Label: IOMERON- iomeprol injection injection, solution

IMPORTANT DRUG INFORMATION
may be found at the following link:
https://imaging.bracco.com/us-en/products/ct-ct-colonography/iomeron

July 6, 2022

Subject: Temporary importation of Iomeron® (iomeprol injection) to address drug shortage issues

Dear Healthcare Professional,

Due to the current critical shortages of Omnipaque™ (iohexol injection), Visipaque™ (iodixanol injection), and Ultravist (iopromide injection) in the U.S. market, Bracco Diagnostics Inc. (hereafter “Bracco”) is coordinating with the U.S. Food and Drug Administration (FDA) to increase the availability of iodinated contrast media indicated for intravascular use.

Accordingly, Bracco has initiated temporary importation of Iomeron® (iomeprol injection), an intravascular iodinated contrast medium, into the U.S. market. This product will be used in adult patients by intravenous or intraarterial route of administration only during the shortage. FDA has not approved Iomeron (iomeprol). Iomeron (iomeprol) drug product is manufactured by BIPSO GmbH in Germany and Patheon Italia S.p.A. in Italy. These facilities are also used to manufacture Bracco’s FDA-approved intravascular iodinated contrast medium Isovue (iopamidol injection).

FDA’s regulatory discretion for the importation and distribution of Iomeron (iomeprol) is limited to Bracco during the critical U.S. shortages of Omnipaque, Visipaque, and Ultravist.

Effective immediately, and during this temporary period, Bracco will offer the following presentations of Iomeron (iomeprol) to the U.S. market:

The imported Iomeron (iomeprol) was originally labelled for use in countries outside the United States. The bottle and box labels will display the text used when marketing Iomeron (iomeprol) in those countries. Note that:

• The prescribing information will be provided with each bottle of Iomeron (iomeprol), in the form of the appropriate Summary of Product Characteristics (SmPC) document approved for the U.K., which is written in English, and is representative of all Iomeron (iomeprol) SmPCs for that presentation.
• Copies of the U.K. SmPCs accompany this letter, along with images of the U.K. bottle and box labels that will be imported.
• The Iomeron (iomeprol) U.K. SmPCs are available on-line at: https://imaging.bracco.com/us-en/products/ct-ct-colonography/iomeron
• For those bottles and box labels not in English, English translations of these labels are available on-line at: https://imaging.bracco.com/us-en/products/ct-ct-colonography/iomeron

There are differences among the currently marketed nonionic, low-osmolar iodinated contrast media in their physico-chemical properties, as can be seen in the below table that compares them at the concentration of 300 mg iodine/mL (except for Visipaque, for which the nearest concentration is 320 mg iodine/mL):

Iomeron multi-dose container’s administration:

The 500 mL presentations of Iomeron are multi-dose containers. The U.K. SmPC states that the Iomeron multi-dose bottle stopper should be pierced only once, and that proper withdrawal cannulas for piercing the stopper and drawing up the contrast medium should be used. For those injectors in which the Iomeron container would be directly inserted (i.e., there would be no use of a transfer set), the injector manufacturer’s procedures for insertion should be followed, keeping in mind that the bottle stopper should be pierced only once.

Microbial contamination studies were performed where Iomeron solutions in multi-dose containers were inoculated with micro-organisms. These studies demonstrated that Iomeron solutions are bacteriostatic, with microbial growth not observed over the 10-hour period of the studies. Based upon these studies, when the 500 mL multi-dose container is used to draw up or administer separate doses of Iomeron, any unused product remaining in the bottle after 10 hours from the stopper being pierced must be discarded.

Please see Appendix 1 of this letter for tables showing the differences among the FDA-approved intra-arterial and intravenous indications for Omnipaque (iohexol), Visipaque (iodixanol), Ultravist (iopromide) and Isovue (iopamidol) vs. the intra-arterial and intravenous indications for Iomeron (iomeprol) approved in the U.K.

Iomeron (iomeprol) will be available only by prescription in the U.S. However, the imported lots do not have the statement “Rx only” on their labeling. Please refer to the Iomeron (iomeprol) U.K. SmPC for the product’s full prescribing information. In addition, please note the following comments and recommendations:

• There are differences between indications for Iomeron (iomeprol) approved in the U.K. and approved indications for iodinated contrast media (ICM) in the US. Tables comparing indications for selected FDA approved ICM and Iomeron (iomeprol) are provided in Appendix 1.
• We recommend that imported Iomeron (iomeprol) be administered only by intravenous and intra-arterial routes.
• We recommend that imported Iomeron (iomeprol) be used only in adult patients. Iomeron (iomeprol) adult dosing per the U.K. SmPC is provided in Appendix 2.
• Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and always have emergency resuscitation equipment and trained personnel available prior to Iomeron administration. Monitor all patients for hypersensitivity reactions.
• Use the lowest necessary dose of Iomeron (iomeprol) in patients with renal impairment or with congestive heart failure.
• Avoid angiocardiography whenever possible in patients with homocystinuria because of the risk of inducing thrombosis and embolism.
• Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of any iodinated contrast agent.
• Administer iodinated contrast agents with extreme caution in patients with known or suspected pheochromocytoma. Inject the minimum amount of contrast necessary, assess the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.
• Severe cutaneous adverse reaction severity may increase and time to onset may decrease with repeat administration of contrast agents; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering Iomeron to patients with a history of a severe cutaneous adverse reaction to Iomeron.
• Stop metformin at the time of, or prior to, Iomeron (Iomeron) administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure and reinstitute metformin only after renal function is stable.
• Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6 to 8 weeks.
• Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular iodinated contrast agents. Administration of any intravascular iodinated contrast agent should therefore be postponed in patients who have recently received a cholecystographic contrast agent.

