HEALTH CARE PROVIDER LETTER SECTION.

IMPORTANT DRUG INFORMATIONmay be found at the following link: https://imaging.bracco.com/us-en/products/ct-ct-colonography/iomeron July 6, 2022Subject: Temporary importation of Iomeron(R) (iomeprol injection) to address drug shortage issuesDear Healthcare Professional,Due to the current critical shortages of Omnipaque(TM) (iohexol injection), Visipaque(TM) (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(R) (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 Braccos FDA-approved intravascular iodinated contrast medium Isovue (iopamidol injection).FDAs 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:Product DescriptionIodine Concentration (mg iodine/mL)Package SizeLot NumberLabel LanguageNDC NumberUK SmPCIomeron (iomeprol injection) 25025056 100 mL2C42685French0270-7250-10Iomeron 300 UK SmPC SDIomeron (iomeprol injection) 30030056 100 mL2C43416KP1552AFrench0270-7300-10Iomeron 300 UK SmPC SDIomeron (iomeprol injection) 30030010 200 mLKP2701FEnglish0270-7300-20Iomeron 300 UK SmPC SDIomeron (iomeprol injection) 3003006 500 mLKP2804ASpanish0270-9300-06Iomeron 300 UK SmPC MDIomeron (iomeprol injection) 35035056 100 mLLP1566CRussian0270-7350-10Iomeron 350 UK SmPC SDIomeron (iomeprol injection) 35035030 150 mL2C42507French0270-7350-15Iomeron 350 UK SmPC SDIomeron (iomeprol injection) 35035010 200 mLLP2705AEnglish0270-7350-20Iomeron 350 UK SmPC SDIomeron (iomeprol injection) 3503506 500 mLLP2807ASpanish0270-9350-06Iomeron 350 UK SmPC MDIomeron (iomeprol injection) 3503509 500 mLLP2810BEnglish0270-9350-09Iomeron 350 UK SmPC MDIomeron (iomeprol injection) 40040056 100 mLMP1577ARussian0270-7400-13Iomeron 400 UK SmPC SDIomeron (iomeprol injection) 40040010 100 mLMP2561CPortuguese0270-7400-10Iomeron 400 UK SmPC SDIomeron (iomeprol injection) 40040056 100 mLMP2556APolish0270-7400-16Iomeron 400 UK SmPC SDIomeron (iomeprol injection) 40040030 200 mLMP2702CSlovenian0270-7400-20Iomeron 400 UK SmPC SDIomeron (iomeprol injection) 4004009 500 mLMP2807CEnglish0270-9400-01Iomeron 400 UK SmPC MDIomeron (iomeprol injection) 4004006 500 mLMP2806AEnglish0270-9400-06Iomeron 400 UK SmPC MDIomeron (iomeprol injection) 4004009 500 mLMP2807APortuguese0270-9400-03Iomeron 400 UK SmPC MDThe 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):Table of Physico-chemical Properties of Iomeron (iomeprol) vs. Comparable U.S. Marketed Products (using concentration of 300 mg iodine/mL or nearest equivalent)ProductViscosity (CP)Osmolality(mOsm/kg water)DensitypH20C37C37C37CIomeron(iomeprol injection) 3008.14.55211.3346.5 7.2Iomeron(iomeprol injection) 3008.84.76161.3396.5 7.5Omnipaque(iohexol injection) 30011.86.36721.3496.8 7.7Optiray (ioversol injection) 3008.2 (25C)5.56511.3526.0 7.4Visipaque(iodixanol injection) 32026.611.82901.3566.8 7.7Ultravist(iopromide injection) 3009.24.96071.3226.5 8.0Iomeron multi-dose containers 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 transfer set), the injector manufacturers 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 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 products 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 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 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 history of 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 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 to weeks.Renal toxicity has been reported in 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 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.otcdiag.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.eventsdiag.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.professionaldiag.bracco.com.Adverse reactions or quality problems experienced with the use of this product may be reported to the FDAs 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 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, MDSenior Vice PresidentChief Medical and Regulatory OfficerBracco GroupAttachments: Iomeron (iomeprol) U.K. SmPCs Images of Iomeron (iomeprol) U.K. Bottle and Box LabelsAppendix 1. Comparisons of approved uses for iodinated contrast media in shortage and those manufactured by Bracco.Table of Approved Intra-arterial Uses for Iodinated Contrast Media in Shortage, and for Those Manufactured by BraccoPOPULATION/INDICATIONOMNIPAQUE(iohexol)mg iodine/mLVISIPAQUE(iodixanol)mg iodine/mLULTRAVIST(iopromide)mg iodine/mLISOVUE(iopamidol)mg iodine/mLIOMERON(iomeprol)mg