiray consistent with a diagnostic result should be used.

The arterial injection of Optiray should never be made following the administration of vasopressors, since they strongly potentiate neurological effects. Renal toxicity has been reported in patients with liver dysfunction who were given oral cholecystographic medicines followed by intravascular contrast agents. Administration of Optiray should therefore be postponed in patients who have recently received a cholecystographic contrast agent.

Not to be used during pregnancy or lactation (see section 4.3 Contraindications). Safety in pregnancy and lactation has not been established.

There has been limited human use of Optiray in pregnancy. However, since any X-ray investigation during pregnancy may involve a potential foetal risk, the risk/benefit ratio should be carefully weighed. If a better known and safer alternative is available, an X-ray investigation involving Optiray should be avoided. Optiray contains iodine which may induce foetal dysthyroidism if the examination takes place after more than 14 weeks of amenorrhoea. Thyroid function of neonates should be closely monitored during the first week of life if iodinated contrast was administered to the mother during pregnancy. It is recommended that thyroid function be monitored again at 2 weeks of age.

It is not known whether Optiray is excreted in human breast milk. However, Optiray may be excreted unchanged in breast milk. Caution should be exercised when Optiray is administered to women breastfeeding their infants, because of potential adverse events, and mothers given Optiray should discontinue breastfeeding for one day.

There is no known effect on the ability to drive and operate machines. However, because of the risk of early reactions driving or operating machinery is not advisable for 1 hour following the time of injection.

Frequencies for adverse drug reactions are defined as follows: Very common (u22651/10) Common (u22651/100 to <1/10) Uncommon (u22651/1000 to <1/100) Rare (u22651/10,000 to <1/1000) Very rare (<1/10,000) Not known (cannot be estimated from the available data)

a. Summary of the safety profile Adverse reactions following the use of Optiray formulations are generally independent of the dose administered. Usually, they are mild to moderate, of short duration and resolve spontaneously (without treatment). However, even mild adverse reactions may be the first indication of a serious, generalized reaction that can occur rarely after iodinated contrast media. Such serious reactions may be life-threatening and fatal and usually affect the cardiovascular system. Most adverse drug reactions to Optiray formulations occur within minutes after administration, however, contrast related hypersensitivity reactions may occur with a delay of some hours up to several days.

b. Tabulated summary of adverse reactions From clinical studies, mild discomfort, including sensation of heat or cold, pain during the injection, and/or transient taste perversion, was noted in 10 % to 50 % of patients. In a large post-marketing study, other side effects occurred in a total of 1,1 % of the patients; the most frequent were nausea (0,4 %), skin reactions such as urticaria or erythema (0,3 %), and vomiting (0,1 %). All other events occurred in less than 0,1 % of the patients.