The Iomeron (iomeprol) barcode may not register accurately on U.S. barcode scanning systems. Institutions should manually input the product into their systems and confirm that their systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients.

To place an order for Iomeron (iomeprol), please contact Bracco Customer Service at 1-877-272-2269 or at Bracco.otc@diag.bracco.com. Hours of operation: Monday-Friday 8:30 AM – 6:00 PM EDT, excluding holidays.

To report adverse events associated with the use of this product, please contact Bracco Drug Safety at 1-800-257-5181, option 1, or at adverse.events@diag.bracco.com.

To report quality problems, or if you have any questions about the information contained in this letter or the use of Iomeron (iomeprol), please contact Bracco Professional Services at 1-800-257-5181, option 2, or at services.professional@diag.bracco.com.

Adverse reactions or quality problems experienced with the use of this product may be reported to the FDA's MedWatch Adverse Event Reporting program either online, by regular mail or by fax.

• Complete and submit the report Online: www.fda.gov/medwatch/report.htm
• Regular Mail or Fax: Download form www.fda.gov/MedWatch/getforms.htm or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178 (1-800-332-0178)

Sincerely,

Alberto Spinazzi, MD
Senior Vice President
Chief Medical and Regulatory Officer
Bracco Group

Attachments:
 Iomeron (iomeprol) U.K. SmPCs
 Images of Iomeron (iomeprol) U.K. Bottle and Box Labels

Appendix 1. Comparisons of approved uses for iodinated contrast media in shortage and those manufactured by Bracco.

Appendix 2. Iomeron (iomeprol injection) adult dosing recommendations per U.K. Summary of Product Characteristics.

UK Iomeron Vial and Carton Labels

Product Description	Iodine Concentration (mg iodine/mL)	Fill Volume	Vial Label	Carton Label
Iomeron (iomeprol injection) 250	250	100 mL
Iomeron (iomeprol injection) 300	300	100 mL
Iomeron (iomeprol injection) 300	300	200 mL
Iomeron (iomeprol injection) 300	300	500 mL
Iomeron (iomeprol injection) 350	350	100 mL
Iomeron (iomeprol injection) 350	350	200 mL
Iomeron (iomeprol injection) 350	350	500 mL
Iomeron (iomeprol injection) 400	400	100 mL
Iomeron (iomeprol injection) 400	400	200 mL
Iomeron (iomeprol injection) 400	400	500 mL

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 250, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 51.03% w/v of iomeprol equivalent to 25% iodine or 250mg iodine/ml.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for:

• venography
• cerebral arteriography
• digital subtraction angiography
• computed tomography enhancement
• urography
• cavernosography
• myelography

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.

Unless otherwise instructed by the doctor, a normal diet may be maintained on the day of the examination.

In myelography, lower doses may be used for lumbar or thoracic studies and higher doses for cervical or total columnar studies. Regardless of the nature of the myelographic study, Iomeron should be injected slowly over 1-2 minutes.

The X ray can be taken up to 60 minutes following injection. Post myelographic CT of the spinal column should be delayed for approximately four hours to allow dilution and clearance of excessive contrast.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.
Intrathecal concomitant administration of corticosteroids with contrast media is contraindicated.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

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 diabetes mellitus, polyuria, oligouria, hyperuricaemia, infants, small children, and elderly patients, should not be exposed to dehydration. Also patients with severely compromised hepatic and renal impairment are more at risk. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, including congestive heart failure.

Rehydration prior to use of iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition

A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighted against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in severe cardiac disease particularly heart failure and coronary artery disease. Reactions may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias. 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 catheterization procedure are increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease e.g. stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier 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 a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intra-arterial administration. Premedication with an alpha and beta receptor blocker is recommended in these patients. Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Renal impairment
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;

avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;

A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children: Infants up to 1 year, especially the new-born, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.

Transient hypothyroidism may occur in neonates when the mother or the neonate has received an iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates 7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.

Elderly: There is special risk of reactions involving the circulatory system such that myocardial ischaemia, major arrhythmias 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 people.

Precautions for dedicated exams

Angiography
Non ionic contrast media have less antiocoagulant activity in vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently to minimise the risk of clotting which, rarely, has led to serious thromboembolic complications.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

Myelography
Following intrathecal use, the patient should rest with the head and the chest elevated for 1 hour and be kept well hydrated. Thereafter, he/she may ambulate carefully, but bending down must be avoided. If remaining in bed, the head and chest should be kept elevated for 6 hours. Patients, suspected of having a lower seizure threshold should be observed during this period.

Venography
Special care is required when venography is performed in patients with thrombosis, phlebitis, severe ischaemic disease, local infection or a totally obstructed artero-venous system.

4.5 Interaction with other medicinal products and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to iomeprol.

Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenotiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

Epidural and intrathecal corticosteroids should never be concurrently administered when iodinated contrast media are used, because corticosteroids may promote and affect the signs and symptoms of arachnoiditis (see section 4.3 - Contraindications).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative. Since, wherever possible, exposure to radiation should be avoided during pregnancy, the benefits of any X ray examination, whether with or without contrast material, should for this reason alone be carefully weighed against the possible risk.

Breastfeeding
No human data exist concerning the excretion of iomeprol in breast milk. Animal studies have demonstrated that the excretion of iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.

Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

After intrathecal administration, it is recommended that the patient should wait 24 hours before driving or operating machinery.

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 4,903 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.

4.8.1 Intravascular administration

Adult patients involved in clinical trials with intravascular administration of Iomeprol were 4,515.