iodine/mLADULTSIntra-arterial digital subtraction angiography140270, 320250, 300Aortography300, 350370350, 400Angiocardiography350320370370300, 350, 400Visceral arteriography300, 350320370370300, 350, 400Cerebral arteriography300320300300250, 300Peripheral arteriography300, 350320300300300, 350, 400Approved uses for Iomeron (iomeprol) are from the U.K.Table of Approved Intravenous Uses for Iodinated Contrast Media in Shortage, and for Those Manufactured by BraccoPOPULATION/INDICATIONOMNIPAQUE(iohexol)mg iodine/mLVISIPAQUE(iodixanol)mg iodine/mLULTRAVIST(iopromide)mg iodine/mLISOVUE(iopamidol)mg iodine/mLIOMERON(iomeprol)mg iodine/mLADULTSCT head240, 300, 350270, 320300, 370250, 300250, 300, 350CT body300, 350270, 320300, 370250, 300250, 300, 350, 400Intravenous digital subtraction angiography350250, 300, 350, 400Peripheral venography240, 300270200250, 300, 350Excretory urography300, 350270, 320300250, 300, 370250, 300, 350, 400Approved uses for Iomeron (iomeprol) are from the U.K.Appendix 2. Iomeron (iomeprol injection) adult dosing recommendations per U.K. Summary of Product Characteristics.Table of adult dosing recommendations for Iomeron 250 single dose( Repeat as necessary)Venography10 100 mLmaximum 250 mL 10 50 mL upper extremity50 100 mL lower extremityCerebral arteriography5 12 mLDigital subtraction angiographyIntra arterial visceral2 20 mL per arteryaorta 25-50 mLboth 250 mL maximum peripheral5 10 mL per arterymaximum 250 mLIntravenous30 60 mLmaximum 250 mLComputed tomographybrain50 150 mLbody40 150 mLmaximum 250 mLUrography intravenous50 150 mLTable of adult dosing recommendations for Iomeron 300 single dose( Repeat as necessary)Peripheral arteriography10 90 mLVenography10 100 mLmaximum 250 mL 10 50 mL upper extremity50 100 mL lower extremityAngiocardiography and left ventriculography30 80 mLmaximum 250 mLCerebral arteriography5 12 mLVisceral arteriography5 50 mL or according to type of examination;maximum 250 mLDigital subtraction angiographyIntra arterial visceral2 20 mL per arteryaorta 25-50 mLboth 250 mL maximum peripheral5 10 mL per arterymaximum 250 mLIntravenous30 60 mLmaximum 250 mLComputed tomographybrain50 150 mLbody40 150 mLmaximum 250 mLUrography intravenous50 150 mLTable of adult dosing recommendations for Iomeron 300 multidose( Repeat as necessary)Computed tomographybrain50 150 mLbody40 150 mLmaximum 250 mLTable of adult dosing recommendations for Iomeron 350 single dose( Repeat as necessary)Peripheral arteriography10 90 mLVenography10 100 mLmaximum 250 mL 10 50 mL upper extremity50 100 mL lower extremityAortography50 80 mLAngiocardiography and left ventriculography30 80 mLmaximum 250 mLCoronary arteriography4 10 mL per arteryVisceral arteriography5 50 mL or according to type of examination;maximum 250 mLIntravenous digital subtraction angiography30 60 mLmaximum 250 mLComputed tomographybrain50 150 mLbody40 150 mLmaximum 250 mLUrography intravenous50 150 mLTable of adult dosing recommendations for Iomeron 350 multidose( Repeat as necessary)Computed tomographybrain50 150 mlbody40 150 mlmaximum 250 mLTable of adult dosing recommendations for Iomeron 400 single dose( Repeat as necessary)Peripheral arteriography10 90 mLAortography50 80 mLAngiocardiography and left ventriculography30 80 mLmaximum 250 mLCoronary arteriography4 10 mL per arteryVisceral arteriography5 50 mL or according to type of examinationIntravenous digital subtraction angiography30 60 mLmaximum 250 mLComputed tomography of the body40 150 mLmaximum 250 mLUrography intravenous50 150 mLTable of adult dosing recommendations for Iomeron 400 multidose( Repeat as necessary)Computed tomography of the body40 150 mLmaximum 250 mLUK Iomeron Vial and Carton Labels Product DescriptionIodine Concentration (mg iodine/mL)Fill VolumeVial LabelCarton LabelIomeron (iomeprol injection) 250250100 mLIomeron (iomeprol injection) 300300100 mLIomeron (iomeprol injection) 300300200 mLIomeron (iomeprol injection) 300300500 mLIomeron (iomeprol injection) 350350100 mLIomeron (iomeprol injection) 350350200 mLIomeron (iomeprol injection) 350350500 mLIomeron (iomeprol injection) 400400100 mLIomeron (iomeprol injection) 400400200 mLIomeron (iomeprol injection) 400400500 mL. 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 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 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 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 history of 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 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 to weeks.. Renal toxicity has been reported in 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 cholecystographic contrast agent.. 