ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are describedin greater detail in other sections: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 to Years ofAge [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 to Years ofAge [see Warnings and Precautions (5.8)] Severe Cutaneous Adverse Reactions [see Warningsand Precautions (5.11)] Most common adverse reactions(incidence >1%) are pain, hot flashes, burning sensation, nausea,and warmth (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or 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 AdultsThe safety of ISOVUEwas evaluated in 2,246 adult patients receiving ISOVUE by intra-arterialor intravenous route in clinical studies. Table shows the commonadverse reactions (>1%).Table 4: Adverse Reactions Reported in >1% of PatientsReceiving Intra-arterial or Intravenous Injection of ISOVUE in ClinicalStudiesAdverseReactionISOVUE (N=2,246) %Pain2.8Hot flashes 1.5Burning sensation1.4Nausea1.2Warmth1.1The following adversereactions occurred in <= 1% of patients receiving intra-arterial orintravenous injection of ISOVUE:Cardiovascular disorders: tachycardia, hypotension, hypertension, myocardial ischemia, circulatorycollapse, S-T segment depression, bigeminy, extrasystoles, ventricularfibrillation, angina pectoris, bradycardia, transient ischemic attack,thrombophlebitisGastrointestinal disorders: vomiting, anorexiaGeneral disorders: headache, fever, chills, excessive sweating, back spasmNervous system disorders: vasovagal reaction, tingling in arms, grimace, faintnessRenal and urinary disorders: urinary retentionRespiratory: throat constriction, dyspnea, pulmonaryedemaSkinand subcutaneous tissues: rash, urticaria, pruritus, flushingSpecial senses: taste alterations, nasal congestion, visual disturbancesAdverse Reactions inPediatric PatientsIn clinical trial with 76 pediatric patientsundergoing angiocardiography, two adverse reactions (2.6%) were reported:worsening cyanosis and worsening peripheral perfusion.. 6.2 Postmarketing Experience. The following adverse reactionshave been identified during post approval use of ISOVUE. Because thereactions are reported voluntarily from population of uncertainsize, it is not always possible to reliably estimate their frequencyor to establish causal relationship to drug exposure.Blood and lymphatic systemdisorders: thrombocytopeniaCardiovascular disorders: cardiopulmonary arrest, cardiac decompensation, arrhythmias, myocardialinfarction, shock, electrocardiographic changes (e.g., increased QTc,increased R-R, increased T- wave amplitude), decreased systolic pressure,deep vein thrombosis, arterial spasms, vasodilation, chest pain, pallorEndocrine disorders: hyperthyroidism, hypothyroidismEye disorders: lacrimationincreased, conjunctivitis, eye pruritus, transient blindness, visualdisturbance, photophobiaGastrointestinal disorders: retching, abdominalpain, salivary hypersecretion, salivary gland enlargementGeneral disorders andadministration site conditions: injection site pain, malaiseImmune system disorders: anaphylaxis characterized by cardiovascular, respiratory, and cutaneousmanifestations (e.g., chest tightness, laryngeal edema, periorbitaledema, facial edema); delayed hypersensitivity reactions includinggeneralized maculopapular rash, erythema, pruritus, localized blistering,skin peelingMusculoskeletal disorders: compartment syndrome followingextravasation, muscle spasm, musculoskeletal pain, muscular weaknessNervous system disorders: coma, seizure, tremors, syncope, depressed level of consciousnessor loss of consciousness, encephalopathyPsychiatric disorders: confusionalstateRespiratorysystem disorders: respiratory arrest, respiratory failure,acute respiratory distress syndrome, respiratory distress, apnea,asthma, sneezing, choking, laryngeal edema, bronchospasm, rhinitisSkin and subcutaneoustissue disorders: Stevens-Johnson syndrome and toxic epidermalnecrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP),erythema multiforme and drug reaction with eosinophilia and systemicsymptoms (DRESS), skin necrosis, face edema.

BOXED WARNING SECTION.

