Imeron 200mg/250mg/300mg/350mg/400mg Solution for injection

IMERON 200: Peripheral phlebography, digital subtraction phlebography, CT (brain and body), cavernosography, intravenous and intra-arterial DSA, ERCP, arthrography, hysterosalpingography, cholangiography, retrograde urethrography and retrograde pyelo-ureterography. IMERON 250: Intravenous urography (in adults and paediatrics), peripheral phlebography, CT (brain and body), intravenous and intra-arterial DSA. IMERON 300: Intravenous urography (in adults and paediatrics), peripheral phlebography, CT (brain and body), cavernosography, intravenous DSA, conventional angiography, intra-arterial DSA, angiocardiography (in adults and paediatrics), conventional selective coronary arteriography, interventional coronary arteriography, ERCP, arthrography, hysterosalpingography, fistulography, discography, galactography, cholangiography, dacryocystography, sialography, retrograde urethrography, retrograde pyelo-ureterography. IMERON 350: Intravenous urography (in adults and paediatrics), CT (body), intravenous DSA, conventional angiography, intra-arterial DSA, angiocardiography (in adults and paediatrics), conventional selective coronary arteriography, interventional coronarography, arthrography, hysterosalpingography, fistulography, galactography, cholangiography, dacryocystography, sialography. IMERON 400: Intravenous urography (in adults including those with renal impairment or diabetes), CT (body), conventional angiography, intra-arterial DSA, angiocardiography (in adults and paediatrics), conventional selective coronary arteriography, interventional coronary arteriography, fistulography, galactography, dacryocystography, sialography. CT: Computed tomography. DSA: Digital subtraction angiography. ERCP: Endoscopic retrograde cholangio-pancreatography. MCU: Micturating cisto-urethrography.

General information

1. Any severe disorders of water and electrolyte balance must be corrected prior to administration. Adequate hydration must be ensured particularly in patients with multiple myeloma, diabetes mellitus, polyuria, oliguria and hyperuricaemia; also in babies, small children and the elderly.
2. Unless otherwise instructed by the doctor, a normal diet may be maintained on the day of the examination. Adequate fluid intake must be ensured. However, for two hours prior to the procedure the patient should refrain from eating.
3. In patients with phaeochromocytoma, premedication with alpha-receptor blockers is recommended because of the risk of blood pressure crisis (see section 4.4).
4. Pronounced states of excitement, anxiety and pain can be the cause of side-effects or intensify contrast-related reactions. These patients may be given a sedative.
5. Neuroleptics and antidepressants should be discontinued 48 hours before the examination because they reduce the seizure threshold. Treatment should not be resumed until 24 hours post-procedure (see section 4.4 and 4.5). Anti-convulsant therapy must not be discontinued and should be administered in optimal dosage.

In relation to procedure

1. Non-ionic contrast media have less anti-coagulant activity in vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique and vascular catheterisation. Non-ionic media should not be allowed to remain in contact with blood in the syringe and intra-vascular catheters should be flushed frequently to minimise the risk of clotting which, rarely, has led to serious thrombo-embolic complications after procedures.
2. Intravascular administration of contrast media should, if possible, be done with the patient lying down. The patient should be kept under observation for at least 30 minutes after the procedure.
3. Vials containing contrast media solution are not intended for the withdrawal of multiple doses. The rubber stopper should never be pierced more than once. The use of proper withdrawal cannulas for piercing the stopper and drawing up the contrast medium is recommended. The contrast medium should not be drawn into the syringe until immediately before use. Solutions not used in one examination session must be discarded.
4. When using IMERON 500 mL bottle, the contrast medium solution should be administered with an automatic injector. The tube connecting the injector to the patient (patient tube) should be replaced after each examination as it may be contaminated with blood. Unused contrast solution remaining in the bottle, the connection tube and the injector should be discarded at the end of the examination day. Follow the instructions given by the manufacturer of the injection system or the equipment.
5. In order to avoid possible incompatibilities, contrast media must not be mixed with other medicines. In consideration of possible complications, the patient should be kept under observation for at least 60 minutes after the administration.