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 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). Alberto Spinazzi Signature. Iomeron 250 Vial 100 mL. Iomeron 250 Carton 100 mL. Iomeron 300 Vial 100 mL. Iomeron 300 Carton 100 mL. Iomeron 300 Vial 200 mL. Iomeron 300 Carton 200 mL. Iomeron 300 Vial 500 mL. Iomeron 300 Carton 500 mL. Iomeron 350 Vial 100 mL. Iomeron 350 Carton 100 mL. Iomeron 350 Vial 200 mL. Iomeron 350 Carton 200 mL. Iomeron 350 Vial 500 mL. Iomeron 350 Carton 500 mL. Iomeron 400 Vial 100 mL. Iomeron 400 Carton 100 mL. Iomeron 400 Vial 200 mL. Iomeron 400 Carton 200 mL. Iomeron 400 Vial 500 mL. Iomeron 400 Carton 500 mL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Iomeron 250 100ml box. Iomeron 300 100ml label. Iomeron 300 500ml label. Iomeron 350 200ml box. Iomeron 350 500ml label. Iomeron 400 200ml label. Iomeron 400 500ml label.

SPL MEDGUIDE SECTION.

1. NAME OF THE MEDICINAL PRODUCTIomeron 250, solution for injection2. QUALITATIVE AND QUANTITATIVE COMPOSITIONContains 51.03% w/vof iomeprol equivalent to 25% iodine or 250mg iodine/ml.For the full list of excipients,see section 6.1.3. PHARMACEUTICAL FORMSolution for injection.4. CLINICAL PARTICULARS4.1 herapeutic indications X-ray contrast medium used for:venographycerebral arteriographydigital subtraction angiographycomputed tomography enhancementurographycavernosographymyelography4.2 Posologyand method of administration Repeat as necessary According tobody size and agevenographyadults10 100mlmax 250ml10 50ml upper extremity50 100 lower extremitycerebral arteriographyadults5 12mlchildren3 7ml or digital subtraction angiographyIntra arterialvisceraladults2 20ml per arteryaorta 25-50mlboth 250ml maxperipheraladults5 10ml per arterymax 250mlintravenousadults30 60mlmax 250mlcomputed tomographybrainadults50 150children bodyadults40 150mlmax 250mlchildren urographyadults50 150mlintravenousneonates3 4.8ml/kgbabies2.5 4ml/kgchildren1 2.5ml/kg or cavernosographyadults40 250mlmyelographyadults12 18mlby lumbar injectionIn elderly patients thelowest 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 maybe used for lumbar or thoracic studies and higher doses for cervicalor total columnar studies. Regardless of the nature of the myelographicstudy, Iomeron should be injected slowly over 1-2 minutes.The ray can be taken up to60 minutes following injection. Post myelographic CT of the spinalcolumn should be delayed for approximately four hours to allow dilutionand clearance of excessive contrast.4.3 Contraindications Hypersensitivityto the active substance or any of the excipients.Intrathecalconcomitant administration of corticosteroids with contrast mediais contraindicated.4.4 Special warnings and special precautions foruse In consideration of possible complications, the patient should bekept under observation for at least 30 minutes after the examination.Extreme caution during injectionof contrast media is necessary to avoid extravasation.HydrationPatients must be well hydrated, and any relevant abnormalitiesof fluid or electrolyte balance should be corrected prior to and followingcontrast media injection. Especially patients with diabetes mellitus,polyuria, oligouria, hyperuricaemia, infants, small children, andelderly patients, should not be exposed to dehydration. Also patientswith severely compromised hepatic and renal impairment are more atrisk. Caution should be exercised in hydrating patients with underlyingconditions that may be worsened by fluid overload, including congestiveheart failure.Rehydrationprior to use of iomeprol is recommended in patients with sickle celldisease.Special populationHypersensitivityto iodinated contrast media, allergic predispositionA positive history of allergy,asthma or untoward reaction during previous similar investigationsindicates need for extra caution since, as with other contrast media,this product may provoke anaphylaxis or other manifestations of allergywith nausea, vomiting, dyspnoea, erythema, urticaria and hypotension.The benefits should clearly outweigh the risks in such patients andappropriate resuscitative measures should be immediately available.The primary treatments are as follows:EffectMajor SymptomsPrimary TreatmentVasomotor effectwarmthnausea/vomitingreassuranceCutaneousscattered