WARNING: RISKS ASSOCIATED WITH INTRATHECAL ADMINISTRATION. Intrathecal administration,even if inadvertent, can cause death, convulsions, cerebral hemorrhage,coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest,seizures, rhabdomyolysis, hyperthermia, and brain edema [seeWarnings and Precautions (5.1)]. ISOVUE is for intra-arterial or intravenous use only [seeDosage and Administration (2.1)]... WARNING: RISKS ASSOCIATEDWITH INTRATHECAL ADMINISTRATIONIntrathecal administration,even if inadvertent, can cause death, convulsions, cerebral hemorrhage,coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest,seizures, rhabdomyolysis, hyperthermia, and brain edema. ISOVUE isfor intra-arterial or intravenous use only. (5.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Intravascular injection of iopamidol opacifies those vessels where the contrast agent is present, permitting radiographic visualization through attenuation of photons.In imaging of the body, iodinated contrast agents diffuse from the vessels into the extravascular space. In normal brain with an intact blood-brain barrier, contrast does not diffuse into the extravascular space. In patients with disrupted blood-brain barrier, contrast agent accumulates in the extravascular space in the region of disruption.. 12.2 Pharmacodynamics. Following administration of ISOVUE,the degree of enhancement is related to the iodine concentration inthe tissue of interest. However, the exposure-response relationshipsand time course of pharmacodynamic response of iopamidol have notbeen fully characterized.. 12.3 Pharmacokinetics. DistributionPlasma concentrations of iodine fall within to 10 minutes due to distribution into the vascular and extracellular fluid compartments. Equilibration with the extracellular compartments is reached in about 10 minutes.The apparent volume of distribution suggests that iopamidol is distributed evenly between blood and extracellular fluid. Iopamidol may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous administration. Iopamidol did not bind to serum or plasma proteins at hour after administration.EliminationThe plasma half-life is approximately hours; the half-life is not dose dependent.MetabolismIopamidol does not undergo significant metabolism, deiodination, or biotransformation.ExcretionIopamidol is excreted primarily through the kidneys. In patients with normal renal function, the cumulative urinary excretion for iopamidol, expressed as percentage of administered intravenous dose, is approximately 35% to 40% at 60 minutes, 80% to 90% at hours, and 90% or greater in the 72- to 96- hour period after administration. In patients with normal renal function, approximately 1% or less of the administered dose appears in cumulative 72- to 96-hour fecal samples.

CLINICAL STUDIES SECTION.

7 DRUG INTERACTIONS. 7.1 Drug-Drug Interactions. MetforminIn patients with renal impairment,metformin can cause lactic acidosis. Iodinated contrast agents appearto increase the risk of metformin-induced lactic acidosis, possiblyas result of worsening renal function. Stop metformin at the timeof, or prior to, ISOVUE administration in patients with an eGFR between30 and 60 mL/min/1.73 m2; in patients witha history of hepatic impairment, alcoholism, or heart failure; orin patients who will be administered intra-arterial iodinated contrastagents. Re-evaluate eGFR 48 hours after the imaging procedure andreinstitute metformin use only after renal function is stable.Radioactive IodineAdministration ofISOVUE may interfere with thyroid uptake of radioactive iodine (I-131and I-123) and decrease therapeutic and diagnostic efficacy. Avoidthyroid therapy or testing for up to weeks post ISOVUE.. 7.2 Drug-Laboratory TestInteractions. Protein-Bound Iodine TestIodinated contrast agents, including ISOVUE,will temporarily increase protein-bound iodine in blood. Avoid protein-boundiodine test for at least 16 days following administration of ISOVUE.However, thyroid function tests that do not depend on iodine estimations,e.g., triiodothyronine (T3) resin uptake andtotal or free thyroxine (T4) assays are notaffected.