The following adverse reactions have been collected after Optiray administration from clinical trials and post-market experience, including post-market surveys. Infections and infestations Rare: rhinitis Immune system disorders Very rare: anaphylactoid (hypersensitivity) reaction Not known: anaphylactic shock Endocrine disorders Not known: hypothyroidism* Psychiatric disorders Very rare: confusional state; agitation; anxiety Nervous system disorders Uncommon: dizziness; dysgeusia; headache; paraesthesia Rare: syncope; tremor Very rare: loss of consciousness; paralysis; speech disorders; somnolence; stupor; aphasia; dysphasia; hypoaesthesia Not known: seizure; contrast-induced encephalopathy; amnesia; dyskinesia Eye disorders Rare: vision blurred; eye swelling; periorbital oedema Very rare: conjunctivitis allergic (including eye irritation, ocular hyperaemia, lacrimation increased, conjunctival oedema) Not known: blindness transient Ear and labyrinth disorders Rare: vertigo Very rare: tinnitus Cardiac disorders Rare: tachycardia Very rare: heart block; arrhythmia; angina pectoris; bradycardia; atrial fibrillation; electrocardiogram abnormal Not known: cardiac arrest; ventricular fibrillation; arteriospasm; coronary extrasystoles; palpitations Vascular disorders Uncommon: blood pressure increased Rare: hypotension; flushing Very rare: cerebrovascular disorder; phlebitis; hypertension; vasodilation Not known: shock; thrombosis; vasospasm; cyanosis; pallor Respiratory, thoracic and mediastinal disorders Uncommon: sneezing Rare: laryngeal oedema; laryngo spasm; dyspnoea; laryngeal obstruction (incl. throat tightness, stridor); nasal congestion; cough; throat irritation Very rare: pulmonary oedema; pharyngitis; hypoxia Not known: respiratory arrest; asthma; bronchospasm; dysphonia Gastrointestinal disorders Common: nausea Uncommon: vomiting Rare: dry mouth Very rare: sialoadenitis; abdominal pain; tongue oedema; dysphagia; salivary hypersecretion Not known: diarrhoea Skin and subcutaneous tissue disorders Uncommon: urticaria; erythema; pruritus Rare: rash Very rare: angioedema; hyperhidrosis (incl. cold sweat) Not known: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS syndrome); Acute Generalized Exanthematous Pustulosis (AGEP); Erythema Multiforme (EM), Stevens Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) Musculoskeletal, connective tissue and bone disorders Very rare: muscle spasms Renal and urinary disorders Rare: micturition urgency Very rare: acute kidney injury; abnormal renal function; incontinence; haematuria; creatinine renal clearance decreased; blood urea increased Not known: anuria; dysuria Congenital, familial and genetic disorders Not known: congenital hypothyroidism General disorders and administration site conditions Very common: feeling hot Common: pain Rare: face oedema; pharyngeal oedema; feeling cold; tremor; chills Very rare: chest pain; injection site reactions (incl. pain, erythema, and haemorrhage up to necrosis especially after extravasation); malaise; asthenia; fatigue; feeling abnormal, oedema, sluggishness Not known: pyrexia

c. Description of selected adverse reactions Adverse reactions may be classified as follows: a. Hypersensitivity reactions: Serious anaphylactic reactions generally affect the cardiovascular and respiratory system. These may be life-threatening and include anaphylactic shock, cardiac and respiratory arrest, or pulmonary oedema. Patients with a history of allergic reactions are at increased risk of developing hypersensitivity reactions. Other type 1 (immediate) reactions such as nausea and vomiting, skin rashes, dyspnoea, rhinitis, paraesthesia or hypotension. b. Vasovagal reactions: e.g. Dizziness or syncope which may be caused either by the contrast medium, or by the procedure. c. Cardiologic side effects: During cardiac catheterisation e.g. angina pectoris, ECG changes, cardiac dysrhythmias, conductivity disorders and coronary spasm, which may be caused by the contrast medium or by the procedure. d. Nephrotoxic reactions: In patients with pre-existing renal damage or renal vasopathy e.g. decrease in renal function with creatinine elevation. These adverse effects may be transient in the majority of cases. In single cases, acute renal failure has been observed. e. Neurotoxic reactions: After intra-arterial injection of the contrast medium e.g. visual disorders, disorientation, paralysis, convulsions, or fits. These symptoms are generally transient and abate spontaneously within several hours or days. Patients with pre-existing damage of the blood-brain barrier are at increased risk of developing neurotoxic reactions. f. Local reactions: At the injection site e.g. rashes, swelling, vasospasm and inflammation. g. Extravasation: Can cause serious tissue reactions, the extent of which is dependent on the amount and strength of the contrast solution in the tissues.

d. Paediatric population Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. *Thyroid dysfunction was observed in paediatric patients 0 to 3 years of age following the administration of iodinated radiopaque agents.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are requested to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. SAHPRA website: https://www.sahpra.org.za Guerbet South Africa (Pty) Ltd: [email protected] Reporting suspected adverse reactions in: Botswana: https://vigiflow-eforms.who-umc.org/bw/adr or [email protected] Namibia: https://vigiflow-eforms.who-umc.org/na/named

In overdose, side effects will be exacerbated and exaggerated. Overdose of Optiray is potentially fatal and may affect the respiratory and cardiovascular system. Treatment should be symptomatic & supportive. Dialysis can be used to remove Optiray from the blood.