hivessevere urticariaH1-antihistaminesH2-antihistaminesBronchospasticwheezingoxygenBeta-2-agonist inhalersAnaphylactoidangioedemaoxygenreactionurticariabronchospasmhypotensioniv fluidsadrenergics (iv epinephrine)Inhaledbeta-2-adrenergicsantihistamines (H1-and H2- blockers)corticosteroidsHypotensivehypotensioniv fluidsVagal reactionhypotensionbradycardiaiv fluidsiv atropineFrom: Bush WH; The ContrastMedia Manual; Katzburg RW Ed.; Williams and Wilkins; Baltimore 1992;Chapter p 23Therisk of bronchospasm-inducing reactions in asthmatic patients is higherafter contrast media administration, especially in patients takingbeta-blockers.Hypersensitivity testingIn patients with suspectedor known hypersensitivity to contrast media, sensitivity test dosesare not recommended, as severe or fatal reactions to contrast mediaare not predictable from sensitivity test.Myelomatosis or paraproteinaemias are conditionspredisposing to renal impairment following CM administration. Thebenefits of the use of contrast-enhanced procedure should be carefullyweighted against the possible risk. Adequate hydration and monitoringof renal function are recommended after CM administration.Cardiovascular diseasesCare should be taken in severe cardiac disease particularlyheart failure and coronary artery disease. Reactions may include pulmonaryoedema, haemodynamic changes, ischaemic ECG changes and arrhythmias.In severe, chronic hypertension the risk of renal damage followingadministration of contrast medium is increased. In these cases therisks associated with the catheterization procedure are increased.The product should be used withcaution in patients with hyperthyroidism or goitre. Use may interferewith thyroid function tests.The administration of iodinated contrastmedia may aggravate myasthenia signs and symptoms.CNS DisordersParticular care is needed in patients with acute cerebral infarction,acute intracranial haemorrhage and any conditions involving damageto the blood brain barrier, brain oedema or acute demyelination. Convulsiveseizures are more likely in patients with intracranial tumours ormetastases or with history of epilepsy.Neurological symptoms related to cerebrovasculardiseases, intracranial tumours/metastases or degenerative or inflammatorypathologies may be exacerbated.There is an increased risk of transient neurologicalcomplications in patients with symptomatic cerebrovascular diseasee.g. stroke, transient ischaemic attacks. Cerebral ischaemic phenomenamay be caused by intravascular injection.Anticonvulsant therapy should not be discontinued.In acute and chronic alcoholismthe increase in blood brain barrier permeability facilitates the passageof the contrast medium into cerebral tissue possibly leading to CNSdisorders. There is possibility of reduced seizure threshold inalcoholics.In patientswith drug addiction there is also the possibility of reduced seizurethreshold.Patientswith phaeochromocytoma may develop severe, occasionally uncontrollablehypertensive crises during intra-arterial administration. Premedicationwith an alpha and beta receptor blocker is recommended in these patients.Pronounced exctextent, anxiety and pain can cause side effects orintensify reaction to the contrast medium. sedative may be given.Renal impairmentIn patients with moderate to severe impairmentof renal function, attention should be paid to renal function parametersbefore re-examining the patient with contrast media.Preventivemeasures include:identification of high-risk patients;ensuring adequate hydration before CM administration, preferablyby maintaining i.v. infusion before and during the procedure and untilthe CM has been cleared by the kidneys;avoiding whenever possible,the administration of nephrotoxic drugs or major surgery or proceduresuch as renal angioplasty, until the CM has been cleared;A combination of severe hepaticand renal impairment delays excretion of the contrast medium thereforesuch patients should not be examined unless absolutely necessary.Diabetes mellitusCare should be taken in renal impairment and diabetes.In these patients it is important to maintain hydration in order tominimise deterioration in renal function.The presenceof renal damage in diabetic patients is one of the factors predisposingto renal impairment following contrast media administration. Thismay precipitate lactic acidosis in patients who are taking metformin(see section 4.5 Interaction with medicaments and other forms