Coronary artery thrombosis and coronary artery embolism have been reported as a complication of coronary catheterization procedures.

Vasospasm and consequent ischaemia have been observed during intra-arterial injections of contrast medium, in particular after coronary and cerebral angiography often procedurally related and possibly triggered by the tip of the catheter or excess catheter pressure.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

4.8.2 Intrathecal administration

Adults

Adults patients involved in clinical trials with intrathecal administration of Iomeprol were 388.

The most frequently reported adverse reactions following intrathecal administration of Iomeprol are headache, dizziness, nausea, vomiting and back pain. These reactions are usually mild to moderate and transient in nature. Rarely, headache may persist for days. Most side effects occur some hours (3 to 6 hours) after the procedure, due to the distribution of the contrast medium in the CSF circulation from the site of administration to the intravascular space (see section 5.2: Pharmacokinetic properties). Most reactions usually occur within 24 hours after injection.

Paediatric patients

No adverse reactions were reported after intrathecal administration of Iomeprol both in clinical trials and in the post-marketing surveillance.

4.8.3 Administration to body cavities

After injection of an iodinated contrast media in body cavities, contrast media are slowly absorbed from the area of administration into the systemic circulation and subsequently cleared by renal elimination.

Blood amylase increased is common following ERCP. Very rare cases of pancreatitis have been described.

The reactions reported in cases of arthrography and fistulography usually represent irritative manifestations superimposed on pre-existing conditions of tissue inflammation.

Hypersensitivity reactions are rare, generally mild and in the form of skin reactions. However, the possibility of severe anaphylactoid reactions cannot be excluded.

As with other iodinated contrast media, pelvic pain and malaise may occur after hysterosalpingography.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary/ intrathecal contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

Following intrathecal administration to animals, iomeprol is completely cleared from the CSF and passes into the plasma compartment.

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Five years

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of containers

Colourless Type I or Type II glass bottles with rubber/aluminium cap.
Quantities of 20, 30, 50, 75, 100, 150, 200 or 250 ml of solution.

6.6 Special precautions for disposal and other handling

Bottles 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.
Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present.

The contrast medium should not be drawn into the syringe until immediately before use. Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions with sterile syringes. Sterile techniques must be used with any spinal puncture or intravascular injection, and with catheters and guidewires. If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

It is desirable that solutions of contrast media for intravascular and intrathecal use should be at body temperature when injected.

Any residue of contrast medium in the syringe must be discarded. Solutions not used in one examination session or waste material, such as the connecting tubes, should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

18920/0003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

11 December 1992 / 29 December 1998

10. DATE OF REVISION OF THE TEXT

19 January 2022

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 300, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 61.24% w/v of iomeprol equivalent to 30% iodine or 300mg iodine/ml.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for:

• peripheral arteriography
• venography
• angiocardiography and left ventriculography
• cerebral arteriography
• visceral arteriography
• digital subtraction angiography
• computed tomography enhancement
• urography
• ERCP
• dacryocystography
• sialography
• fistulography
• galactography
• myelography

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.

Unless otherwise instructed by the doctor, a normal diet may be maintained on the day of the examination.

In myelography, lower doses may be used for lumbar or thoracic studies and higher doses for cervical or total columnar studies. Regardless of the nature of the myelographic study, Iomeron should be injected slowly over 1-2 minutes.

The X ray can be taken up to 60 minutes following injection. Post myelographic CT of the spinal column should be delayed for approximately four hours to allow dilution and clearance of excessive contrast.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.
Intrathecal concomitant administration of corticosteroids with contrast media is contraindicated.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

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 diabetes mellitus, polyuria, oligouria, hyperuricaemia, infants, small children, and elderly patients, should not be exposed to dehydration. Also patients with severely compromised hepatic and renal impairment are more at risk. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, including congestive heart failure.

Rehydration prior to use of iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition
A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighted against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in severe cardiac disease particularly heart failure and coronary artery disease. Reactions may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias.

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 catheterization procedure are increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease eg stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier permeability facilitates the passage of the contrast medium into cerebral tissue possibly leading to CMS disorders. There is a possibility of a reduced seizure threshold in alcoholics.

In patients with a drug addiction there is also the possibility of a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intra-arterial administration. Premedication with an alpha and beta receptor blocker is recommended in these patients.

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

Renal impairment
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters, in particular before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;

avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;

A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children:
Infants up to 1 year, especially the new-born, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.

Transient hypothyroidism may occur in neonates when the mother or the neonate has received an iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates 7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.

Elderly:
There is special risk of reactions involving the circulatory system such that myocardial ischaemia, major arrhythmias 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 people.

Precautions for dedicated exams

Angiography
Non ionic contrast media have less antiocoagulant activity in vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently to minimise the risk of clotting which, rarely, has led to serious thromboembolic complications.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

Myelography
Following intrathecal use, the patient should rest with the head and the chest elevated for 1 hour and be kept well hydrated. Thereafter, he/she may ambulate carefully, but bending down must be avoided. If remaining in bed, the head and chest should be kept elevated for 6 hours. Patients, suspected of having a lower seizure threshold should be observed during this period.

Venography
Special care is required when venography is performed in patients with thrombosis, phlebitis, severe ischaemic disease, local infection or a totally obstructed artero-venous system.

4.5 Interaction with other medicaments and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to iomeprol.

Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenotiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

Epidural and intrathecal corticosteroids should never be concurrently administered when iodinated contrast media are used, because corticosteroids may promote and affect the signs and symptoms of arachnoiditis (see section 4.3 - Contraindications).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative.
Since, wherever possible, exposure to radiation should be avoided during pregnancy, the benefits of any X ray examination, whether with or without contrast material, should for this reason alone be carefully weighed against the possible risk.

