ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The followingclinically significant adverse reactions are described elsewhere inthe labeling:Risks Associated with Intrathecal Administration [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions(5.2)] Acute Kidney Injury [see Warnings and Precautions(5.3)] Cardiovascular Adverse Reactions [see Warnings andPrecautions (5.4)] Thromboembolic Events [see Warnings and Precautions(5.5)] Extravasation and Injection Site Reactions [seeWarnings and Precautions (5.6)] Thyroid Dysfunction in Pediatric Patients Years to Yearsof Age [see Warnings and Precautions (5.8)] Severe Cutaneous Adverse Reactions [see Warningsand Precautions (5.11)] Risks Associated with Intrathecal Administration [see Warnings and Precautions (5.1)] Hypersensitivity Reactions [see Warnings and Precautions(5.2)] Acute Kidney Injury [see Warnings and Precautions(5.3)] Cardiovascular Adverse Reactions [see Warnings andPrecautions (5.4)] Thromboembolic Events [see Warnings and Precautions(5.5)] Extravasation and Injection Site Reactions [seeWarnings and Precautions (5.6)] Thyroid Dysfunction in Pediatric Patients Years to Yearsof Age [see Warnings and Precautions (5.8)] Severe Cutaneous Adverse Reactions [see Warningsand Precautions (5.11)] Most common adverse reactions (incidence >=0.5%)are feeling hot, headache, nausea, chest pain, back pain, and vomiting.(6.1)To report SUSPECTED ADVERSE REACTIONS,contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials areconducted under widely varying conditions, adverse reaction ratesobserved in the clinical trials of drug cannot be directly comparedto rates in the clinical trials of another drug and may not reflectthe rates observed in practice.Adverse Reactions in Adult PatientsThe safety of IOMERVUwas evaluated in 4,621 adult patients who received 1,500 mg to 86,000mg iodine doses of IOMERVU intra-arterially or intravenously in clinicaltrials. The average age was 60 years (range 18 years to 99 years),and 34% were female. The racial and ethnic distribution was 83% White,10% Asian, 1% Black, 1% Hispanic, and 5% patients of other or unspecifiedgroups.Table providesa summary of the adverse reactions reported in >=0.5% of adult patients.Table 5: Adverse Reactions Reported in >=0.5% of 4,621 Adult PatientsReceiving Intra-arterial or Intravenous Administration of IOMERVUin Clinical TrialsAdverse ReactionIncidence(%)Feeling hot2Headache1.2Nausea1Chest pain0.6Back pain0.5Vomiting0.5The following adversereactions were observed in <0.5% of the adult patients receivingIOMERVU:Blood and lymphatic system disorders: activated partialthromboplastin time prolonged, prothrombin time prolongedCardiovascular disorders: ventricular fibrillation, hypertensive crisis, coronary arteriospasm,congestive cardiac failure, cardiac flutter, atrioventricular block,right bundle branch block, hypotension, arrhythmia, bradycardia, supraventricularextrasystoles, ventricular extrasystoles, increased blood pressure,flushing Ear and labyrinth disorders: vertigo, ear discomfortEye disorder: vision blurred, periorbital edema, photopsiaGastrointestinal: esophagealvarices hemorrhage, abdominal pain, abdominal distension, alanineaminotransferase (ALT) increased, constipation, diarrhea, dry mouth,salivary hypersecretion, oral paresthesiaGeneral disorders: pain,injection site reactions (pain, discomfort, or warmth), peripheraledema, chills, asthenia, malaiseMusculoskeletal and connectivetissue disorders: arthralgia, pain in jaw Nervous system disorders: cerebrovascular disorder, dysarthria, visual field defect, burningsensation, presyncope, dizziness, dysgeusia, paresthesiaPsychiatric disorders: delirium, anxiety, insomniaRenal and urinary disorders: acute kidney injury, increased blood creatinine, urinary urgencyRespiratory, thoracic,and mediastinal disorders: respiratory arrest, pulmonaryedema, bronchospasm, dyspnea, cough, rhinitis, throat irritation ortightness, sneezingSkin and subcutaneous tissue disorders: urticaria,blister, purpura, ecchymosis, rash, pruritus, erythemaAdverse Reactionsin Pediatric PatientsThe safety of IOMERVU was evaluated in184 pediatric patients who received 1,800 mg to 76,000 mg iodine dosesof IOMERVU intra-arterially or intravenously in clinical trials. Theaverage age was years (range 11 days to 17 years), and 47% werefemale. The racial distribution was 98% White, 1% Black, and 1% patientsof other or unspecified groups. The overall character, quality, andseverity of adverse reactions reported in pediatric patients weresimilar to those reported in adult patients.. 6.2 Post Marketing Experience. The following adverse reactionshave been identified during post-approval use of IOMERVU outside theUnited States. Because these reactions are reported voluntarily froma population of uncertain size, it is not always possible to reliablyestimate their frequency or establish causal relationship to drugexposure. Blood and lymphatic system disorders: thrombocytopenia,leukopenia, leukocytosisCardiovascular disorders: cardio-respiratory arrest, circulatory collapse or shock, myocardialinfarction, atrial fibrillation, cyanosis, pallorEndocrine disorders: hyperthyroidism,hypothyroidismEye disorders: transient blindness, conjunctivitis, increasedlacrimationGastrointestinal disorders: salivary gland enlargement,increased aspartate aminotransferase (AST), dysphagiaGeneral disorders and administrationsite conditions:injection site swelling (usuallydue to extravasation)Immune system disorders: hypersensitivity reactionsincluding fatal anaphylaxisNervous system disorders: coma, loss of consciousness, encephalopathy, transient ischemicattack, paralysis, convulsion, syncope, amnesia, somnolencePsychiatric disorders: confusional stateRespiratory, thoracic, and mediastinal disorders: acute respiratory distress syndrome (ARDS), laryngeal edema, pharyngealedema, dysphoniaSkin and subcutaneous tissue disorders: severe reactions(Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN),acute generalized exanthematous pustulosis (AGEP), drug reaction witheosinophilia and systemic symptoms (DRESS)) and mild reactions (rash,erythema, pruritus, urticaria, and skin discoloration).