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. ISOVUE (iopamidol) injectionis radiographic contrast agent for intra-arterial or intravenoususe.Iopamidol isdesignated chemically as (S)-N,N-bis[2-hydroxy-1-(hydroxymethyl)-ethyl]-2,4,6-triiodo-5-lactamidoisophthalamide with molecular weight of 777.09, an empiricalformula of C17H22I3N3O8, and the following structural formula:ISOVUE is sterile, clear, colorless topale yellow solution available in four concentrations of iodine:ISOVUE 200 mg iodine/mL: Each mL contains 408 mg iopamidol(providing 200 mg organically bound iodine) and the following inactiveingredients: 0.26 mg edetate calcium disodium (providing 0.029 mg(0.001 mEq) sodium) and mg tromethamine.ISOVUE 250 mg iodine/mL: Each mL contains 510 mg iopamidol(providing 250 mg organically bound iodine) and the following inactiveingredients: 0.33 mg edetate calcium disodium (providing 0.036 mg(0.002 mEq) sodium) and mg tromethamine.ISOVUE 300 mg iodine/mL: Each mL contains 612 mg iopamidol(providing 300 mg organically bound iodine) and the following inactiveingredients: 0.39 mg edetate calcium disodium (providing 0.043 mg(0.002 mEq) sodium) and mg tromethamine.ISOVUE 370 mg iodine/mL: Each mL contains 755 mg iopamidol(providing 370 mg organically bound iodine) and the following inactiveingredients: 0.48 mg edetate calcium disodium (providing 0.053 mg(0.002 mEq) sodium) and mg tromethamine.The pH of ISOVUE hasbeen adjusted to 6.5 to 7.5 with hydrochloric acid and/or sodium hydroxide.Physicochemical characteristicsare shown in Table 5. ISOVUE is hypertonic as compared to plasma andcerebrospinal fluid (approximately 285 and 301 mOsm/kg water, respectively).Table 5: Physicochemical Characteristics of ISOVUEConcentration (mg Iodine/mL) 200250300370Osmolality 37C (mOsm/kg water) 413524616796Viscosity (cP) 37C2.03.04.79.4Viscosity (cP) 20C3.35.18.820.9Specific Gravity 37C1.2271.2811.3391.405. ISOVUE 200 mg iodine/mL: Each mL contains 408 mg iopamidol(providing 200 mg organically bound iodine) and the following inactiveingredients: 0.26 mg edetate calcium disodium (providing 0.029 mg(0.001 mEq) sodium) and mg tromethamine.. ISOVUE 250 mg iodine/mL: Each mL contains 510 mg iopamidol(providing 250 mg organically bound iodine) and the following inactiveingredients: 0.33 mg edetate calcium disodium (providing 0.036 mg(0.002 mEq) sodium) and mg tromethamine.. ISOVUE 300 mg iodine/mL: Each mL contains 612 mg iopamidol(providing 300 mg organically bound iodine) and the following inactiveingredients: 0.39 mg edetate calcium disodium (providing 0.043 mg(0.002 mEq) sodium) and mg tromethamine.. ISOVUE 370 mg iodine/mL: Each mL contains 755 mg iopamidol(providing 370 mg organically bound iodine) and the following inactiveingredients: 0.48 mg edetate calcium disodium (providing 0.053 mg(0.002 mEq) sodium) and mg tromethamine.. iopamidol-structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Individualize the volume and concentration according tothe specific dosing tables accounting for factors such as age, bodyweight, size of the vessel, and the rate of blood flow within thevessel. (2.2, 2.3, 2.4)See full prescribing information for important dosage andadministration information. (2.1). Individualize the volume and concentration according tothe specific dosing tables accounting for factors such as age, bodyweight, size of the vessel, and the rate of blood flow within thevessel. (2.2, 2.3, 2.4). See full prescribing information for important dosage andadministration information. (2.1). 2.1 Important Dosingand Administration Information. ISOVUE is for intra-arterial or intravenous use only andmust not be administered intrathecally [see Warnings and Precautions(5.1)].Specific concentrations of ISOVUE are recommended for eachtype of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4)].Individualize the volume, concentration, and injection rateof ISOVUE according to the specific dosing tables [see Dosageand Administration (2.2, 2.3, 2.4)]. Consider factors such as: age, body weight, blood vesselsize and blood flow rate, anticipated pathology and degree and extentof opacification required, structures or area to be examined, concomitantmedical conditions, imaging equipment, and technique to be employed.Hydrate patients before and after ISOVUE administration [see Warnings and Precautions (5.3)].Use aseptic technique for all handling and administrationof ISOVUE.ISOVUE may be administered at either body temperature (37C,98.6F) or room temperature (20C to 25C, 68F to 77F).Visually inspect ISOVUE for particulate matter or discolorationbefore administration. Do not administer ISOVUE if particulate matteror discolorations are observed.Do not mix ISOVUE with other drugs or inject in intravenouslines containing other drugs or total nutritional admixtures. ISOVUE single-dose containers are intended for one procedureonly. Discard any unused portion.. ISOVUE is for intra-arterial or intravenous use only andmust not be administered intrathecally [see Warnings and Precautions(5.1)].. Specific concentrations of ISOVUE are recommended for eachtype of imaging procedure [see Dosage and Administration (2.2, 2.3, 2.4)].. Individualize the volume, concentration, and injection rateof ISOVUE according to the specific dosing tables [see Dosageand Administration (2.2, 2.3, 2.4)]. Consider factors such as: age, body weight, blood vesselsize and blood flow rate, anticipated