Breastfeeding
No human data exist concerning the excretion of iomeprol in breast milk. Animal studies have demonstrated that the excretion of iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.

Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

After intrathecal administration, it is recommended that the patient should wait 24 hours before driving or operating machinery.

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 4,903 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.

4.8.1 Intravascular administration

Adult patients involved in clinical trials with intravascular administration of Iomeprol were 4,515.

Coronary artery thrombosis and coronary artery embolism have been reported as a complication of coronary catheterization procedures.

Vasospasm and consequent ischaemia have been observed during intra-arterial injections of contrast medium, in particular after coronary and cerebral angiography often procedurally related and possibly triggered by the tip of the catheter or excess catheter pressure.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

4.8.2 Intrathecal administration

Adults

Adults patients involved in clinical trials with intrathecal administration of Iomeprol were 388.

The most frequently reported adverse reactions following intrathecal administration of Iomeprol are headache, dizziness, nausea, vomiting and back pain. These reactions are usually mild to moderate and transient in nature. Rarely, headache may persist for days. Most side effects occur some hours (3 to 6 hours) after the procedure, due to the distribution of the contrast medium in the CSF circulation from the site of administration to the intravascular space (see section 5.2: Pharmacokinetic properties). Most reactions usually occur within 24 hours after injection.

Paediatric patients

No adverse reactions were reported after intrathecal administration of Iomeprol both in clinical trials and in the post-marketing surveillance.

4.8.3 Administration to body cavities

After injection of an iodinated contrast media in body cavities, contrast media are slowly absorbed from the area of administration into the systemic circulation and subsequently cleared by renal elimination.

Blood amylase increased is common following ERCP. Very rare cases of pancreatitis have been described.

The reactions reported in cases of arthrography and fistulography usually represent irritative manifestations superimposed on pre-existing conditions of tissue inflammation.

Hypersensitivity reactions are rare, generally mild and in the form of skin reactions. However, the possibility of severe anaphylactoid reactions cannot be excluded.

As with other iodinated contrast media, pelvic pain and malaise may occur after hysterosalpingography.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary/ intrathecal contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

Following intrathecal administration to animals, iomeprol is completely cleared from the CSF and passes into the plasma compartment.

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Five years

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of container

Colourless Type I or Type II glass bottles with rubber/aluminium cap.
Quantities of 20, 30, 50, 75, 100, 150, 200 or 250 ml of solution.

6.6 Special precautions for disposal and other handling

Bottles 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.

Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present.

The contrast medium should not be drawn into the syringe until immediately before use. Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions with sterile syringes. Sterile techniques must be used with any spinal puncture or intravascular injection, and with catheters and guidewires. If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

It is desirable that solutions of contrast media for intravascular and intrathecal use should be at body temperature when injected.

Any residue of contrast medium in the syringe must be discarded. Solutions not used in one examination session or waste material, such as the connecting tubes, should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

18920/0004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

11 December 1992 / 29 December 1998

10. DATE OF REVISION OF THE TEXT

19 January 2022

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 350, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 71.44% w/v of iomeprol equivalent to 35% iodine or 350mg iodine/ml.

For the full list of excipients, see section 6.1.For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for:

• peripheral arteriography
• venography
• aortography
• angiocardiography and left ventriculography
• coronary arteriography
• visceral arteriography
• digital subtraction angiography
• computed tomography enhancement
• urography
• dacryocystography
• sialography
• fistulography
• galactography

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.
Unless otherwise instructed by the doctor, a normal diet may be maintained on the day of the examination.

The X ray can be taken up to 60 minutes following injection.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

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 diabetes mellitus, polyuria, oligouria, hyperuricaemia, infants, small children, and elderly patients, should not be exposed to dehydration. Also patients with severely compromised hepatic and renal impairment are more at risk. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, including congestive heart failure.

Rehydration prior to use of iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition
A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighted against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in severe cardiac disease particularly heart failure and coronary artery disease. Reactions may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias.
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 catheterization procedure are increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease eg stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier permeability facilitates the passage of 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 a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intra-arterial administration. Premedication with an alpha and beta receptor blocker is recommended in these patients. Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Renal impairment
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;

avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;

A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children: Infants up to 1 year, especially the new-born, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.

Transient hypothyroidism may occur in neonates when the mother or the neonate has received an iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates 7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.

Elderly: There is special risk of reactions involving the circulatory system such that myocardial ischaemia, major arrhythmias 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 people.

Precautions for dedicated exams
Angiography
Non ionic contrast media have less antiocoagulant activity in vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently to minimise the risk of clotting which, rarely, has led to serious thromboembolic complications.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

Venography
Special care is required when venography is performed in patients with thrombosis, phlebitis, severe ischaemic disease, local infection or a totally obstructed artero-venous system.

4.5 Interaction with other medicaments and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to iomeprol.

Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenotiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative.

Breastfeeding
No human data exist concerning the excretion of iomeprol in breast milk. Animal studies have demonstrated that the excretion of iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.
Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 4,903 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.

4.8.1 Intravascular administration

Adult patients involved in clinical trials with intravascular administration of Iomeprol were 4,515.

Coronary artery thrombosis and coronary artery embolism have been reported as a complication of coronary catheterization procedures.

Vasospasm and consequent ischaemia have been observed during intra-arterial injections of contrast medium, in particular after coronary and cerebral angiography often procedurally related and possibly triggered by the tip of the catheter or excess catheter pressure.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

4.8.2 Administration to body cavities

After injection of an iodinated contrast media in body cavities, contrast media are slowly absorbed from the area of administration into the systemic circulation and subsequently cleared by renal elimination.