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Iomeprol is radiographic iodinated contrast agent that opacifiesthe vessels and body structures where the contrast agent is presentfollowing intravenous or intra-arterial administration, permittingradiographic visualization of the internal structures through attenuationof X-ray photons. In imaging of the body, iodinated contrast agents diffuse from thevessels into the extravascular space. In normal brain with an intactblood-brain barrier, the contrast agent does not diffuse into theextravascular space and contrast enhancement is generally due to thepresence of contrast within the vascular space. In patients with adisrupted blood-brain barrier, the contrast agent accumulates in theextravascular space in the region of disruption.. 12.2 Pharmacodynamics. The degree of radiographic enhancement by iomeprol is related tothe iodine concentration in the tissue of interest following the administrationof IOMERVU. However, the exposure-response relationships and timecourse of pharmacodynamic response of iomeprol have not been fullycharacterized.. 12.3 Pharmacokinetics. Thepharmacokinetic parameters of iomeprol are presented as mean (standarddeviation, SD) unless otherwise specified.The maximum concentration (Cmax) and area under the concentration-time curve (AUC) are dose-proportionalacross the dose range of 250 mg iodine/kg to 1,250 mg iodine/kg bodyweight. DistributionThe volume of distribution ofiomeprol is 0.28 (0.05) L/kg. Iomeprol does not bind to plasma proteins.EliminationThe elimination half-life of iomeprol is 1.8 (0.33) hoursand the total body clearance is 0.10 (0.01) L/hr/kg. Metabolism Iomeprol does not undergo significant metabolism.Excretion Approximately90% of the iomeprol dose is excreted unchanged in urine within 24hours.Specific PopulationsPediatric PatientsNo clinicallysignificant differences in the pharmacokinetics of iomeprol were observedin pediatric patients aged years to 17 years compared to adult patientswho received IOMERVU. No clinically significant differences in Cmax and concentration of iomeprol within minutes afterIOMERVU administration between pediatric patients younger than yearsof age and adults are expected based on pharmacokinetic simulations.Patients with RenalImpairmentThe renal clearance of iomeprol decreasedby 28% in patients with mild (GFR 51 75 mL/min, estimated by inulinclearance (CLinulin)), 66% with moderate (GFR26 50 mL/min, by CLinulin), and 84% withsevere (GFR <= 25 mL/min, by CLinulin) renalimpairment. Similarly, mean half-life increased 1.6-fold in mild,2.9-fold in moderate, and 6.4-fold in severe renal impairment.Iomeprol is dialyzable. Iomeprolplasma concentrations decreased by 83% in patients with severe renalimpairment who underwent hemodialysis hours after single administrationof 20,000 mg iodine dose of IOMERVU by intravenous route.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Intra-arterial Studies. Cerebral arteriography was evaluated inone blinded read study incorporating two prospective, randomized,double-blind, multi-center clinical studies of 61 adult patients (35male, 26 female) who were administered IOMERVU 300 mg Iodine/mL byintra-arterial route. The mean age was 52 years (range 17 years to86 years), and 23% of patients were >=65 years old. The mean totaliodine dose administered was 29,000 mg. The racial and ethnic representationswere 62% White, 15% Black, 20% Hispanic, and 3% Asian. Visualizationwas independently assessed as adequate or inadequate by three blindedreaders. Visualization was rated as adequate in 100% of patients. Visceral and peripheral arteriographywere evaluated in one blinded read study incorporating two prospective,randomized, double-blind, multi-center clinical studies of 60 adultpatients (36 male, 24 female) who were administered IOMERVU 300 mgIodine/mL by intra-arterial route. The mean age was 67 years (range29 years to 95 years) and 62% of patients were >=65 years old. Themean total iodine dose administered was 48,000 mg. The racial andethnic representations were 92% White, 7% Black, and 1% Hispanic.Visualization was independently assessed as adequate or inadequateby three blinded readers. Visualization was rated as adequate in 98%of patients.Similarcerebral arteriography, visceral arteriography, and peripheral arteriographystudies with digital subtraction angiography (DSA) were completedwith comparable findings.Coronary arteriography and cardiac ventriculographywere evaluated in one blinded read study incorporating four prospective,randomized, double-blind, multi-center clinical studies of 59 adultpatients (41 male, 18 female) who were administered IOMERVU 400 mgIodine/mL, and 59 adult patients (43 male, 16 female) who were administeredIOMERVU 300 mg Iodine/mL by intra-arterial route. The mean age was60 years (range 22 years to 85 years), and 42% of patients were >=65 yearsold. The mean total iodine dose administered was 45,000 mg. The racialand ethnic representations were 75% White, 15% Black, 6% Hispanic,1% Asian, and 3% other racial or ethnic groups. Visualization wasindependently assessed as adequate or inadequate by three blindedreaders. Visualization was rated as adequate in 93% 100% of patientsfor both concentrations.. 14.2 Intravenous Studies. CT of the head and body was evaluated inone blinded read study incorporating four prospective, randomized,double-blind, multi-center clinical studies of 59 adult patients (22male, 37 female) who were administered IOMERVU 400 mg Iodine/mL and59 adult patients (26 male, 33 female) who were administered IOMERVU250 mg Iodine/mL by intravenous route. The mean age was 55 years (range19 years to 80 years), and 30% of patients were >=65 years old. Themean total iodine dose administered was 41,000 mg. The racial andethnic representations were 78% White, 16% Black, 4% Hispanic, 1%Asian, and 1% other racial or ethnic groups. Visualization was independentlyassessed as adequate or inadequate by three blinded readers. Visualizationwas rated as adequate in 98% 100% of patients for both concentrations. CT angiography was evaluatedin two prospective, single-center clinical studies enrolling totalof 262 adult patients (202 male, 60 female) with suspected or knownperipheral arterial disease who were administered IOMERVU 400 mg Iodine/mLby intravenous route. The mean age was 62 years (range 36 years to88 years). Both studies assessed the diagnostic performance for detectionof significant stenosis at the arterial segment level using