ofinteraction).Children:Infants up to year, especially the new-born, are particularly susceptibleto electrolyte imbalance and haemodynamic alterations. Care shouldbe taken regarding the dosage used.Transient hypothyroidism may occur in neonateswhen the mother or the neonate has received an iodinated contrastagent. Thyroid function tests (usually TSH and T4) are recommendedin neonates 7-10 days and month after exposure to Iomeron especiallyin preterm neonates.Elderly: There isspecial risk of reactions involving the circulatory system such thatmyocardial ischaemia, major arrhythmias and extrasystoles are morelikely to occur. combination of neurological disturbances and vascularpathologies present serious complication. The probability of acuterenal insufficiencies is higher in these people.Precautions for dedicated examsAngiographyNon ionic contrast media have less antiocoagulant activityin vitro than ionic media. Meticulous attention should therefore bepaid to angiographic technique. Non ionic media should not be allowedto remain in contact with blood in syringe, and intravascular cathetersshould be flushed frequently to minimise the risk of clotting which,rarely, has led to serious thromboembolic complications.Intravascular administrationshould be performed if possible with the patient lying down. The patientshould be kept in this position and closely observed for at least30 minutes after the procedure since the majority of severe incidentsoccur with this time.MyelographyFollowing intrathecal use,the patient should rest with the head and the chest elevated for 1hour and be kept well hydrated. Thereafter, he/she may ambulate carefully,but bending down must be avoided. If remaining in bed, the head andchest should be kept elevated for hours. Patients, suspected ofhaving lower seizure threshold should be observed during this period.VenographySpecial care is required when venography is performed in patientswith thrombosis, phlebitis, severe ischaemic disease, local infectionor totally obstructed artero-venous system.4.5 Interaction with othermedicinal products and other forms of interaction Use of the productmay interfere with tests for thyroid function. Vasopressor agentsshould not be administered prior to iomeprol.Treatment with drugs that lower the seizurethreshold such as certain neuroleptics (MAO inhibitors, tricyclicantidepressants), analeptics, and anti-emetics and phenotiazine derivativesshould be discontinued 48 hours before the examination. Treatmentshould not be resumed until 24 hours post-procedure.It has been reported that cardiac and/orhypertensive patients under treatment with diuretics, ACE-inhibitors,and/or beta blocking agents are at higher risk of adverse reactionswhen administered iodinated contrast media.Beta-blockers may impair the response totreatment of bronchospasm induced by contrast medium.Patients with normal renal function can continueto 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 procedureand withheld for 48 hours subsequent to the procedure and reinstitutedonly after renal function has been re-evaluated and found to be normalIn emergency patients in whom renal function is either impaired orunknown, the physician shall weigh out risk and benefit of an examinationwith contrast medium and take precautions. Metformin should be stoppedfrom time of contrast medium administration. After the procedure thepatient should be monitored for signs of lactic acidosis. Metforminshould be restarted 48 hours after contrast medium if serum creatinine/eGFRis unchanged from the pre-imaging level.Allergy-like reactions to contrast mediaare more frequent and may manifest as delayed reactions in patientstreated with immuno-modulators, like Interleukin-2 (IL-2).Epidural and intrathecal corticosteroidsshould never be concurrently administered when iodinated contrastmedia are used, because corticosteroids may promote and affect thesigns and symptoms of arachnoiditis (see section 4.3 Contraindications).4.6 Fertility,pregnancy and lactation Women of childbearing potentialAppropriate investigations and measures should be takenwhen exposing women of child-bearing potential to any X-ray examination,whether with or without contrast medium.PregnancyAnimal studies have not indicated any harmful effects with respectto 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 avoidedduring pregnancy, the benefits of any ray examination, whether withor without contrast material, should for this