Blood amylase increased is common following ERCP. Very rare cases of pancreatitis have been described.

The reactions reported in cases of arthrography and fistulography usually represent irritative manifestations superimposed on pre-existing conditions of tissue inflammation.

Hypersensitivity reactions are rare, generally mild and in the form of skin reactions. However, the possibility of severe anaphylactoid reactions cannot be excluded.
As with other iodinated contrast media, pelvic pain and malaise may occur after hysterosalpingography.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. No other drug should be mixed with the contrast medium.

6.3 Shelf Life

Five years

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of containers

Colourless Type I or Type II glass bottles with rubber/aluminium cap.
Quantities of 20, 30, 50, 75, 100, 150, 200 or 250 ml of solution.

6.6 Special precautions for disposal and other handling

Bottles 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.

Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present.

The contrast medium should not be drawn into the syringe until immediately before use. Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions with sterile syringes. Sterile techniques must be used with any spinal puncture or intravascular injection, and with catheters and guidewires. If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

It is desirable that solutions of contrast media for intravascular and intrathecal use should be at body temperature when injected.

Any residue of contrast medium in the syringe must be discarded. Solutions not used in one examination session or waste material, such as the connecting tubes, should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

18920/0005

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

11 December 1992 / 29 December 1998

10. DATE OFREVISION OF THE TEXT

19 January 2022

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 400, solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 81.65% w/v of iomeprol equivalent to 40% iodine or 400mg iodine/ml.

For the full list of excipients, see section 6.1.For excipients, see 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for:

• peripheral arteriography
• aortography
• angiocardiography and left ventriculography
• coronary arteriography
• visceral arteriography
• digital subtraction angiography
• computed tomography enhancement
• urography
• dacryocystography
• sialography
• fistulography
• galactography

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.
Unless otherwise instructed by the doctor, a normal diet may be maintained on the day of the examination.

The X ray can be taken up to 60 minutes following injection.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

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 diabetes mellitus, polyuria, oligouria, hyperuricaemia, infants, small children, and elderly patients, should not be exposed to dehydration. Also patients with severely compromised hepatic and renal impairment are more at risk. Caution should be exercised in hydrating patients with underlying conditions that may be worsened by fluid overload, including congestive heart failure.

Rehydration prior to use of iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition
A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighted against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in severe cardiac disease particularly heart failure and coronary artery disease. Reactions may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias.
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 catheterization procedure are increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease eg stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier permeability facilitates the passage of the contrast medium into cerebral tissue possibly leading to CMS disorders. There is a possibility of a reduced seizure threshold in alcoholics.

In patients with a drug addiction there is also the possibility of a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intra-arterial administration. Premedication with an alpha and beta receptor blocker is recommended in these patients. Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Renal impairment
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;

avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;
A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children: Infants up to 1 year, especially the newborn, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.

Transient hypothyroidism may occur in neonates when the mother or the neonate has received an iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates 7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.

Elderly: There is special risk of reactions involving the circulatory system such that myocardial ischaemia, major arrhythmias 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 people.

Precautions for dedicated exams

Angiography
Non ionic contrast media have less antiocoagulant activity in vitro than ionic media. Meticulous attention should therefore be paid to angiographic technique. Non ionic media should not be allowed to remain in contact with blood in a syringe, and intravascular catheters should be flushed frequently to minimise the risk of clotting which, rarely, has led to serious thromboembolic complications.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

Venography
Special care is required when venography is performed in patients with thrombosis, phlebitis, severe ischaemic disease, local infection or a totally obstructed artero-venous system.

4.5 Interaction with other medicaments and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to iomeprol.

Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenotiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative.
Since, wherever possible, exposure to radiation should be avoided during pregnancy, the benefits of any X ray examination, whether with or without contrast material, should for this reason alone be carefully weighed against the possible risk

Breastfeeding
No human data exist concerning the excretion of iomeprol in breast milk. Animal studies have demonstrated that the excretion of iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.

Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 4,903 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.

4.8.1 Intravascular administration

Adult patients involved in clinical trials with intravascular administration of Iomeprol were 4,515.

Coronary artery thrombosis and coronary artery embolism have been reported as a complication of coronary catheterization procedures.

Vasospasm and consequent ischaemia have been observed during intra-arterial injections of contrast medium, in particular after coronary and cerebral angiography often procedurally related and possibly triggered by the tip of the catheter or excess catheter pressure.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

4.8.2 Administration to body cavities

After injection of an iodinated contrast media in body cavities, contrast media are slowly absorbed from the area of administration into the systemic circulation and subsequently cleared by renal elimination.

Blood amylase increased is common following ERCP. Very rare cases of pancreatitis have been described.

The reactions reported in cases of arthrography and fistulography usually represent irritative manifestations superimposed on pre-existing conditions of tissue inflammation.

Hypersensitivity reactions are rare, generally mild and in the form of skin reactions. However, the possibility of severe anaphylactoid reactions cannot be excluded.

As with other iodinated contrast media, pelvic pain and malaise may occur after hysterosalpingography.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. No other drug should be mixed with the contrast medium.

6.3 Shelf Life

Five years

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of containers

Colourless Type I or Type II glass bottles with rubber/aluminium cap.
Quantities of 20, 30, 50, 75, 100, 150, 200 or 250 ml of solution.

6.6 Special precautions for disposal and other handling

Bottles 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.

Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present.