digitalsubtraction angiography as the reference standard. In the first study,212 patients (7,392 segments, 42% positive by reference standard)were independently evaluated by three blinded readers. The reportedsegment-level sensitivity and specificity (95% confidence interval)for the detection of >=70% stenosis were 99% (98%, 99%) and 97% (96%,97%), respectively. In the second study, 50 patients (929 to 933 lesions,34% positive by reference standard) were evaluated by two blindedreaders. The reported lesion-level sensitivity and specificity (95%confidence interval) for the detection of >50% stenosis were 93% (91%,96%) and 97% (95%, 98%), respectively, for reader and 90% (87%,93%) and 96% (94%, 97%), respectively, for reader 2. Coronary CT angiography was evaluated intwo prospective, single-center clinical studies enrolling totalof 301 adult patients (259 male, 42 female) with suspected coronaryartery disease who were administered IOMERVU 400 mg Iodine/mL by intravenousroute. The mean age was 64 years. Both studies assessed the diagnosticperformance for detection of >=50% stenosis at the coronary arterysegment level using invasive coronary angiography as the referencestandard. In the first study, 210 patients (2,532 segments, 22% positiveby reference standard) were independently evaluated by two blindedreaders with discrepancies resolved by consensus. The segment-levelsensitivity and specificity (95% confidence interval) were 84% (81%,87%) and 94% (92%, 95%), respectively. In the second study, 91 patients(1,456 segments, 18% positive by reference standard) were independentlyevaluated by two blinded readers with discrepancies resolved by athird reader. The segment-level sensitivity and specificity (95% confidenceinterval) were 97% (95%, 99%) and 91% (89%, 92%), respectively.CT urography was evaluated intwo retrospective, single-center clinical studies of 185 adult patients(130 male, 55 female) who were administered IOMERVU 350 mg Iodine/mLby intravenous route. The mean age was 55 years (range 20 years to89 years). In the first study, two readers assessed parenchymal imagequality on 3-point scale (inadequate, diagnostic, or very good orexcellent) as very good or excellent in 64% to 98% of the patientsdepending on scan protocol. In the second study, two blinded readersassessed visualization quality for the urinary system overall (calyces,renal pelvis, ureter, and bladder), on scale of (absence of visualization)to (excellent visualization), with the mean score (SD) for reader1 being 4.2 (1.4) and for reader being 4.1 (1.5).

DESCRIPTION SECTION.

11 DESCRIPTION. IOMERVU (iomeprol) injection is tri-iodinated, non-ionic radiographic contrast agent for intra-arterial or intravenous use. It is provided as sterile, nonpyrogenic, clear, colorless to pale yellow solution.The chemical name for iomeprol is N,N-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)-methylamino]-2,4,6-tri-iodo-1,3-benzenedicarboxamide. Iomeprol has molecular formula of C17H22I3N3O8, molecular weight of 777.09 (iodine content of 49%), and the following structural formula: IOMERVU injection is available in four iodine concentrations: IOMERVU 250 mg Iodine/mL: Each mL contains 510 mg iomeprol (providing 250 mg bound iodine) and mg tromethamine. IOMERVU 300 mg Iodine/mL: Each mL contains 612 mg iomeprol (providing 300 mg bound iodine) and mg tromethamine.IOMERVU 350 mg Iodine/mL: Each mL contains 714 mg iomeprol (providing 350 mg bound iodine) and mg tromethamine. IOMERVU 400 mg Iodine/mL: Each mL contains 816 mg iomeprol (providing 400 mg bound iodine) and mg tromethamine.The pH of IOMERVU has been adjusted to 6.5 to 7.2 with hydrochloric acid.Physical characteristics are noted in Table 6. IOMERVU has osmolalities approximately 1.5 to 2.5 times that of plasma (285 mOsm/kg water) as shown in the table below and are hypertonic under conditions of use.Table 6. Physical Characteristics of IOMERVUConcentration(mg Iodine/mL)Density(d204 +- 0.0002)Osmolality(mOsmol/kg)Viscosity(mPa.s)37C20C37C2501.2784354.92.93001.3345218.14.53501.39061814.57.54001.44672627.512.6. IOMERVU 250 mg Iodine/mL: Each mL contains 510 mg iomeprol (providing 250 mg bound iodine) and mg tromethamine. IOMERVU 300 mg Iodine/mL: Each mL contains 612 mg iomeprol (providing 300 mg bound iodine) and mg tromethamine.. IOMERVU 350 mg Iodine/mL: Each mL contains 714 mg iomeprol (providing 350 mg bound iodine) and mg tromethamine. IOMERVU 400 mg Iodine/mL: Each mL contains 816 mg iomeprol (providing 400 mg bound iodine) and mg tromethamine.. Iomeprol-Structural-Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Individualize the volume and concentration according tothe specific dosing tables accounting for factors such as age, bodyweight, vessel size, rate of blood flow within the vessel, and structuresor areas to be examined. (2.2, 2.3, 2.4, 2.5)See full prescribing information for complete dosage andadministration information. (2). Individualize the volume and concentration according tothe specific dosing tables accounting for factors such as age, bodyweight, vessel size, rate of blood flow within the vessel, and structuresor areas to be examined. (2.2, 2.3, 2.4, 2.5). See full prescribing information for complete dosage andadministration information. (2). 2.1 Important Dosing and Administration Information. IOMERVU is for intra-arterial or intravenous use only andmust not be administered intrathecally [see Warnings and Precautions(5.1)].Specific concentrations of IOMERVU are recommended for eachtype of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. Individualize the volume, concentration, and injection rateof IOMERVU within the specified ranges [see Dosage and Administration(2.2, 2.3, 2.4, 2.5)]. Consider factors such as age, body weight, vessel size,rate of blood flow within the vessel, anticipated pathology, degreeand extent of opacification required, structures or area to be examined,disease processes affecting the patient, and equipment and techniqueto be employed.Hydrate patients before and after IOMERVU administration [see Warnings and Precautions (5.3)].Use aseptic technique for all handling and administrationof IOMERVU. IOMERVU may be administered at either body temperature (37C,98.6F) or room temperature (20C to 25C, 68F to 77F).Visually inspect IOMERVU for particulate matter or discolorationbefore