Table 2: Indications

Formulation mg (iodine)/mL Proposed dosages

Intravenous urography 250, 300, 350, 400 Adults: 50 u2013 50 mL Neonates: 3 u2013 4,8 mL/kg Babies: 2,5 u2013 4 mL/kg u2264 1 year Children: 1 u2013 2,5 mL/kg u2265 1 year

Peripheral phlebography 200, 250, 300 Adults: 10 u2013 100 mL, repeat if necessary b (10 u2013 50 mL upper extremities; 50 u2013 100 mL lower extremities)

Phlebography in DSA 200 Adults: 10 u2013 100 mL, repeat if necessary b (10 u2013 50 mL upper extremities; 50 u2013 100 mL lower extremities)

CT brain 200, 250, 300 Adults: 50 u2013 200 mL Children a

CT body 200, 250, 300, 350, 400 Adults: 100 u2013 200 mL Children a

Cavernosography 200, 300 Adults: up to 100 mL

Intravenous DSA 250, 300, 350, 400 Adults: 100 u2013 250 mL Children a

Conventional angiography: - Arteriography of upper extremities 300, 350 Adults b - Arteriography of pelvis and lower extremities 300, 350, 400 Adults b - Abdominal arteriography 300, 350, 400 Adults b - Arteriography of descending aorta 300, 350 Adults b - Pulmonary angiography 300, 350, 400 Adults: up to 170 mL - Cerebral angiography 300, 350 Adults: up to 100 mL - Paediatric arteriography 300 Children: up to 130 mL a - Interventional arteriography 300, 350, 400 Adults b Children a

Intra-arterial DSA - Cerebral 200, 300, 350 Adults: 30 - 60 ml for general view; 5 u2013 10 mL for selective angiography Children a - Thoracic 200, 300 Adults b: 20 u2013 25 mL (aorta) repeat if necessary 20 mL (bronchial arteries) - Aortic arch 200, 300, 350 Adults c - Abdomen 200, 250, 300 Adults c - Aortography 200, 300, 350 Adults c - Translumbar aortography 200, 300 Adults b - Peripheral arteriography 200, 250, 300 Adults: 5 u2013 10 mL for selective injections up to 250 ml Children a - Interventional 200, 300 Adults: 10 u2013 30 mL for selective injections up to 250 mL Children a

Angiocardiography 300, 350, 400 Adults b Children: 3 u2013 5 mL/kg

Conventional selective coronary arteriography 300, 350, 400 Adults: 4 u2013 10 mL per artery, repeat if necessary

ERCP 200, 300 Adults: up to 100 mL

Arthrography 200, 300, 350 Adults: up to 10 mL/injection

Hysterosalpingography 200, 300, 350 Adults: up to 35 mL

Fistulography 300, 350, 400 Adults: up to 100 mL

Discography 300 Adults: up to 4 mL

Galactography 300, 350, 400 Adults: 0,15 u2013 1.2 mL for injection

Dacryocystography 300, 350, 400 Adults: 2,5 u2013 8 mL for injection

Sialography 300, 350, 400 Adults: 1 u2013 3 mL for injection

Retrograde cholangiography 200, 300, 350 Adults: up to 60 mL

Retrograde urethrography 200, 300 Adults: 20 u2013 100 mL

Retrograde pyelo-ureterography 200, 300 Adults: 10 u2013 20 mL for injection

a = According to body weight and age. b = Do not exceed 250 mL. Single injection volume depends on the vascular area to be examined. c = Do not exceed 350 mL

Method of administration: The following methods of administration can be used: intravenous and intra-arterial.