The contrast medium should not be drawn into the syringe until immediately before use. Withdrawal of contrast agents from their containers should be accomplished under aseptic conditions with sterile syringes. Sterile techniques must be used with any spinal puncture or intravascular injection, and with catheters and guidewires. If non-disposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

It is desirable that solutions of contrast media for intravascular and intrathecal use should be at body temperature when injected.

Any residue of contrast medium in the syringe must be discarded. Solutions not used in one examination session or waste material, such as the connecting tubes, should be disposed in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

18920/0006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

11 December 1992 / 29 December 1998

10. DATE OF REVISION OF THE TEXT

19 January 2022

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 300, solution for injection, multi-dose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 61.24% w/v of Iomeprol equivalent to 30% iodine or 300 mg iodine/ml.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.
A clear colourless to pale yellow solution supplied in glass multi-dose container.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for computed tomography enhancement, including CTA (CT Angiography).

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

A normal diet should be maintained until the patient refrains from eating 2 hours before the procedure.

Hydration
Any severe disorders of water and electrolyte balance must be corrected prior to administration. Adequate hydration must be ensured particularly in patients with diabetes mellitus, polyuria, oliguria and hyperuricaemia; also in babies, small children and the elderly. Rehydration prior to use of Iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition
A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighed against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in patients with severe cardiac disease particularly heart failure and coronary artery disease. Cardiac manifestations may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias. In severe, chronic hypertension the risk of renal damage following administration of a contrast medium is increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease eg stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier permeability facilitates the passage of the contrast medium into cerebral tissue possibly leading to CMS disorders. There is a possibility of a reduced seizure threshold in alcoholics.

In patients with a drug addiction there is also the possibility of a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intravascular administration. Premedication with an alpha and beta receptor-blocker is recommended in these patients. Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Renal failure
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters, in particular before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;
• avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;

A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children:
Infants up to 1 year, especially the new-born, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.
Transient hypothyroidism may occur in neonates when the mother or the neonate has received an
iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates
7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.
Elderly:
The elderly are at special risk of reactions due to reduced physiological functions, especially when high dosage of contrast media is used. A combination of neurological disturbances and vascular pathologies present a serious complication. The probability of acute renal insufficiencies is higher in these people.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

4.5 Interaction with other medicinal products and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to Iomeprol.

Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenothiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of Iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative.
Since, wherever possible, exposure to radiation should be avoided during pregnancy, the benefits of any X ray examination, whether with or without contrast material, should for this reason alone be carefully weighed against the possible risk.

Breastfeeding
No human data exist concerning the excretion of Iomeprol in breast milk. Animal studies have demonstrated that the excretion of Iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.

Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 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 4,515.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary/ intrathecal contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered Iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of Iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and Iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that Iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Five years
The maximum use time after a bottle stopper has been pierced is 10 hours.

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of container

Colourless type I or type II glass bottles with chlorobutyl or bromobutyl rubber stopper/aluminium cap containing 500 ml of solution.
Boxes of 1, 5 and 6 bottles.

6.6 Special precautions for disposal and other handling

Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present. The stopper should be pierced only once. The use of proper withdrawal cannulas for piercing the stopper and drawing up the contrast medium is recommended.
Multi-dose containers should be used only in conjunction with an automatic injector which has been approved for multipatient use.
After each patient, the connector between the injector and the patient should be replaced. All other devices should be replaced following the injector manufacturer’s instructions. In any case, strictly follow the manufacturer’s instructions.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 18920/0041

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

14/11/2018

10. DATE OF REVISION OF THE TEXT

12/11/2021

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 350, solution for injection, multi-dose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 71.44% w/v of Iomeprol equivalent to 35% iodine or 350 mg iodine/ml.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.
A clear colourless to pale yellow solution supplied in glass multi-dose container.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for computed tomography enhancement, including CTA (CT Angiography).

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

A normal diet should be maintained until the patient refrains from eating 2 hours before the procedure.

Hydration
Any severe disorders of water and electrolyte balance must be corrected prior to administration. Adequate hydration must be ensured particularly in patients with diabetes mellitus, polyuria, oliguria and hyperuricaemia; also in babies, small children and the elderly. Rehydration prior to use of Iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition
A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighed against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in patients with severe cardiac disease particularly heart failure and coronary artery disease. Cardiac manifestations may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias. In severe, chronic hypertension the risk of renal damage following administration of a contrast medium is increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease eg stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier permeability facilitates the passage of 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 a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intravascular administration. Premedication with an alpha and beta receptor-blocker is recommended in these patients. Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Renal failure
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters, before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;
• avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;

A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children: Infants up to 1 year, especially the new-born, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.
Transient hypothyroidism may occur in neonates when the mother or the neonate has received an
iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates
7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.

Elderly:
The elderly are at special risk of reactions due to reduced physiological functions, especially when high dosage of contrast media is used. A combination of neurological disturbances and vascular pathologies present a serious complication. The probability of acute renal insufficiencies is higher in these people.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

4.5 Interaction with other medicinal products and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to Iomeprol.

Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenothiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of Iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative.
Since, wherever possible, exposure to radiation should be avoided during pregnancy, the benefits of any X ray examination, whether with or without contrast material, should for this reason alone be carefully weighed against the possible risk.

Breastfeeding
No human data exist concerning the excretion of Iomeprol in breast milk. Animal studies have demonstrated that the excretion of Iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.
Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 4,903 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 4,515.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary/ intrathecal contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered Iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of Iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and Iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that Iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Five years
The maximum use time after a bottle stopper has been pierced is 10 hours.