administration, whenever the solution and container permit.Do not administer IOMERVU if particulate matter or discoloration isobserved. Do not mix IOMERVU with, or inject in intravenous linescontaining, other drugs or total nutritional admixtures. Each single-dose container of IOMERVU injection is intendedfor one procedure only. Discard any unused portion.. IOMERVU is for intra-arterial or intravenous use only andmust not be administered intrathecally [see Warnings and Precautions(5.1)].. Specific concentrations of IOMERVU are recommended for eachtype of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)]. Individualize the volume, concentration, and injection rateof IOMERVU within the specified ranges [see Dosage and Administration(2.2, 2.3, 2.4, 2.5)]. Consider factors such as age, body weight, vessel size,rate of blood flow within the vessel, anticipated pathology, degreeand extent of opacification required, structures or area to be examined,disease processes affecting the patient, and equipment and techniqueto be employed.. Hydrate patients before and after IOMERVU administration [see Warnings and Precautions (5.3)].. Use aseptic technique for all handling and administrationof IOMERVU. IOMERVU may be administered at either body temperature (37C,98.6F) or room temperature (20C to 25C, 68F to 77F).. Visually inspect IOMERVU for particulate matter or discolorationbefore administration, whenever the solution and container permit.Do not administer IOMERVU if particulate matter or discoloration isobserved. Do not mix IOMERVU with, or inject in intravenous linescontaining, other drugs or total nutritional admixtures. Each single-dose container of IOMERVU injection is intendedfor one procedure only. Discard any unused portion.. 2.2 Recommended Dosage for Intra-arterial Procedures in Adults. Recommended doses of IOMERVU in adults for intra-arterial procedures are shown in Table 1.Inject at rates approximately equal to the flow rate in the vessel being injected.Table 1. Recommended Concentrations and Volumes of IOMERVU to Administer per Single Injection into Selected Arteries for Intra-arterial Procedures in AdultsImaging ProcedureConcentration (mg Iodine/mL)Volume(mL)Maximum Total Dose (mL)Cerebral arteriography300Carotid, subclavian, and vertebral arteries: mL to 12 mLAortic arch: 30 mL to 50 mL200 mLVisceral and peripheral arteriography; aortography300Aortography: 30 mL to 70 mL Renal arteries: 10 mL to 12 mLOther major branches of aorta: 20 mL to 60 mL200 mLIntra-arterial digital subtraction angiography300Carotid, subclavian, and vertebral arteries: mL to 12 mLAortic arch: 20 mL to 25 mLAortography: 15 mL to 40 mLRenal arteries: mL to 16 mLOther major branches of aorta: 10 mL to 40 mLIlio-femoral runoff: mL to 40 mL200 mLCoronary arteriography and cardiac ventriculography300Coronary arteries: mL to mLCardiac ventriculography: 30 mL to 45 mL286 mL350245 mL400215 mL. Recommended doses of IOMERVU in adults for intra-arterial procedures are shown in Table 1.. Inject at rates approximately equal to the flow rate in the vessel being injected.. Carotid, subclavian, and vertebral arteries: mL to 12 mL. Aortic arch: 30 mL to 50 mL. Aortography: 30 mL to 70 mL Renal arteries: 10 mL to 12 mL. Other major branches of aorta: 20 mL to 60 mL. Carotid, subclavian, and vertebral arteries: mL to 12 mL. Aortic arch: 20 mL to 25 mL. Aortography: 15 mL to 40 mL. Renal arteries: mL to 16 mL. Other major branches of aorta: 10 mL to 40 mL. Ilio-femoral runoff: mL to 40 mL. Coronary arteries: mL to mL. Cardiac ventriculography: 30 mL to 45 mL. 2.3 Recommended Dosage for Intra-arterial Procedures in Pediatric Patients Recommended doses of IOMERVU in pediatric patients for intra-arterial procedures are shown in Table 2.Inject at rates approximately equal to the flow rate in the vessel being injected.Table 2. Recommended Concentrations and Volumes per Body Weight of IOMERVU to Administer per Single Injection for Intra-arterial Procedures in Pediatric PatientsImaging ProcedureConcentration (mg Iodine/mL)Volume (mL/kg body weight)Maximum Total Dose (mL/kg)Cerebral arteriography3000.5 mL/kg to mL/kg5 mL/kgDo not exceed adult maximum dose (see Table 1)Visceral and peripheral arteriography; aortography3000.5 mL/kg to mL/kgIntra-arterial digital subtraction angiography3000.3 mL/kg to mL/kgRadiographic evaluation of cardiac chambers and related arteries300, 350, or 4000.5 mL/kg to mL/kg. Recommended doses of IOMERVU in pediatric patients for intra-arterial procedures are shown in Table 2.. Inject at rates approximately equal to the flow rate in the vessel being injected.. mL/kg. Do not exceed adult maximum dose (see Table 1). 2.4 Recommended Dosagefor Intravenous Procedures in Adults. Recommended doses of IOMERVU in adults forintravenous procedures are shown in Table 3.Table 3. Recommended Concentrations, Volumes, and Injection Ratesof IOMERVU for Intravenous Procedures in Adults Imaging ProcedureConcentration (mg Iodine/mL)Volume (mL)InjectionRate3 (mL/s)CT of Head and Body250 or 300100 mL to 190mL2mL/s to mL/s350 or 40075 mL to 150mLCT Angiography1 300, 350, or40080 mL to 130mL4 mL/s to mL/sCoronary CT Angiography1 40050 mL to 90 mL4 mL/s to mL/sCT Urography2 35090 mL to 120mL2.5 mL/s1 The IOMERVU volume may be immediately followed by 40 mL to 50 mL0.9% sodium chloride injection flush at the same flow rate as thecontrast volume.2 The IOMERVUvolume may be administered either as single bolus, or for dual-phaseprotocols as divided doses.3 The injection rate of IOMERVU should be determined according to theclinical indication and the location, size, and type of the intravenousaccess.. 2.5 Recommended Dosage for Intravenous Procedures in Pediatric Patients. Recommended doses of IOMERVUin pediatric patients for intravenous procedures are shown in Table4.Table 4. Recommended Concentrations, Volumes per Body Weight, andInjection Rates of IOMERVU for Intravenous Procedures in PediatricPatientsImaging ProcedureConcentration (mg Iodine/mL)Volume (mL/kg body weight)InjectionRate (mL/s)CT of Head and Body250 or 3001.5 mL/kg to2.5 mL/kg1mL/s to mL/s350 or 4001 mL/kg to 2mL/kgCT Angiography300, 350, or4001 mL/kg to 2mL/kg2 mL/s to mL/sCoronary CT Angiography300 or 4001 mL/kg to 2mL/kg2 mL/s to mL/sCT Urography3001 mL/kg to 2mL/kg1 mL/s to mL/s The injection rate ofIOMERVU should be determined according to the clinical indicationand the location, size, and type of the intravenous access. In neonatesand patients <15 kg in whom 24-gauge angiocatheter is the onlyoption, an injection rate of mL/s is recommended.