pathology and degree and extentof opacification required, structures or area to be examined, concomitantmedical conditions, imaging equipment, and technique to be employed.. Hydrate patients before and after ISOVUE administration [see Warnings and Precautions (5.3)].. Use aseptic technique for all handling and administrationof ISOVUE.. ISOVUE may be administered at either body temperature (37C,98.6F) or room temperature (20C to 25C, 68F to 77F).. Visually inspect ISOVUE for particulate matter or discolorationbefore administration. Do not administer ISOVUE if particulate matteror discolorations are observed.. Do not mix ISOVUE with other drugs or inject in intravenouslines containing other drugs or total nutritional admixtures. ISOVUE single-dose containers are intended for one procedureonly. Discard any unused portion.. 2.2 Recommended Dosage for Intra-arterial Procedures in Adults. The recommended doses for intra-arterial procedures in adults are shown in Table 1.Table 1: Recommended Concentrations and Volumes of ISOVUE for Intra-arterial Procedures in AdultsImaging ProcedureConcentration (mg Iodine/mL)Volume to Administer per Single Injection for Selected Injection SitesMaximum Cumulative Total DoseCerebral Arteriography3008 mL to 12 mL by carotid puncture or transfemoral catheterization90 mLPeripheral Arteriography3005 mL to 40 mL into the femoral artery or subclavian artery25 mL to 50 mL into the aorta for distal runoff250 mLSelective Visceral Arteriography and Aortography370Up to 10 mL for the renal arteriesUp to 50 mL into the larger vessels such as the aorta or celiac artery225 mLCoronary Arteriography and Cardiac Ventriculography3702 mL to 10 mL for selective coronary artery injection25 mL to 50 mL for cardiac ventriculography or for nonselective opacification of multiple coronary arteries following injection at the aortic root200 mL. mL to 40 mL into the femoral artery or subclavian artery. 25 mL to 50 mL into the aorta for distal runoff. Up to 10 mL for the renal arteries. Up to 50 mL into the larger vessels such as the aorta or celiac artery. mL to 10 mL for selective coronary artery injection. 25 mL to 50 mL for cardiac ventriculography or for nonselective opacification of multiple coronary arteries following injection at the aortic root. 2.3 Recommended Dosagefor Intravenous Procedures in Adults. The recommended doses for intra-arterial proceduresin adults are shown in Table 2.Table 2: Recommended Concentrations and Volumes ofISOVUE for Intravenous Procedures in AdultsImaging ProcedureConcentration (mg Iodine/mL) Volume to AdministerExcretory Urography25050 mL to 100 mL by rapid injection30050 mL by rapid injection37040 mL by rapid injectionCT of the Head250130 mL to 240 mL300100 mL to 200 mLCT of the Body250130 mL to 240 mL by rapid infusion or bolus injection300100 mL to 200 mL by rapid infusion or bolus injection37080 mL to 160 mL by rapid infusion or bolus injectionPeripheral Venography20025 mL to 150 mL per lower extremity; the maximum total dose is350 mL. 2.4 Recommended Dosage in Pediatric Patients. The recommended doses in pediatricpatients are shown in Table 3.Table 3: Recommended Concentrations and Volumes perBody Weight of ISOVUE for Intra- arterial and Intravenous Proceduresin Pediatric PatientsImagingProcedureConcentration(mg Iodine/mL) Volumeper Body Weight to AdministerMaximumDoseIntra-arterialProceduresAngiocardiography3700.5 mL/kg to 2mL/kg per single injectionMaximum CumulativeDose by WeightNeonates: mL/kgAged weeks and older: mL/kgDo not exceed maximum cumulative doses by age below.Maximum CumulativeDose by Age<2 years 40 mL2 years to years 50 mL5 years to years 100 mL10 years to 18 years 125 mLIntravenousProceduresExcretory Urography2501.2 mL/kg to 3.6 mL/kg120 mL3001 mL/kg to mL/kg100 mLCT of the Headand Body2501.2 mL/kg to 3.6 mL/kg120 mL3001 mL/kg to mL/kg100 mL. Neonates: mL/kg. Aged weeks and older: mL/kg. Do not exceed maximum cumulative doses by age below.. <2 years 40 mL. years to years 50 mL. years to years 100 mL. 10 years to 18 years 125 mL.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: Clear, colorlessto pale yellow solution available in the following concentrationsof iodine:Concentration (mg Iodine/mL)Package Size Package Type200200 mLSingle-Dose Bottle250100 mLSingle-Dose Bottle30030 mL and 50 mLSingle-Dose Vial100 mL and 150 mLSingle-Dose Bottle37050 mLSingle-Dose Vial75 mL, 100 mL, 125 mL, and 150mL Single-Dose Bottle. Injection: 200 mg Iodine/mL,250 mg Iodine/mL, 300 mg Iodine/mL, and 370 mg Iodine/mL in single-dosevials or bottles(3).