reason alone be carefullyweighed against the possible risk.BreastfeedingNo human data exist concerning the excretion of iomeprol in breastmilk. Animal studies have demonstrated that the excretion of iomeprolin breast milk is similar to that of other contrast agents and thatthese compounds are only minimally absorbed by the gastrointestinaltract of the young. Adverse effects on the nursing infant are thereforeunlikely to occur.Stopping breastfeeding is unnecessary.4.7 Effects on ability todrive and use machines There is no known effect on the ability todrive and operate machines.After intrathecal administration, it is recommendedthat the patient should wait 24 hours before driving or operatingmachinery.4.8 Undesirable effects GeneralThe use of iodinatedcontrast media may cause untoward side effects. They are usually mildto moderate and transient in nature. However, severe and life-threateningreactions sometimes leading to death have been reported. In most cases,reactions occur within minutes of dosing but at times reactions mayoccur at later time.Anaphylaxis (anaphylactoid/hypersensitivity reactions) may manifestwith various symptoms, and rarely does any one patient develop allthe symptoms. Typically, in to 15 min (but rarely after as longas h), the patient complains of feeling abnormal, agitation, flushing,feeling hot, sweating increased, dizziness, increased lacrimation,rhinitis, palpitations, paresthesia, pruritus, sore throat and throattightness, dysphagia, cough, sneezing, urticaria, erythema, mild localisedoedema, angioneurotic oedema and dyspnoea due to glottic/laryngeal/pharyngealoedema 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 administeredor the route of administration, may represent the first signs of circulatorycollapse.Administration of the contrast medium must bediscontinued immediately and, if needed, appropriate specific treatmenturgently initiated via venous access.Severe reactionsinvolving the cardiovascular system, such as vasodilatation, withpronounced hypotension, tachycardia, dyspnoea, agitation, cyanosisand loss of consciousness progressing to respiratory and/or cardiacarrest may result in death. These events can occur rapidly and requirefull and aggressive cardio-pulmonary resuscitation.Primarycirculatory collapse can occur as the only and/or initial presentationwithout respiratory symptoms or without other signs or symptoms outlinedabove.The adversereactions reported in clinical trials among 4,903 adult patients andfrom post-marketing surveillance are represented in the tables belowby 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 administrationAdult patients involvedin clinical trials with intravascular administration of Iomeprol were4,515. Since the reactions were not observed during clinicaltrials with 4515 patients, best estimate is that their relative occurrenceis rare >=1/10,000 to <1/1000).The most appropriateMedDRA term is used to describe certain reaction and its symptomsand related conditions. Injection site reactions compriseinjection site pain and swelling. In the majority of cases they aredue to extravasation of contrast medium. These reactions are usuallytransient and result in recovery without sequelae. Cases of extravasationwith inflammation, skin necrosis and even development of compartmentsyndrome have been reported.AdultsSystem Organ ClassAdverse ReactionsClinical TrialsPost-marketingSurveillanceCommon(>=1/100 o <1/10)Uncommon(>=1/1000 to <1/100)Rare(>=1/10,000 to <1/1000)FrequencyunknownBlood and lymphaticsystem disordersThrombocytopenia,Haemolytic anaemiaImmune system disordersAnaphylactoid reactionPsychiatric disordersAnxietyConfusional stateNervous systemdisordersHeadache DizzinessPresyncopeComaTransient ischaemic attackParalysisSyncopeConvulsionLoss of consciousnessDysarthriaParaesthesiaAmnesiaSomnolenceTaste abnormalityEye disordersBlindness transientVisual disturbanceConjunctivitisLacrimationincreasedPhotopsiaCardiac disordersBradycardiaTachycardiaExtrasystolesCardiac arrest Myocardial infarctionCardiac failureAnginapectorisArrhythmiaVentricular or atrial fibrillationAtrioventricular blockPalpitationsCyanosisVascular disordersHypertensionHypotensionCirculatory collapseor shockHot flushFlushingPallorRespiratory, thoracicand mediastinal disordersDyspnoeaRespiratory arrestAcute respiratory distress syndrome (ARDS)PulmonaryoedemaLaryngeal oedemaPharyngeal oedemaBronchospasmAsthmaCoughHyperventilationPharynx discomfortLaryngeal