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. IOMERVU is radiographic contrastagent indicated for: Intra-arterial Procedures (1.1)Cerebral arteriography, includingintra-arterialdigital subtraction angiography (IA-DSA), in adults and pediatricpatientsVisceral and peripheral arteriography and aortography, includingIA-DSA, in adults and pediatric patientsCoronary arteriography and cardiac ventriculography in adultsRadiographic evaluation of cardiac chambers and relatedarteries in pediatric patients Intravenous Procedures+ (1.2)Computed tomography (CT) of the head and body in adultsand pediatric patientsCT angiography of intracranial, visceral, and lower extremityarteries in adults and pediatric patientsCoronary CT angiography in adults and pediatric patientsCT urography in adults and pediatric patients+Specificconcentrations are recommended for each type of imaging procedure.(2.2, 2.3, 2.4, 2.5). Cerebral arteriography, includingintra-arterialdigital subtraction angiography (IA-DSA), in adults and pediatricpatients. Visceral and peripheral arteriography and aortography, includingIA-DSA, in adults and pediatric patients. Coronary arteriography and cardiac ventriculography in adults. Radiographic evaluation of cardiac chambers and relatedarteries in pediatric patients Computed tomography (CT) of the head and body in adultsand pediatric patients. CT angiography of intracranial, visceral, and lower extremityarteries in adults and pediatric patients. Coronary CT angiography in adults and pediatric patients. CT urography in adults and pediatric patients. 1.1 Intra-arterial Procedures+ IOMERVUis indicated for:Cerebral arteriography, including intra-arterial digitalsubtraction angiography (IA-DSA), in adults and pediatric patientsVisceral and peripheral arteriography and aortography, includingIA-DSA, in adults and pediatric patientsCoronary arteriography and cardiac ventriculography in adultsRadiographic evaluation of cardiac chambers and relatedarteries in pediatric patients. Cerebral arteriography, including intra-arterial digitalsubtraction angiography (IA-DSA), in adults and pediatric patients. Visceral and peripheral arteriography and aortography, includingIA-DSA, in adults and pediatric patients. Coronary arteriography and cardiac ventriculography in adults. Radiographic evaluation of cardiac chambers and relatedarteries in pediatric patients. 1.2 Intravenous Procedures+ IOMERVUis indicated for:Computed tomography (CT) of the head and body in adultsand pediatric patientsCT angiography of intracranial, visceral, and lower extremityarteries in adults and pediatric patients Coronary CT angiography in adults and pediatric patients CT urography in adults and pediatric patients+Specific concentrations of IOMERVU are recommended for each typeof imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4, 2.5)].. Computed tomography (CT) of the head and body in adultsand pediatric patients. CT angiography of intracranial, visceral, and lower extremityarteries in adults and pediatric patients Coronary CT angiography in adults and pediatric patients CT urography in adults and pediatric patients.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Intra-arterial UseThe safety and effectivenessof IOMERVU have been established in pediatric patients for cerebral,visceral, and peripheral arteriography, aortography including intra-arterialdigital subtraction angiography, and radiographic evaluation of cardiacchambers and related arteries.Use of IOMERVU is supported by evidencefrom adequate and well-controlled studies of IOMERVU in adults, pharmacokineticdata in pediatric patients aged years to 17 years, pharmacokineticsimulation in pediatric patients younger than years of age, andsafety data obtained in 44 pediatric patients including 29 who were< years of age, 14 children (2 years to 11 years), and adolescent(12 years to 17 years). In general, adverse reactions reported inpediatric patients were similar to those in adults [see AdverseReactions (6.1), Clinical Pharmacology(12.3), and Clinical Studies (14.1)].Intravenous UseThe safety and effectivenessof IOMERVU have been established in pediatric patients for CT of thehead and body, CT angiography of intracranial, visceral, and lowerextremity arteries, coronary CT angiography, and CT urography. Use of IOMERVU is supportedby evidence from adequate and well-controlled studies of IOMERVU inadults, pharmacokinetic data in pediatric patients aged years to17 years, pharmacokinetic simulation in pediatric patients youngerthan years of age, and safety data obtained in 140 pediatric patientsincluding 22 who were 2 years of age, 92 children (2 years to11 years), and 26 adolescents (12 years to 17 years). In general,adverse reactions reported in pediatric patients were similar to thosein adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].Intra-arterialand Intravenous UsePediatricpatients at higher risk of experiencing an adverse reaction duringand after administration of any contrast agent may include those withasthma, sensitivity to medication and/or allergens, cyanotic and acyanoticheart disease, heart failure, or serum creatinine greater than 1.5mg/dL, or those less than 12 months of age. Pediatric patients withimmature renal function or dehydration may be at increased risk foradverse events due to slower elimination of iodinated contrast agents [See Clinical Pharmacology (12.3)]. Thyroidfunction tests indicative of thyroid dysfunction, characterized byhypothyroidism or transient thyroid suppression have been reportedfollowing iodinated contrast agent administration in pediatric patients,including term and preterm neonates. Some patients were treated forhypothyroidism. After exposure to iodinated contrast agents, individualizethyroid function monitoring in pediatric patients years to yearsof age based on underlying risk factors, especially in term and pretermneonates [See Warnings and Precautions (5.8) and Adverse Reactions(6.