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedISOVUE (iopamidol) injection is clear, colorless to pale yellow solution available in the following presentations:Concentration (mg Iodine/mL) Package SizePackage Type Sale UnitNDC200200 mLSingle-Dose Bottle Carton of 10 0270-1314-15250100 mLSingle-Dose Bottle Carton of 10 0270-1317-0230030 mL Single-Dose VialCarton of 10 0270-1315-2550 mLSingle-Dose VialCarton of 10 0270-1315-30100 mLSingle-Dose Bottle Carton of 10 0270-1315-35150 mLSingle-Dose Bottle Carton of 10 0270-1315-5037050 mLSingle-Dose VialCarton of 10 0270-1316-3075 mLSingle-Dose Bottle Carton of 10 0270-1316-52100 mLSingle-Dose Bottle Carton of 10 0270-1316-35125 mLSingle-Dose Bottle Carton of 10 0270-1316-04150 mLSingle-Dose Bottle Carton of 10 0270-1316-37Storage and HandlingStore at 20C to 25C (68F to 77F) [See USP controlled room temperature]. Protect from light.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ISOVUE is radiographic contrast agent indicated for:Intra-arterial Procedures (1.1)Cerebral arteriography in adultsPeripheral arteriography in adultsSelective visceral arteriography and aortography in adultsCoronary arteriography and cardiac ventriculography in adultsAngiocardiography in pediatric patientsIntravenous Procedures+ (1.2)Excretory urography in adults and pediatric patientsComputed tomography (CT) of head and body in adults and pediatric patientsPeripheral venography in adults+Specific concentrations are recommended for each type of imaging procedure. (2.2, 2.3, 2.4). Cerebral arteriography in adults. Peripheral arteriography in adults. Selective visceral arteriography and aortography in adults. Coronary arteriography and cardiac ventriculography in adults. Angiocardiography in pediatric patients. Excretory urography in adults and pediatric patients. Computed tomography (CT) of head and body in adults and pediatric patients. Peripheral venography in adults. 1.1 Intra-arterial Procedures+ ISOVUE is indicated for:Cerebral arteriography in adultsPeripheral arteriography in adultsSelective visceral arteriography and aortography in adultsCoronary arteriography and cardiac ventriculography in adultsAngiocardiography in pediatric patients. Cerebral arteriography in adults. Peripheral arteriography in adults. Selective visceral arteriography and aortography in adults. Coronary arteriography and cardiac ventriculography in adults. Angiocardiography in pediatric patients. 1.2 Intravenous Procedures+ ISOVUE is indicated for:Excretory urography in adults and pediatric patientsComputerized tomography (CT) of the head and body in adultsand pediatric patientsPeripheral venography in adults+Specific concentrations of ISOVUE are recommended for each type ofimaging procedure [see Dosage and Administration (2.2, 2.3, 2.4)].. Excretory urography in adults and pediatric patients. Computerized tomography (CT) of the head and body in adultsand pediatric patients. Peripheral venography in adults.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Hypersensitivity ReactionsAdvise the patientconcerning the risk of hypersensitivity reactions that can occur bothduring and after ISOVUE administration. Advise the patient to reportany signs or symptoms of hypersensitivity reactions during the procedureand to seek immediate medical attention for any signs or symptomsexperienced after discharge [see Warnings and Precautions(5.2)]. Advise patients to inform their physicianif they develop rash after receiving ISOVUE [see Warningsand Precautions (5.11)]. AcuteKidney InjuryAdvise the patient concerning appropriate hydration to decrease therisk of contrast induced kidney injury [see Warnings and Precautions(5.3)]. ExtravasationIf extravasation occurs duringinjection, advise patients to seek medical care for progression ofsymptoms [see Warnings and Precautions (5.6)]. Thyroid DysfunctionAdvise parents/caregivers about the risk ofdeveloping thyroid dysfunction after ISOVUE administration. Adviseparents/caregivers about when to seek medical care for their childto monitor for thyroid function [see Warnings and Precautions(5.8)]. LactationAdvise lactating woman thatinterruption of breastfeeding is not necessary, however, to minimizeexposure to breastfed infant, lactating woman may consider pumpingand discarding breast milk for 10 hours after ISOVUE administration [see Use in Specific Populations (8.2)]. Manufactured for:Bracco DiagnosticInc.Monroe Township, NJ 08831 Manufacturedby: BIPSO GmbH78224 Singen (Germany) ISOVUE is registered trademark of Bracco DiagnosticsInc.RevisedDecember 2024.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility. Long-term studies in animals have not beenperformed with iopamidol to evaluate carcinogenic potential. No evidenceof genetic toxicity was obtained in in vitro tests.In animal reproduction studies performed on rats, intravenously administerediopamidol did not induce adverse effects on fertility or general reproductiveperformance.

OVERDOSAGE SECTION.