discomfortRhinitisDysphoniaGastrointestinaldisordersNauseaVomitingDiarrhoeaAbdominal painSalivary hypersecretionDysphagiaSalivary gland enlargementSkin and subcutaneoustissue disordersErythemaUrticariaPruritusRashAcute generalizedexanthematous pustulosisAngioedemaCold sweatSweating increasedMusculoskeletaland connective tissue disorderBack painArthralgiaRenal and urinarydisordersRenal failureGeneral disordersand administration site conditionsFeeling hotChest painInjectionsite warmth and painAstheniaRigorsPyrexiaInjection sitereactionColdness localFatigueMalaiseThirstInvestigationsBlood creatinineincreasedElectrocardiogramST segment elevationElectrocardiogram abnormalCoronary artery thrombosisand coronary artery embolism have been reported as complicationof coronary catheterization procedures.Vasospasm and consequent ischaemia have beenobserved during intra-arterial injections of contrast medium, in particularafter coronary and cerebral angiography often procedurally relatedand possibly triggered by the tip of the catheter or excess catheterpressure.As with otheriodinated contrast media, very rare cases of mucocutaneous syndromes,including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyellsyndrome) and erythema multiforme, have been reported following theadministration of Iomeprol injection.Paediatric patientsThere is limitedexperience with paediatric patients. The clinical trial paediatricsafety database comprises 167 patients.The Iomeprol safety profile is similar inchildren and adults.4.8.2 Intrathecal administrationAdultsAdults patients involved in clinicaltrials with intrathecal administration of Iomeprol were 388.The most frequently reportedadverse reactions following intrathecal administration of Iomeprolare headache, dizziness, nausea, vomiting and back pain. These reactionsare usually mild to moderate and transient in nature. Rarely, headachemay persist for days. Most side effects occur some hours (3 to hours)after the procedure, due to the distribution of the contrast mediumin the CSF circulation from the site of administration to the intravascularspace (see section 5.2: Pharmacokinetic properties). Most reactionsusually occur within 24 hours after injection. Since the reactions were not observed during clinicaltrials with 388 patients, best estimate is that their relative occurrenceis uncommon (>= 1/1000 to <1/100. The most appropriateMedDRA term is used to describe certain reaction and its symptomsand related conditions. Injection site reactions compriseapplication site pain, injection site discomfort, injection site painand injection site warmth.System Organ ClassAdverse ReactionsClinical TrialsPost-marketing SurveillanceVery common(>=1/10)Common(>=1/100 to <1/10)Uncommon(>=1/1000 to <1/100)Frequency unknownImmune system disordersAnaphylactoid reactionNervous systemdisordersHeadacheDizzinessHypoaesthesiaParaesthesiaParaparesisLoss of consciousnessSomnolenceEpilepsyVascular disordersHypertensionHypotensionFlushingGastrointestinaldisordersNauseaVomitingSkin and subcutaneoustissue disordersHyperhidrosis PruritusRashMusculoskeletaland connective tissue disorderBack painPain in extremityMusculoskeletalstiffnessNeck painGeneral disordersand administration site conditionsInjection sitereactionFeeling hotPyrexiaPaediatricpatientsNo adverse reactions were reported after intrathecal administrationof Iomeprol both in clinical trials and in the post-marketing surveillance.4.8.3 Administration tobody cavitiesAfter injection of an iodinated contrast media in body cavities,contrast media are slowly absorbed from the area of administrationinto the systemic circulation and subsequently cleared by renal elimination.Blood amylase increased is commonfollowing ERCP. Very rare cases of pancreatitis have been described.The reactions reported in casesof arthrography and fistulography usually represent irritative manifestationssuperimposed on pre-existing conditions of tissue inflammation.Hypersensitivity reactions arerare, generally mild and in the form of skin reactions. However, thepossibility of severe anaphylactoid reactions cannot be excluded.As with other iodinated contrastmedia, pelvic pain and malaise may occur after hysterosalpingography.Reporting of suspectedadverse reactionsReporting suspected adversereactions after authorisation of the medicinal product is important.It allows continued monitoring of the benefit/risk balance of themedicinal product. Healthcare professionals are asked to