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Thepharmacokinetic parameters of iomeprol are presented as mean (standarddeviation, SD) unless otherwise specified.The maximum concentration (Cmax) and area under the concentration-time curve (AUC) are dose-proportionalacross the dose range of 250 mg iodine/kg to 1,250 mg iodine/kg bodyweight. DistributionThe volume of distribution ofiomeprol is 0.28 (0.05) L/kg. Iomeprol does not bind to plasma proteins.EliminationThe elimination half-life of iomeprol is 1.8 (0.33) hoursand the total body clearance is 0.10 (0.01) L/hr/kg. Metabolism Iomeprol does not undergo significant metabolism.Excretion Approximately90% of the iomeprol dose is excreted unchanged in urine within 24hours.Specific PopulationsPediatric PatientsNo clinicallysignificant differences in the pharmacokinetics of iomeprol were observedin pediatric patients aged years to 17 years compared to adult patientswho received IOMERVU. No clinically significant differences in Cmax and concentration of iomeprol within minutes afterIOMERVU administration between pediatric patients younger than yearsof age and adults are expected based on pharmacokinetic simulations.Patients with RenalImpairmentThe renal clearance of iomeprol decreasedby 28% in patients with mild (GFR 51 75 mL/min, estimated by inulinclearance (CLinulin)), 66% with moderate (GFR26 50 mL/min, by CLinulin), and 84% withsevere (GFR <= 25 mL/min, by CLinulin) renalimpairment. Similarly, mean half-life increased 1.6-fold in mild,2.9-fold in moderate, and 6.4-fold in severe renal impairment.Iomeprol is dialyzable. Iomeprolplasma concentrations decreased by 83% in patients with severe renalimpairment who underwent hemodialysis hours after single administrationof 20,000 mg iodine dose of IOMERVU by intravenous route.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from literature and postmarketingreports on iomeprol use in pregnant women over decades have not identifieda drug-associated risk of major birth defects, miscarriage, or otheradverse maternal or fetal outcomes. In animal reproduction studies,no adverse developmental outcomes were observed with intravenous administrationof iomeprol to pregnant rats and rabbits at doses up to 0.45-timesthe maximum recommended human dose of 86,000 mg iodine. Animal studiesshow that iomeprol crosses the placenta (see Data).The backgroundrisk of major birth defects and miscarriage for the indicated populationis unknown. All pregnancies have background risk of birth defects,loss or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimalDataEmbryo-fetaldevelopmental toxicity studies were performed with intravenous administrationof iomeprol in rats at daily doses of 600 mg, 1,500 mg, or 4,000 mgiodine/kg (0.07-, 0.17- or 0.45-fold the human equivalent dose (HED,mg/m2) using the maximum human dose of86,000 mg iodine per administration) from gestation days (GD) to15 and in rabbits at daily doses of 300 mg, 800 mg, or 2,000 mg iodine/kg(0.07-, 0.18- or 0.45-fold the HED using the maximum human dose of86,000 mg iodine per administration) from GD to 18. Iomeprol didnot result in fetal harm at the highest doses evaluated, 0.45-timesthe maximum recommended human dose of 86,000 mg iodine.A biodistribution study witha single intravenous administration of 1,000 mg iodine/kg (0.11-foldthe HED using the maximum human dose of 86,000 mg iodine per administration)of radiolabeled iomeprol to pregnant rats showed that iomeprol crossesthe placenta. No accumulation of radioactivity in fetal tissues wasobserved.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: lactating woman may pump and discardbreast milk for 10 hours after IOMERVU administration. (8.2). 8.1 Pregnancy. Risk SummaryAvailable data from literature and postmarketingreports on iomeprol use in pregnant women over decades have not identifieda drug-associated risk of major birth defects, miscarriage, or otheradverse maternal or fetal outcomes. In animal reproduction studies,no adverse developmental outcomes were observed with intravenous administrationof iomeprol to pregnant rats and rabbits at doses up to 0.45-timesthe maximum recommended human dose of 86,000 mg iodine. Animal studiesshow that iomeprol crosses the placenta (see Data).The backgroundrisk of major birth defects and miscarriage for the indicated populationis unknown. All pregnancies have background risk of birth defects,loss or other adverse outcomes. In the U.S. general population, theestimated background risk of major birth defects and miscarriage inclinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.DataAnimalDataEmbryo-fetaldevelopmental toxicity studies were performed with intravenous administrationof iomeprol in rats at daily doses of 600 mg, 1,500 mg, or 4,000 mgiodine/kg (0.07-, 0.17- or 0.45-fold the human equivalent dose (HED,mg/m2) using the maximum human dose of86,000 mg iodine per administration) from gestation days (GD) to15 and in rabbits at daily doses of 300 mg, 800 mg, or 2,000 mg iodine/kg(0.07-, 0.18- or 0.45-fold the HED using the maximum human dose of86,000 mg iodine per administration) from GD to 18. Iomeprol didnot result in fetal harm at the highest doses evaluated, 0.45-timesthe maximum recommended human dose of 86,000 mg iodine.A biodistribution study witha single intravenous administration of 1,000 mg iodine/kg (0.11-foldthe HED using the maximum human dose of 86,000 mg iodine per administration)of radiolabeled iomeprol to pregnant rats showed that iomeprol crossesthe placenta. No accumulation of radioactivity in fetal tissues wasobserved.. 