Hypersensitivity to iomeprol or to any of the ingredients of IMERON (listed in section 6.1). IMERON should be avoided in case of Waldenstru00f6m's paraproteinaemia, multiple myeloma and severe liver or renal impairment. Investigations of the female genitalia are contraindicated in suspected or confirmed pregnancy (see section 4.6) and in cases of acute inflammation. IMERON 200: Hysterosalpingography is not to be carried out in pregnancy or in acute pelvic inflammatory conditions. IMERON 200/250/300: Intrathecal concomitant administration of corticosteroids with contrast media, such as IMERON, is contraindicated.

Diagnostic procedures which involve the use of any radiopaque medium should be carried out under the direction of personnel with the prerequisite training and with a thorough knowledge of the particular procedure to be performed. Appropriate facilities should be available for coping with any complication of the procedure, as well as for emergency treatment of severe reaction to the contrast medium itself. Fatal reactions have been associated with the administration of water-soluble contrast media. Particular caution must be exercised in the case of hypersensitivity to iodinated contrast media. Experience shows that patients with an allergic disposition suffer more frequently from hypersensitivity reactions. Premedication with antihistamines and/or corticoids may be considered. However, contrast media and prophylactic medicines should not be administered as mixed together (see section 6.2).

Treatment with medicines that lower the seizure threshold such as analgesics, antidepressants and anti-emetics of the phenothiazine class, and neuroleptics should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure (see section 4.5). A positive history of allergy, asthma or untoward reactions during previous similar investigations indicates a need for extra caution since, as with other contrast media, IMERON may provoke anaphylaxis or other manifestations of allergy with nausea, vomiting, dyspnoea, erythema, urticaria and hypotension. The benefits should clearly outweigh the risks in such patients and appropriate resuscitative measure should be immediately available. The primary treatments are tabulated as follows:

Effect Major symptoms Primary treatment

Vasomotor effect Warmth, nausea/vomiting Reassurance

Cutaneous Scattered hives Severe urticaria H1-antihistamines, H2-antihistamines.

Bronchospastic Wheezing Oxygen, beta 2-agonist inhalers.

Anaphylactoid reaction Angio-oedema Urticaria Bronchospasm Hypotension Oxygen. IV fluids. Adrenergics. (IV epinephrine/adrenaline). Inhaled beta 2-adrenergics Antihistamines (H1- and H2-blockers) Corticosteroids.

Hypotensive Hypotension IV fluids.

Vagal reaction Hypotension Bradycardia IV fluids. IV atropine.

In consideration of possible complications, the patient should be kept under observation for at least 60 minutes after the administration.

Elderly: There is a special risk of reactions involving the circulatory system such that myocardial ischaemia, major dysrhythmias and extrasystoles are more likely to occur. A combination of neurological disturbances and vascular pathologies present a serious complication. The probability of acute renal insufficiencies is higher in these patients.

Patients using beta-adrenergic blocking medicines, 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 of adrenaline.

Hydration: Patients must be well hydrated, and any relevant abnormalities of fluid or electrolyte balance should be corrected prior to and following contrast media injection. Especially patients with sickle cell disease, diabetes mellitus, polyuria, oligouria, hyperuricaemia, infants, elderly patients, and patients with severe systemic disease should not be exposed to dehydration. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, including congestive heart failure.

Thyroid function and thyroid function tests: The small amount of free inorganic iodide that may be present in contrast media might have some effects on thyroid function and these effects appear more evident in patients with latent or overt hyperthyroidism or goitre. Thyroid storms have been reported following administration of IMERON. Use may interfere with thyroid function tests. Following administration of iodinated contrast media, the capacity of the thyroid tissue to take up radio-isotopes for the diagnosis of thyroid disorders is reduced for up to two weeks, or even longer in individual cases.