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of containers

Colourless type I or type II glass bottles with chlorobutyl or bromobutyl rubber stopper/aluminium cap containing 500 ml of solution.
Boxes of 1, 5 and 6 bottles.

6.6 Special precautions for disposal and other handling

Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present. The stopper should be pierced only once. The use of proper withdrawal cannulas for piercing the stopper and drawing up the contrast medium is recommended.
Multi-dose containers should be used only in conjunction with an automatic injector which has been approved for multipatient use.
After each patient, the connector between the injector and the patient should be replaced. All other devices should be replaced following the injector manufacturer’s instructions. In any case, strictly follow the manufacturer’s instructions.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 18920/0042

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

14/11/2018

10. DATE OF REVISION OF THE TEXT

12/11/2021

1. NAME OF THE MEDICINAL PRODUCT

Iomeron 400, solution for injection, multi-dose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Contains 81.65% w/v of Iomeprol equivalent to 40% iodine or 400 mg iodine/ml.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.
A clear colourless to pale yellow solution supplied in glass multi-dose container.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

X-ray contrast medium used for computed tomography enhancement, including CTA (CT Angiography).

4.2 Posology and method of administration

In elderly patients the lowest effective dose should be used.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients.

4.4 Special warnings and special precautions for use

In consideration of possible complications, the patient should be kept under observation for at least 30 minutes after the examination.

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

A normal diet should be maintained until the patient refrains from eating 2 hours before the procedure.

Hydration
Any severe disorders of water and electrolyte balance must be corrected prior to administration. Adequate hydration must be ensured particularly in patients with diabetes mellitus, polyuria, oliguria and hyperuricaemia; also in babies, small children and the elderly. Rehydration prior to use of Iomeprol is recommended in patients with sickle cell disease.

Special population
Hypersensitivity to iodinated contrast media, allergic predisposition
A positive history of allergy, asthma or untoward reaction during previous similar investigations indicates a need for extra caution since, as with other contrast media, this product 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 measures should be immediately available. The primary treatments are as follows:

From: Bush WH; The Contrast Media Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992; Chapter 2 p 23

The risk of bronchospasm-inducing reactions in asthmatic patients is higher after contrast media administration, especially in patients taking beta-blockers.

Hypersensitivity testing
In patients with suspected or known hypersensitivity to contrast media, sensitivity test doses are not recommended, as severe or fatal reactions to contrast media are not predictable from sensitivity test.

Myelomatosis or paraproteinaemias are conditions predisposing to renal impairment following CM administration. The benefits of the use of a contrast-enhanced procedure should be carefully weighed against the possible risk. Adequate hydration and monitoring of renal function are recommended after CM administration.

Cardiovascular diseases
Care should be taken in patients with severe cardiac disease particularly heart failure and coronary artery disease. Cardiac manifestations may include pulmonary oedema, haemodynamic changes, ischaemic ECG changes and arrhythmias. In severe, chronic hypertension the risk of renal damage following administration of a contrast medium is increased.

The product should be used with caution in patients with hyperthyroidism or goitre. Use may interfere with thyroid function tests.

The administration of iodinated contrast media may aggravate myasthenia signs and symptoms.

CNS Disorders
Particular care is needed in patients with acute cerebral infarction, acute intracranial haemorrhage and any conditions involving damage to the blood brain barrier, brain oedema or acute demyelination. Convulsive seizures are more likely in patients with intracranial tumours or metastases or with a history of epilepsy.

Neurological symptoms related to cerebrovascular diseases, intracranial tumours/metastases or degenerative or inflammatory pathologies may be exacerbated.

There is an increased risk of transient neurological complications in patients with symptomatic cerebrovascular disease eg stroke, transient ischaemic attacks. Cerebral ischaemic phenomena may be caused by intravascular injection.

Anticonvulsant therapy should not be discontinued.

In acute and chronic alcoholism the increase in blood brain barrier permeability facilitates the passage of the contrast medium into cerebral tissue possibly leading to CMS disorders. There is a possibility of a reduced seizure threshold in alcoholics

In patients with a drug addiction there is also the possibility of a reduced seizure threshold.

Patients with phaeochromocytoma may develop severe, occasionally uncontrollable hypertensive crises during intravascular administration. Premedication with an alpha and beta receptor-blocker is recommended in these patients. Pronounced excitement, anxiety and pain can cause side effects or intensify reaction to the contrast medium. A sedative may be given.

Renal failure
In patients with moderate to severe impairment of renal function, attention should be paid to renal function parameters, before re-examining the patient with a contrast media.
Preventive measures include:

• identification of high-risk patients;
• ensuring adequate hydration before CM administration, preferably by maintaining i.v. infusion before and during the procedure and until the CM has been cleared by the kidneys;
• avoiding whenever possible, the administration of nephrotoxic drugs or major surgery or procedure such as renal angioplasty, until the CM has been cleared;

A combination of severe hepatic and renal impairment delays excretion of the contrast medium therefore such patients should not be examined unless absolutely necessary.

Diabetes mellitus
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.
The presence of renal damage in diabetic patients is one of the factors predisposing to renal impairment following contrast media administration. This may precipitate lactic acidosis in patients who are taking metformin (see section 4.5 - Interaction with medicaments and other forms of interaction).

Children: Infants up to 1 year, especially the newborn, are particularly susceptible to electrolyte imbalance and haemodynamic alterations. Care should be taken regarding the dosage used.
Transient hypothyroidism may occur in neonates when the mother or the neonate has received an
iodinated contrast agent. Thyroid function tests (usually TSH and T4) are recommended in neonates
7-10 days and 1 month after exposure to Iomeron especially in preterm neonates.