8.2 Lactation. Risk SummaryThere are no data on the presenceof iomeprol in human milk, the effects on the breastfed infant, orthe effects on milk production. Iomeprol is present in animal milk (see Data). When drug is present in animal milk, it islikely that the drug will be present in human milk. Iodinated contrastagents are excreted unchanged in human milk in very low amounts, withpoor absorption from the gastrointestinal tract of breastfed infant.The developmental and health benefits of breastfeeding should be consideredalong with the mothers clinical need for IOMERVU and any potentialadverse effects on the breastfed infant from IOMERVU or from the underlyingmaternal condition.Clinical ConsiderationsInterruption of breastfeeding after exposureto iodinated contrast agents is not necessary because the potentialexposure of the breastfed infant to iodine is small. However, lactatingwoman may consider interrupting breastfeeding and pumping and discardingbreast milk for 10 hours (approximately elimination half-lives)after IOMERVU administration to minimize any potential drug exposureto breastfed infant.DataAn animal study with single intravenousadministration of 500 mg iodine/kg (0.06-fold the HED using the maximumhuman dose of 86,000 mg iodine per administration) of radiolabelediomeprol to lactating rats showed that iomeprol rapidly distributedinto the milk. 8.4 Pediatric Use. Intra-arterial UseThe safety and effectivenessof IOMERVU have been established in pediatric patients for cerebral,visceral, and peripheral arteriography, aortography including intra-arterialdigital subtraction angiography, and radiographic evaluation of cardiacchambers and related arteries.Use of IOMERVU is supported by evidencefrom adequate and well-controlled studies of IOMERVU in adults, pharmacokineticdata in pediatric patients aged years to 17 years, pharmacokineticsimulation in pediatric patients younger than years of age, andsafety data obtained in 44 pediatric patients including 29 who were< years of age, 14 children (2 years to 11 years), and adolescent(12 years to 17 years). In general, adverse reactions reported inpediatric patients were similar to those in adults [see AdverseReactions (6.1), Clinical Pharmacology(12.3), and Clinical Studies (14.1)].Intravenous UseThe safety and effectivenessof IOMERVU have been established in pediatric patients for CT of thehead and body, CT angiography of intracranial, visceral, and lowerextremity arteries, coronary CT angiography, and CT urography. Use of IOMERVU is supportedby evidence from adequate and well-controlled studies of IOMERVU inadults, pharmacokinetic data in pediatric patients aged years to17 years, pharmacokinetic simulation in pediatric patients youngerthan years of age, and safety data obtained in 140 pediatric patientsincluding 22 who were 2 years of age, 92 children (2 years to11 years), and 26 adolescents (12 years to 17 years). In general,adverse reactions reported in pediatric patients were similar to thosein adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].Intra-arterialand Intravenous UsePediatricpatients at higher risk of experiencing an adverse reaction duringand after administration of any contrast agent may include those withasthma, sensitivity to medication and/or allergens, cyanotic and acyanoticheart disease, heart failure, or serum creatinine greater than 1.5mg/dL, or those less than 12 months of age. Pediatric patients withimmature renal function or dehydration may be at increased risk foradverse events due to slower elimination of iodinated contrast agents [See Clinical Pharmacology (12.3)]. Thyroidfunction tests indicative of thyroid dysfunction, characterized byhypothyroidism or transient thyroid suppression have been reportedfollowing iodinated contrast agent administration in pediatric patients,including term and preterm neonates. Some patients were treated forhypothyroidism. After exposure to iodinated contrast agents, individualizethyroid function monitoring in pediatric patients years to yearsof age based on underlying risk factors, especially in term and pretermneonates [See Warnings and Precautions (5.8) and Adverse Reactions(6.2)]. 8.5 Geriatric Use. Of thetotal number of subjects in clinical studies of IOMERVU, 1,977 (43%)patients were 65 years and older, while 629 (14%) patients were 75years and older. No overall differences in safety or effectivenesswere observed between these patients and younger patients. Iomeprol is excreted by thekidneys, and the risk of adverse reactions to IOMERVU is greater inpatients with renal impairment. Because elderly patients are morelikely to have renal impairment, care should be taken in dose selection,and it may be useful to monitor renal function [see Warningsand Precautions (5.3) and Use in Specific Populations (8.6)].. 8.6 Renal Impairment. Preexisting renal impairmentincreases the risk for acute kidney injury. Renalimpairment reduces the rate of elimination of iomeprol. Iomeprol can be removed by dialysis [see Warnings and Precautions(5.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: Life-threatening or fatal reactionscan occur. Always have emergency resuscitation equipment and trainedpersonnel available. (5.2)Acute Kidney Injury: Acute injury including renal failurecan occur. Minimize dose and maintain adequate hydration to minimizerisk. (5.3)Cardiovascular Adverse Reactions: Hemodynamic disturbancesincluding shock and cardiac arrest may occur during or after administration.(5.4)Thyroid Dysfunction in Pediatric Patients Years to Yearsof Age: Individualize thyroid function monitoring based on risk factorssuch as prematurity. (5.8). Hypersensitivity Reactions: Life-threatening or fatal reactionscan occur. Always have emergency resuscitation equipment and trainedpersonnel available. (5.2). Acute Kidney Injury: Acute injury including renal failurecan occur. Minimize dose and maintain adequate hydration to minimizerisk. (5.3). Cardiovascular Adverse Reactions: Hemodynamic disturbancesincluding shock and cardiac arrest may occur during or after administration.(5.4). Thyroid Dysfunction in Pediatric Patients Years to Yearsof Age: Individualize thyroid function monitoring based on risk factorssuch as prematurity. (5.8). 5.1 Risks Associated with Inadvertent Intrathecal Administration. IOMERVU is for intra-arterialor intravenous use only and must not be administered intrathecally [see Dosage and Administration (2.1)]. Intrathecal administration, even if inadvertent, cancause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis,acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia,and brain edema.. 5.2 Hypersensitivity Reactions. IOMERVU can cause life-threatening or fatalhypersensitivity reactions including anaphylaxis. Manifestations includerespiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions (6.2)]. Most severe reactions develop shortly after the start of injection(e.g., within to minutes), but delayed reactions can occur. Thereis an increased risk in patients with history of previous reactionto contrast agents, and known allergic disorders (i.e., bronchialasthma, drug, or food allergies) or other hypersensitivities. Premedicationwith antihistamines or corticosteroids to minimize possible allergicreactions does not prevent serious life-threatening reactions, butmay reduce their incidence and severity.Obtain history of allergy, hypersensitivity,and hypersensitivity reactions to iodinated contrast agents. Alwayshave emergency resuscitation equipment and trained personnel availablebefore use of IOMERVU. Monitor all patients for hypersensitivity reactions.. 