Renal failure: Pre-existing renal impairment may predispose to acute renal dysfunction following contrast media administration, attention should be paid to renal function parameters before re-examining the patient with a contrast medium. Preventive measures include:

• identification of high risk patients;
• ensuring adequate hydration before contrast media administration, preferably by maintaining IV infusion before and during the procedure and until the contrast medium has been cleared by the kidneys;
• avoiding, whenever possible, the administration of nephrotoxic medicines or major surgery or procedures such as renal angioplasty, until the contrast medium has been cleared;
• postponing a new contrast agent examination until renal function returns to pre-examination levels. Patients on dialysis may receive contrast media, such as IMERON, which may be cleared by dialysis.

Diabetes mellitus: Renal impairment may precipitate lactacidosis in diabetic patients with renal damage, treated with biguanides (metformin). To prevent onset of lactic acidosis in these patients, metformin should be stopped at the time or 48 hours prior to the administration of the contrast medium, and only re-instated after 48 hours if serum creatinine/estimated glomerular filtration rate (eGFR) is unchanged from the pre-imaging level. Care should be taken in renal impairment and diabetes. In these patients it is important to maintain hydration in order to minimise deterioration in renal function. Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intravascular administration. Premedication with an alpha-blocker is recommended in these patients before intra-arterial injection of contrast media under the supervision of a medical practitioner.

Anxiety, pain: Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Cardiac disorders: Care should be taken in severe cardiac disease particularly heart failure and coronary artery disease. Reactions may include pulmonary oedema, haemodynamic changes, ischaemic electrocardiogram (ECG) changes and dysrhythmias. In severe, chronic hypertension the risk of renal damage following administration of a contrast medium is increased. In these cases, the risks associated with the catheterisation procedure are increased.

Central nervous system (CNS) disorder: Particular care should be paid to the intravascular administration of IMERON in patients with acute cerebral infarction, acute intracranial haemorrhage and conditions involving blood brain barrier (BBB) damage, brain oedema or acute demyelination. The presence of intracranial tumours or metastases and a history of epilepsy may increase the probability of the occurrence of convulsive seizures. Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastasis or degenerative, ischaemic or inflammatory pathologies may be exacerbated. These patients have an increased risk of transient neurological complications.

Contrast induced encephalopathy: Encephalopathy has been reported with the use of IMERON (see section 4.8). Contrast encephalopathy may manifest with symptoms and signs of neurological dysfunction such as headache, visual disturbance, cortical blindness, confusion, seizures, loss of coordination, hemiparesis, aphasia, unconsciousness, coma and cerebral oedema within minutes to hours after administration of IMERON, and generally resolves within days. The product should be used with caution in patients with conditions that disrupt the integrity of the 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 IMERON should be discontinued and appropriate medical management should be initiated. Cerebral ischaemic phenomena may be caused by intravascular injection. In acute and chronic alcoholism, the increase in BBB permeability facilitates the passage of the contrast medium into cerebral tissue possibly leading to CNS disorders. There is a possibility of a reduced seizure threshold in alcoholics. In patients with a drug addiction there is also the possibility of reduced seizure threshold.

Extravasation: Extreme caution during injection of contrast media is necessary to avoid extravasation.

Myasthenia gravis: The administration of iodinated contrast media may worsen myasthenia signs and symptoms.

Vascular disorders: Special care is required when investigations are performed in patients with suspected thrombosis, phlebitis, severe ischaemic disease, local infection or a totally obstructed arterovenous system.

Paediatric population: Children: Infants up to 1 year, especially newborn, are particularly susceptible to electrolyte imbalances and haemodynamic alterations. Care should be taken regarding the dosage to be used. Transient thyroid suppression or hypothyroidism has been observed in children after exposure to iodinated contrast media. Following a diagnostic procedure, this has been more frequently observed in neonates and premature infants and also following procedures associated with higher doses. Neonates may also be exposed via maternal exposure. In neonates, especially preterm infants, who have been exposed to IMERON, either through the mother during pregnancy or in the neonatal period, it is recommended to monitor thyroid function. If hypothyroidism is detected, the need for treatment should be considered and thyroid function should be monitored until normalized.