Elderly:
The elderly are at special risk of reactions due to reduced physiological functions, especially when high dosage of contrast media is used. A combination of neurological disturbances and vascular pathologies present a serious complication. The probability of acute renal insufficiencies is higher in these people.

Intravascular administration should be performed if possible with the patient lying down. The patient should be kept in this position and closely observed for at least 30 minutes after the procedure since the majority of severe incidents occur with this time.

4.5 Interaction with other medicinal products and other forms of interaction

Use of the product may interfere with tests for thyroid function. Vasopressor agents should not be administered prior to Iomeprol.
Treatment with drugs that lower the seizure threshold such as certain neuroleptics (MAO inhibitors, tricyclic antidepressants), analeptics, and anti-emetics and phenothiazine derivatives should be discontinued 48 hours before the examination. Treatment should not be resumed until 24 hours post-procedure.

It has been reported that cardiac and/or hypertensive patients under treatment with diuretics, ACE-inhibitors, and/or beta blocking agents are at higher risk of adverse reactions when administered iodinated contrast media.

Beta-blockers may impair the response to treatment of bronchospasm induced by contrast medium.

Patients with normal renal function can continue to take metformin normally. In diabetic patients with diabetic nephropathy, under treatment with metformin and with moderate renal impairment, metformin should be stopped at the time of, or prior to the procedure and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal 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 and take precautions. Metformin should be stopped from 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.

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).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential
Appropriate investigations and measures should be taken when exposing women of child-bearing potential to any X-ray examination, whether with or without contrast medium.

Pregnancy
Animal studies have not indicated any harmful effects with respect to the course of pregnancy or on the health of the unborn or neonate. The safety of Iomeprol in human pregnancy however has not been established. Therefore avoid in pregnancy unless there is no safer alternative.
Since, wherever possible, exposure to radiation should be avoided during pregnancy, the benefits of any X ray examination, whether with or without contrast material, should for this reason alone be carefully weighed against the possible risk.

Breastfeeding
No human data exist concerning the excretion of Iomeprol in breast milk. Animal studies have demonstrated that the excretion of Iomeprol in breast milk is similar to that of other contrast agents and that these compounds are only minimally absorbed by the gastrointestinal tract of the young. Adverse effects on the nursing infant are therefore unlikely to occur.

Stopping breastfeeding is unnecessary.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

General

The use of iodinated contrast media may cause untoward side effects. They 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 min (but rarely after as long as 2 h), the patient complains of feeling abnormal, agitation, flushing, feeling hot, sweating increased, dizziness, increased lacrimation, rhinitis, palpitations, paresthesia, pruritus, sore throat and throat tightness, dysphagia, cough, sneezing, urticaria, erythema, mild localised oedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngeal oedema and/or spasm 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 the contrast medium 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 4,903 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 4,515.

As with other iodinated contrast media, very rare cases of mucocutaneous syndromes, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell syndrome) and erythema multiforme, have been reported following the administration of Iomeprol injection.

Paediatric patients

There is limited experience with paediatric patients. The clinical trial paediatric safety database comprises 167 patients.

The Iomeprol safety profile is similar in children and adults.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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. Iomeprol does not bind to plasma or serum proteins and is therefore dialyzable.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: V08AB10

Iomeprol is a low osmolality, non-ionic organic molecule with radio-opacity conferred by an iodine content of 49% of the molecular weight. It is formulated for use as an intravascular/intracavitary/ intrathecal contrast medium in concentrations of up to 400mg iodine per ml. Even at this concentration the low viscosity allows delivery of high doses through thin catheters.

5.2 Pharmacokinetic properties

The pharmacokinetics of intravascularly administered Iomeprol are similar to those of other iodinated contrast media and conform to a two-compartment model with a rapid distribution and a slower elimination phase. In healthy subjects, the mean distribution and elimination half-lives of Iomeprol were 0.5 hours and 1.9 hours respectively.

Distribution volume is similar to that of extra cellular fluid. There is no significant serum protein binding and Iomeprol is not metabolized.

Elimination is almost exclusively through the kidneys (90% of the dose recovered in the urine within 96 hours of its administration) and is rapid (50% of an intravascularly administered dose within 2 hours).

5.3 Preclinical Safety Data

Pre-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, toxicity to reproduction.

Results from studies in rats, mice and dogs demonstrate that Iomeprol has an acute intravenous or intra-arterial toxicity similar to that of the other non ionic contrast media, as well as a good systemic tolerability after repeated intravenous administrations in rats and dogs.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

trometamol
hydrochloric acid
water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Five years
The maximum use time after a bottle stopper has been pierced is 10 hours.

6.4 Special precautions for storage

Store below 30°C
Protect from light

6.5 Nature and contents of containers

Colourless type I or type II glass bottles with chlorobutyl or bromobutyl rubber stopper/aluminium cap containing 500 ml of solution.
Boxes of 1, 5 and 6 bottles.

6.6 Special precautions for disposal and other handling

Before use, examine the product to assure that the container and closure have not been damaged. Do not use the solution if it is discolored or particulate matter is present. The stopper should be pierced only once. The use of proper withdrawal cannulas for piercing the stopper and drawing up the contrast medium is recommended.
Multi-dose containers should be used only in conjunction with an automatic injector which has been approved for multipatient use.
After each patient, the connector between the injector and the patient should be replaced. All other devices should be replaced following the injector manufacturer’s instructions. In any case, strictly follow the manufacturer’s instructions.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Bracco UK Ltd
Magdalen Centre
The Oxford Science Park
Oxford, OX4 4GA
United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 18920/0043

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

14/11/2018

10. DATE OF REVISION OF THE TEXT

12/11/2021