report anysuspected adverse reactions via the Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard or search for MHRA YellowCard in the Google Play or Apple App Store.4.9 Overdose The effectsof overdose on the pulmonary and cardiovascular systems may becomelife-threatening. Treatment consists of support of the vital functionsand prompt use of symptomatic therapy. Iomeprol does not bind to plasmaor serum proteins and is therefore dialyzable.5 PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties ATC code: V08AB10Iomeprol is low osmolality, non-ionic organicmolecule 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 iodineper ml. Even at this concentration the low viscosity allows deliveryof high doses through thin catheters.5.2 Pharmacokinetic properties The pharmacokineticsof intravascularly administered iomeprol are similar to those of otheriodinated contrast media and conform to two-compartment model witha rapid distribution and slower elimination phase. In healthy subjects,the mean distribution and elimination half-lives of iomeprol were0.5 hours and 1.9 hours respectively.Distribution volume is similar to that ofextra cellular fluid. There is no significant serum protein bindingand iomeprol is not metabolized.Elimination is almost exclusively throughthe kidneys (90% of the dose recovered in the urine within 96 hoursof its administration) and is rapid (50% of an intravascularly administereddose within hours).Following intrathecal administration to animals, iomeprol is completelycleared from the CSF and passes into the plasma compartment.5.3 PreclinicalSafety Data Pre-clinical data reveal no special hazardfor humans based on conventional studies of safety pharmacology, repeateddose toxicity, genotoxicity, toxicity to reproduction.Results from studies in rats,mice and dogs demonstrate that iomeprol has an acute intravenous orintra-arterial toxicity similar to that of the other non ionic contrastmedia, as well as good systemic tolerability after repeated intravenousadministrations in rats and dogs.6. PHARMACEUTICAL PARTICULARS6.1 List of excipients trometamolhydrochloric acidwater for injection6.2 Incompatibilities In the absence of compatibilitystudies, this medicinal product must not be mixed with other medicinalproducts.6.3 Shelf Life Five years6.4 Special precautionsfor storage Store below 30CProtect fromlight6.5 Nature and contents of containers Colourless Type or Type II glass bottleswith rubber/aluminium cap.Quantities of 20, 30, 50, 75,100, 150, 200 or 250 ml of solution.6.6 Special precautionsfor disposal and other handling Bottles containing contrast media solutionare not intended for the withdrawal of multiple doses. The rubberstopper should never be pierced more than once. The use of properwithdrawal cannulas for piercing the stopper and drawing up the contrastmedium is recommended.Before use, examine the productto assure that the container and closure have not been damaged. Donot use the solution if it is discolored or particulate matter ispresent.The contrastmedium should not be drawn into the syringe until immediately beforeuse. Withdrawal of contrast agents from their containers should beaccomplished under aseptic conditions with sterile syringes. Steriletechniques must be used with any spinal puncture or intravascularinjection, and with catheters and guidewires. If non-disposable equipmentis used, scrupulous care should be taken to prevent residual contaminationwith traces of cleansing agents.It is desirable that solutions of contrastmedia for intravascular and intrathecal use should be at body temperaturewhen injected.Anyresidue of contrast medium in the syringe must be discarded. Solutionsnot used in one examination session or waste material, such as theconnecting tubes, should be disposed in accordance with local requirements.7. MARKETING AUTHORISATIONHOLDERBraccoUK LtdMagdalen CentreThe Oxford Science ParkOxford, OX4 4GAUnited Kingdom8. MARKETING AUTHORISATION NUMBER18920/00039. DATE OF FIRST AUTHORISATION/RENEWALOF AUTHORISATION11 December 1992 29 December 199810. DATE OF REVISION OF THE TEXT19 January 2022. venography. cerebral arteriography. digital subtraction angiography. computed tomography enhancement. urography. cavernosography. myelography. identification of high-risk patients;. ensuring adequate hydration before CM administration, preferablyby maintaining i.v. infusion before and during the procedure and untilthe CM has been cleared by the kidneys;.