10 OVERDOSAGE. The manifestations of overdosage are life-threatening and affectmainly the pulmonary and cardiovascular systems. Treatment of an overdoseis directed toward support of all vital functions and the prompt institutionof symptomatic therapy. Iopamidol can be removed by dialysis.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Isovue 200: 200mL vial labelNDC 0270-1314-15. Isovue-200 Bottle 200 ml.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published literatureand postmarketing cases from decades of use with iopamidol duringpregnancy have not identified drug-associated risk of major birthdefects, miscarriage, or other adverse maternal or fetal outcomes.Iopamidol crosses the placenta and reaches fetal tissues in smallamounts (see Data ). Inanimal reproduction studies, no adverse developmental outcomes wereobserved with intravenous administration of iopamidol to pregnantrats and rabbits during organogenesis at doses up to 2.7 and 1.4 times,respectively, the maximum recommended human dose (see Data ).The background risk of major birth defectsand miscarriage for the indicated population is unknown. All pregnancieshave background risk of birth defect, loss, or other adverse outcomes.In the U.S. general population, the estimated background risk of majorbirth defects and miscarriage in clinically recognized pregnanciesis to 4% and 15 to 20%, respectively.DataHuman DataLiterature reports show that intravenouslyadministered iopamidol crosses the placenta and is visualized in thedigestive tract of exposed infants after birth.Animal DataIopamidol did not affect fetaldevelopment and did not induce teratogenic changes in the offspringin either rats or rabbits at the following dose levels tested: 600mg, 1,500 mg, or 4,000 mg iodine/kg in rats, administered intravenouslyonce day during days through 15 of pregnancy; 300 mg, 800 mg,or 2,000 mg iodine/kg in rabbits, administered intravenously oncea day during days through 18 of pregnancy.

SPL UNCLASSIFIED SECTION.

1.1 Intra-arterial Procedures+ ISOVUE is indicated for:Cerebral arteriography in adultsPeripheral arteriography in adultsSelective visceral arteriography and aortography in adultsCoronary arteriography and cardiac ventriculography in adultsAngiocardiography in pediatric patients. Cerebral arteriography in adults. Peripheral arteriography in adults. Selective visceral arteriography and aortography in adults. Coronary arteriography and cardiac ventriculography in adults. Angiocardiography in pediatric patients.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: lactating woman maypump and discard breast milk for 10 hours after ISOVUE administration.(8.2) 8.1 Pregnancy. Risk SummaryAvailable data from published literatureand postmarketing cases from decades of use with iopamidol duringpregnancy have not identified drug-associated risk of major birthdefects, miscarriage, or other adverse maternal or fetal outcomes.Iopamidol crosses the placenta and reaches fetal tissues in smallamounts (see Data ). Inanimal reproduction studies, no adverse developmental outcomes wereobserved with intravenous administration of iopamidol to pregnantrats and rabbits during organogenesis at doses up to 2.7 and 1.4 times,respectively, the maximum recommended human dose (see Data ).The background risk of major birth defectsand miscarriage for the indicated population is unknown. All pregnancieshave background risk of birth defect, loss, or other adverse outcomes.In the U.S. general population, the estimated background risk of majorbirth defects and miscarriage in clinically recognized pregnanciesis to 4% and 15 to 20%, respectively.DataHuman DataLiterature reports show that intravenouslyadministered iopamidol crosses the placenta and is visualized in thedigestive tract of exposed infants after birth.Animal DataIopamidol did not affect fetaldevelopment and did not induce teratogenic changes in the offspringin either rats or rabbits at the following dose levels tested: 600mg, 1,500 mg, or 4,000 mg iodine/kg in rats, administered intravenouslyonce day during days through 15 of pregnancy; 300 mg, 800 mg,or 2,000 mg iodine/kg in rabbits, administered intravenously oncea day during days through 18 of pregnancy.. 8.2 Lactation. Risk SummaryThere are no dataon the presence of iopamidol in human milk, the effects on the breastfedinfant, or the effects on milk production. Iodinated contrast agentsare present unchanged in human milk in very low amounts, with poorabsorption from the gastrointestinal tract of breastfed infant.The developmental and health benefits of breastfeeding should be consideredalong with the mothers clinical need for ISOVUE and any potentialadverse effects on the breastfed infant from ISOVUE 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 half- lives) after ISOVUEadministration in order to minimize drug exposure to breastfed infant.. 