5.3 Acute Kidney Injury. Acute kidney injury, includingrenal failure, may occur after IOMERVU administration. Risk factorsinclude pre-existing renal impairment, dehydration, diabetes mellitus,heart failure, advanced vascular disease, advanced age, concomitantuse of nephrotoxic or diuretic medications, multiple myeloma or otherparaproteinemia, and repetitive or large doses of IOMERVU.Use the lowest necessary doseof IOMERVU in patients with renal impairment. Adequately hydrate patientsprior to and following IOMERVU administration. Do not use laxatives,diuretics, or preparatory dehydration prior to IOMERVU administration.. 5.4 Cardiovascular AdverseReactions. IOMERVU increases the circulatory osmotic load and may induce acuteor delayed hemodynamic disturbances in patients with heart failure,severely impaired renal function, combined renal and hepatic disease,or combined renal and cardiac disease, particularly when repetitiveor large doses are administered.Life-threatening or fatal cardiovascularreactions including hypotension, shock, and cardiac arrest have occurredwith the use of IOMERVU. Most deaths occur within 10 minutes of injection,with cardiovascular disease as the main underlying factor. Cardiacdecompensation, serious arrhythmias, and myocardial ischemia or infarctioncan occur during coronary arteriography and ventriculography.Based upon literature reports,deaths from the administration of iodinated contrast agents rangefrom 6.6 per million (0.00066 percent) to in 10,000 patients (0.01percent). Use the lowest necessary dose of IOMERVU in patients withheart failure and always have emergency resuscitation equipment andtrained personnel available. Monitor all patients for severe cardiovascularreactions.. 5.5 Thromboembolic Events. Serious, in some cases fatal,thromboembolic events including myocardial infarction and stroke canoccur during angiographic procedures with iodinated contrast agentsincluding IOMERVU. During these procedures, increased thrombosis andactivation of the complement system can occur. Risk factors for developingthromboembolic events include length of procedure, catheter and syringematerial, underlying disease state, and concomitant medications.To reduce risk of thromboembolicevents, use meticulous angiographic techniques and minimize the lengthof the procedure. Avoid blood remaining in contact with syringes containingIOMERVU, which increases the risk of clotting. Avoid angiocardiographyin patients with homocystinuria because of the risk of inducing thrombosisand embolism.. 5.6 Extravasation andInjection Site Reactions. Extravasation can occur with IOMERVU administration,particularly in patients with severe arterial or venous disease. Inflammation,blistering, skin necrosis, and compartment syndrome have been reportedfollowing extravasation. In addition, injection site reactions suchas pain and swelling at the injection site can also occur [see Adverse Reactions (6.1, 6.2)]. Ensure intravascular placementof catheters prior to injection. Monitor patients for extravasationand advise patients to seek medical care for progression of symptoms.. 5.7 Thyroid Storm inPatients with Hyperthyroidism. Thyroid storm has occurred after the intravascularuse of iodinated contrast agents in patients with hyperthyroidismor with an autonomously functioning thyroid nodule. Evaluate the riskin such patients before use of IOMERVU.. 5.8 Thyroid Dysfunctionin Pediatric Patients Years to Years of Age. Thyroid dysfunction characterizedby hypothyroidism or transient thyroid suppression has been reportedafter both single exposure and multiple exposures to iodinated contrastagents in pediatric patients years to years of age.Younger age, very low birth weight,prematurity, underlying medical conditions affecting thyroid function,admission to neonatal or pediatric intensive care units, and congenitalcardiac conditions are associated with an increased risk of hypothyroidismafter iodinated contrast agent exposure. Pediatric patients with congenitalcardiac conditions may be at greatest risk given that they often requirehigh doses of contrast during invasive cardiac procedures.An underactive thyroid duringearly life may be harmful for cognitive and neurological developmentand may require thyroid hormone replacement therapy. After exposureto IOMERVU, individualize thyroid function monitoring based on underlyingrisk factors, especially in term and preterm neonates.. 5.9 Hypertensive Crisisin Patients with Pheochromocytoma. Hypertensive crisis has occurred afterthe use of iodinated contrast agents in patients with pheochromocytoma.Closely monitor patients when administering IOMERVU if pheochromocytomaor catecholamine-secreting paragangliomas are suspected. Inject theminimum amount of IOMERVU necessary, assess blood pressure throughoutthe procedure, and have measures for treatment of hypertensive crisisreadily available.. 5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease. Iodinated contrast agents whenadministered intravascularly may promote sickling in individuals whoare homozygous for sickle cell disease. Hydrate patients prior toand following IOMERVU administration and use IOMERVU only if the necessaryimaging information cannot be obtained with alternative imaging modalities.. 5.11 Severe Cutaneous Adverse Reactions. Severe cutaneous adverse reactions (SCAR)may develop from hour to several weeks after intravascular contrastagent administration. These reactions include Stevens-Johnson syndromeand toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematouspustulosis (AGEP), and drug reaction with eosinophilia and systemicsymptoms (DRESS). Reaction severity may increase and time to onsetmay decrease with repeat administration of contrast agent; prophylacticmedications may not prevent or mitigate severe cutaneous adverse reactions.Avoid administering IOMERVU to patients with history of severecutaneous adverse reaction to IOMERVU.. 5.12 Interference with Laboratory Tests. IOMERVU can interfere with protein-boundiodine tests [see Drug Interactions (7.2)].