Use of IMERON may interfere with tests for thyroid function. The results of protein binding iodine and radioactive iodine uptake studies, which depend on iodine estimations, will not accurately reflect thyroid function for up to 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 affected. Any test that might be affected by contrast media should be performed prior to administration of the contrast medium. These findings have not been associated with clinical manifestations. Vasopressor medicines should not be administered prior to IMERON. The presence of renal damage in diabetic patients is one of the risk factors predisposing to renal impairment following contrast media administration. Renal damage may precipitate lactic acidosis patients who are taking metformin (see section 4.4). Allergy-like reactions to contrast media are more frequent and may manifest as delayed reactions in patients treated with immuno-modulators, like interleukin-2 (IL-2), and interferon. Contrast media may interfere with laboratory tests for bilirubin, proteins or inorganic substances (e.g. iron, copper, calcium, and phosphate). IMERON 200/250/300: Epidural and intrathecal corticosteroids should never be concurrently administered with IMERONu00ae, because corticosteroids may promote and affect the signs and symptoms of arachnoiditis (see section 4.3).

Fertility: Elective exposure to diagnostic radiation should be restricted as far as possible to the first ten days of the ovulatory cycle.

Pregnancy: The safety of IMERON in human pregnancy has not been established. Therefore avoid use in pregnancy (see section 4.3). In neonates who have been exposed to IMERON in utero, it is recommended to monitor thyroid function (see section 4.4).

Breastfeeding: No human data exist concerning the excretion of IMERON in breast milk. Animal studies have demonstrated that the excretion of IMERON in breast milk is similar to that of other contrast agents. As a precautionary measure, breastfeeding should be discontinued prior to the administration of IMERON and should not be recommenced until 24 hours after the administration of the contrast medium.

There is no known effect on the ability to drive or operate machines.

Summary of the safety profile: Side-effects are usually mild to moderate and transient in nature. However, severe and life-threatening reactions sometimes leading to death have been reported. In most cases, reactions occur within minutes of dosing but, at times reactions may occur at later time. Anaphylaxis (anaphylactoid/hypersensitivity reactions) may manifest with various symptoms, and rarely does any one patient develop all the symptoms. Typically, in 1 to 15 minutes (but rarely after as long as 2 hours), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, lacrimation increased, rhinitis, palpitations, paraesthesia, pruritus, head throbbing, pharyngolaryngeal pain and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, and mild localised oedema or angioedema, and dyspnoea owing to tongue and laryngeal oedema and/or laryngospasm manifesting with wheezing and bronchospasm. Nausea, vomiting, abdominal pain and diarrhoea are also reported. These reactions, which can occur independently of the dose administered or the route of administration, may represent the first signs of circulatory collapse.

Administration of IMERON must be discontinued immediately and, if needed, appropriate specific treatment urgently initiated via venous access. Severe reactions involving the cardiovascular system, such as vasodilatation, with pronounced hypotension, tachycardia, dyspnoea, agitation, cyanosis and loss of consciousness progressing to respiratory and/or cardiac arrest may result in death. These events can occur rapidly and require full and aggressive cardio-pulmonary resuscitation. Primary circulatory collapse can occur as the only and/or initial presentation without respiratory symptoms or without other signs or symptoms outlined above.

The adverse reactions reported in clinical trials among 4,920 adult patients and from post-marketing surveillance are represented in the tables below by frequency and classified by MedDRA system organ class. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adult patients involved in clinical trials with intravascular administration of iomeprol were 4,739.

Tabulated summary of adverse reactions: The following terminologies have been used in order to classify the occurrence of adverse reactions: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to, < 1/100); rare (u2265 1/10 000 to < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated from the available data).

The effects of overdose on the pulmonary and cardiovascular systems may become life-threatening. Treatment consists of support of the vital functions and prompt use of symptomatic therapy. IMERON does not bind to plasma or serum proteins and is therefore dialyzable.