8.4 Pediatric Use. The safety and effectivenessof ISOVUE have been established in pediatric patients for angiocardiography,excretory urography, and contrast computed tomography (head and body).Pediatric patients at higherrisk of experiencing adverse reactions during and after contrast mediumadministration may include those having asthma, sensitivity to medicationor allergens, cyanotic heart disease, congestive heart failure, orserum creatinine greater than 1.5 mg/dL, or those less than 12 monthsof age.Thyroid functiontests indicative of thyroid dysfunction, characterized by hypothyroidismor transient thyroid suppression have been reported following iodinatedcontrast media administration in pediatric patients, including termand preterm neonates; some patients were treated for hypothyroidism.After exposure to iodinated contrast media, individualize thyroidfunction monitoring in pediatric patients years to years of agebased on underlying risk factors, especially in term and preterm neonates [see Warning and Precautions (5.8) and Adverse Reactions (6.2)]. The safety and effectivenessof ISOVUE for cerebral, peripheral, and selective visceral arteriography,aortography, coronary arteriography, cardiac ventriculography, andperipheral venography have not been established in pediatric patients.. 8.5 Geriatric Use. Iopamidol is excreted by the kidney, andthe risk of adverse reactions to ISOVUE may be greater in patientswith renal impairment. Because patients 65 years of age and olderare more likely to have renal impairment, care should be taken indose selection, and it may be useful to monitor renal function [see Warnings and Precautions (5.3) and Use in Specific Populations [8.6]). 8.6 Renal Impairment. The clearance of iopamidol decreaseswith increasing degree of renal impairment and results in delayedopacification of the urinary system. In addition, preexisting renalimpairment increases the risk for acute kidney injury [seeWarnings and Precautions (5.3)]. Iopamidol can be removed by dialysis.

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. Use the lowest dose and maintain adequate hydration tominimize risk. (5.3)Cardiovascular Adverse Reactions: Hemodynamic disturbancesincluding shock and cardiac arrest may occur during or after ISOVUEadministration. (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. Use the lowest dose and maintain adequate hydration tominimize risk. (5.3). Cardiovascular Adverse Reactions: Hemodynamic disturbancesincluding shock and cardiac arrest may occur during or after ISOVUEadministration. (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 Intrathecal Administration. Intrathecal administration,even if inadvertent, can cause death, convulsions, cerebral hemorrhage,coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest,seizures, rhabdomyolysis, hyperthermia, and brain edema. ISOVUE isfor intra-arterial or intravenous use only and must not be administeredintrathecally [see Dosage and Administration (2.1)].. 5.2 HypersensitivityReactions. ISOVUE can cause life-threatening or fatal hypersensitivity reactionsincluding anaphylaxis. Manifestations include respiratory arrest,laryngospasm, bronchospasm, angioedema, and shock [see AdverseReactions (6.2)]. Most severereactions develop shortly after the start of injection (e.g., within1 to minutes), but delayed reactions can also occur. There is increasedrisk of hypersensitivity reactions in patients with history of previousreactions to contrast agents, and allergic disorders (i.e., bronchialasthma, allergic rhinitis, and food allergies) or other hypersensitivities.Premedication with antihistaminesor corticosteroids to avoid or minimize possible allergic reactionsdoes not prevent serious life-threatening reactions but may reduceboth their incidence and severity. Obtain history of allergy, hypersensitivity,or hypersensitivity reactions to iodinated contrast agents and alwayshave emergency resuscitation equipment and trained personnel availableprior to ISOVUE administration. Monitor all patients for hypersensitivityreactions.. 5.3 Acute Kidney Injury. Acute kidney injury, including renal failure,may occur after ISOVUE administration. Risk factors include: pre-existingrenal insufficiency, dehydration, diabetes mellitus, congestive heartfailure, advanced vascular disease, elderly age, concomitant use ofnephrotoxic or diuretic medications, multiple myeloma or other paraproteinemias,and repetitive or large doses of ISOVUE.Use the lowest necessary dose of ISOVUEin patients with renal impairment. Adequately hydrate patients priorto and following ISOVUE administration. Do not use laxatives, diuretics,or preparatory dehydration prior to ISOVUE administration.. 5.4 Cardiovascular Adverse Reactions. ISOVUE increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, and combined renal and cardiac disease, particularly when repetitive or large doses are administered. Fatal cardiovascular reactions have occurred mostly within 10 minutes of ISOVUE injection; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Hypotensive collapse and shock have occurred. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography.The administration of ISOVUE may cause pulmonary edema in patients with heart failure. Based upon published reports, deaths associated with the administration of iodinated contrast agents range from 6.6 per million (0.00066 percent) to in 10,000 patients (0.01 percent). Use the lowest necessary dose of ISOVUE in patients with congestive heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions.. 5.5 Thromboembolic Events. Serious, in some cases fatal, thromboembolic events, including myocardial infarction and stroke, can occur during angiographic procedures. During these procedures, increased thrombosis and activation of the complement system occurs. Risk factors for developing thromboembolic events include: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications.To minimize thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing iodinated contrast agents, which increases risk of clotting. Avoid angiocardiography in patients with homocystinuria because of the risk of inducing thrombosis and embolism.. 5.6 Extravasation and Injection Site Reactions. Extravasation can occur with ISOVUE administration, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur [see Adverse Reactions (6.2)]. Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and 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 agents in patients with hyperthyroidism or with anautonomously functioning thyroid nodule. Evaluate the risk in suchpatients before use of ISOVUE.. 5.8 Thyroid Dysfunction in Pediatric Patients Years to Years of Age. Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast agents 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 congenital cardiac conditions are associated with an increased risk of hypothyroidism after iodinated contrast agent exposure. Pediatric patients with congenital cardiac conditions may be at greatest risk given that they often require high doses of contrast during invasive cardiac procedures.An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to iodinated contrast agents, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.. 5.9 Hypertensive Crisisin Patients with Pheochromocytoma. Hypertensive crisis in patients with pheochromocytomahas occurred with iodinated contrast agents. Closely monitor patientswhen administering ISOVUE if pheochromocytoma or catecholamine-secretingparagangliomas are suspected. Inject the minimum amount of ISOVUEnecessary and have measures for treatment of hypertensive crisis readilyavailable.. 5.10 Sickle Cell Crisisin Patients with Sickle Cell Disease. Iodinated contrast agents can promote sicklingin individuals who are homozygous for sickle cell disease. Hydratepatients prior to and following ISOVUE administration and use onlyif the necessary imaging information cannot be obtained with alternativeimaging modalities.. 5.11 Severe CutaneousAdverse 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 ISOVUE to patients with history of severecutaneous adverse reaction to ISOVUE.. 5.12 Interference withLaboratory Tests. ISOVUE can interfere with protein-boundiodine test [see Drug Interactions (7.2)].

DRUG ABUSE AND DEPENDENCE SECTION.

2.6 Directions for Dilution of ISOVUE for Oral Administration. Dilute ISOVUE to mg iodine/mL or mg iodine/mL in water or clear liquids such as apple juice according to Table 5.Use diluted ISOVUE immediately.Discard any unused portion after the procedure.Table 5: Volumes of ISOVUE and Added Liquid to Dilute ISOVUE for Oral Administration for CT of the Abdomen and PelvisUse water or clear liquids such as apple juice.Final Concentration of Diluted ISOVUE (mg Iodine/mL)ISOVUEVolume of Added Liquid (mL)Concentration (mg Iodine/mL)Volume (mL)620030970250249763002098037016984920045955250369643003097037024976. Dilute ISOVUE to mg iodine/mL or mg iodine/mL in water or clear liquids such as apple juice according to Table 5.. Use diluted ISOVUE immediately.. Discard any unused portion after the procedure.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Indications and Usage, Oral Procedures (1.3)10/2025Dosage and AdministrationRecommended Dosage for Oral Procedures in Pediatric Patients and Adults (2.5)Directions for Dilution of ISOVUE for Oral Administration (2.6) 10/2025. Recommended Dosage for Oral Procedures in Pediatric Patients and Adults (2.5). Directions for Dilution of ISOVUE for Oral Administration (2.6).

REFERENCES SECTION.

2.5 Recommended Dosage for Oral Procedures in Pediatric Patients and Adults. The recommended concentration of diluted ISOVUE is either mg iodine/mL or mg iodine/mL administered orally as shown in Table 4.See Table for dilution instructions of ISOVUE [see Dosage and Administration (2.6)] Table 4: Recommended Volumes of Diluted ISOVUE for Oral Administration for CT of the Abdomen and Pelvis in Pediatric Patients and Adults Prepare diluted ISOVUE solution to concentration of either mg iodine/mL or mg iodine/mL according to Table [see Dosage and Administration (2.6)]. AgeVolume of Diluted ISOVUE to AdministerAdministration InstructionsPediatric patients less than years of age50 mL to 300 mLAdminister the oral dose approximately 60 minutes before beginning the CT procedure.Pediatric patients years to years of age300 mL to 360 mLPediatric patients years to 11 years of age360 mL to 500 mLPediatric patients 12 years of age and older500 mL to 1,000 mLAdults. The recommended concentration of diluted ISOVUE is either mg iodine/mL or mg iodine/mL administered orally as shown in Table 4.. See Table for dilution instructions of ISOVUE [see Dosage and Administration (2.6)].