PRECAUTIONS SECTION.

PRECAUTIONS. General. Diagnostic procedureswhich involve the use of any radiopaque agent should be carried outunder the direction of personnel with the prerequisite training andwith thorough knowledge of the particular procedure to be performed.Appropriate facilities should be available for coping with any complicationof the procedure, as well as for emergency treatment of severe reactionto the contrast agent itself. After parenteral administration of aradiopaque agent, competent personnel and emergency facilities shouldbe available for at least 30 to 60 minutes since severe delayed reactionsmay occur. Caution should be exercised in hydrating patients withunderlying conditions that may be worsened by fluid overload, suchas congestive heart failure.Diabetic nephropathy may predispose to acute renal impairment followingintravascular contrast media administration. Acute renal impairmentfollowing contrast media administration may precipitate lactic acidosisin patients who are taking biguanides.The administration of iodinated contrast media mayaggravate the symptoms of myasthenia gravis.Preparatory dehydration is dangerous and may contributeto acute renal failure in patients with advanced vascular disease,diabetic patients, and in susceptible nondiabetic patients (oftenelderly with preexisting renal disease). Patients should bewell hydrated prior to and following iopamidol administration. The possibility of reaction, including serious, life-threatening,fatal, anaphylactoid or cardiovascular reactions, should always beconsidered (see ADVERSE REACTIONS). Patients at increased risk include those with history of previousreaction to contrast medium, patients with known sensitivity toiodine per se, and patients with known clinical hypersensitivity(bronchial asthma, hay fever, and food allergies). The occurrenceof severe idiosyncratic reactions has prompted the use of severalpretesting methods. However, pretesting cannot be relied upon to predictsevere reactions and may itself be hazardous for the patient. It issuggested that thorough medical history with emphasis on allergyand hypersensitivity, prior to the injection of any contrast medium,may be more accurate than pretesting in predicting potential adversereactions. positive history of allergies or hypersensitivity doesnot arbitrarily contraindicate the use of contrast agent where adiagnostic procedure is thought essential, but caution should be exercised.Premedication with antihistamines or corticosteroids to avoid or minimizepossible allergic reactions in such patients should be considered.Recent reports indicate that such pretreatment does not prevent seriouslife-threatening reactions but may reduce both their incidence andseverity.Pre-existing conditions,such as pacemakers or cardiac medications, specifically beta-blockers,may mask or alter the signs or symptoms of an anaphylactoid reaction,as well as masking or altering the response to particular medicationsused for treatment. For example, beta-blockers inhibit tachycardiacresponse, and can lead to the incorrect diagnosis of vasovagal ratherthan an anaphylactoid reaction. Special attention to this possibilityis particularly critical in patients suffering from serious, life-threateningreactions.General anesthesiamay be indicated in the performance of some procedures in selectedpatients; however, higher incidence of adverse reactions has beenreported with radiopaque media in anesthetized patients, which maybe attributable to the inability of the patient to identify untowardsymptoms, or to the hypotensive effect of anesthesia which can reducecardiac output and increase the duration of exposure to the contrastagent.Even though the osmolalityof iopamidol is low compared to diatrizoate or iothalamate based ionicagents of comparable iodine concentration, the potential transitoryincrease in the circulatory osmotic load in patients with congestiveheart failure requires caution during injection. These patients shouldbe observed for several hours following the procedure to detect delayedhemodynamic disturbances. Injection site pain and swelling may occur.In the majority of cases it is due to extravasation of contrast medium.Reactions are usually transient and recover without sequelae. However,inflammation and even skin necrosis have been seen on very rare occasions.In angiographic procedures, the possibilityof dislodging plaques or damaging or perforating the vessel wall,or inducing vasospasm, and or subsequent ischemic events, should beborne in mind during catheter manipulations and contrast medium injection.Test injections to ensure proper catheter placement are suggested.Selective coronary arteriography shouldbe performed only in selected patients and those in whom the expectedbenefits outweigh the procedural risk. The inherent risks of angiocardiographyin patients with pulmonary hypertension must be weighed against thenecessity for performing this procedure. Angiography should be avoidedwhenever possible in patients with homocystinuria, because of therisk of inducing thrombosis and embolism. See also Pediatric Use.In addition to the general precautions previously described,special care is required when venography is performed in patientswith suspected thrombosis, phlebitis, severe ischemic disease, localinfection or totally obstructed venous system. Extreme caution duringinjection of contrast media is necessary to avoid extravasation andfluoroscopy is recommended. This is especially important in patientswith severe arterial or venous disease.. Information for Patients. Patients receiving injectable radiopaque diagnosticagents should be instructed to:Inform your physician if you are pregnant.Inform your physician if you are diabetic or if you havemultiple myeloma, pheochromocytoma, homozygous sickle cell disease,or known thyroid disorder (see WARNINGS).Inform your physician if you are allergic to any drugs,food, or if you had any reactions to previous injections of substancesused for x-ray procedures (see PRECAUTIONS-General).Inform your physician about any other medications you arecurrently taking, including nonprescription drugs, before you havethis procedure.Advise patients to inform their physician if they developa rash after receiving Isovue.. Inform your physician if you are pregnant.. Inform your physician if you are diabetic or if you havemultiple myeloma, pheochromocytoma, homozygous sickle cell disease,or known thyroid disorder (see WARNINGS).. Inform your physician if you are allergic to any drugs,food, or if you had any reactions to previous injections of substancesused for x-ray procedures (see PRECAUTIONS-General).. Inform your physician about any other medications you arecurrently taking, including nonprescription drugs, before you havethis procedure.. Advise patients to inform their physician if they developa rash after receiving Isovue.. Drug Interactions. Renal toxicity has been reported in afew patients with liver dysfunction who were given oral cholecystographicagents followed by intravascular contrast agents. Administration ofintravascular agents should therefore be postponed in any patientwith known or suspected hepatic or biliary disorder who has recentlyreceived cholecystographic contrast agent.Other drugs should not be admixed with iopamidol.. Drug/Laboratory Test Interactions. The results of PBI and radioactive iodine uptakestudies, which depend on iodine estimations, will not accurately reflectthyroid function for up to 16 days following administration of iodinatedcontrast media. However, thyroid function tests not depending on iodineestimations, e.g., T3 resin uptake and total or free thyroxine (T4)assays are not affected.Any test which might be affected by contrast media should be performedprior to administration of the contrast medium.. Laboratory Test Findings. In vitro studies withanimal blood showed that many radiopaque contrast agents, includingiopamidol, produced slight depression of plasma coagulation factorsincluding prothrombin time, partial thromboplastin time, and fibrinogen,as well as slight tendency to cause platelet and/or red blood cellaggregation (see PRECAUTIONS-General).Transitory changesmay occur in red cell and leucocyte counts, serum calcium, serum creatinine,serum glutamic oxaloacetic transaminase (SGOT), and uric acid in urine;transient albuminuria may occur.These findings have not been associated with clinical manifestations.. Carcinogenesis, Mutagenesis,Impairment of Fertility. Long-term studies in animals have not been performed to evaluatecarcinogenic potential. No evidence of genetic toxicity was obtainedin in vitro tests.. Pregnancy: TeratogenicEffects Reproduction studies have been performed in rats andrabbits at doses up to 2.7 and 1.4 times the maximum recommended humandose (1.48 gl/kg in 50 kg individual), respectively, and have revealedno evidence of impaired fertility or harm to the fetus due to iopamidol.There are, however, no adequate and well-controlled studies in pregnantwomen. Because animal reproduction studies are not always predictiveof human response, this drug should be used during pregnancy onlyif clearly needed.. Nursing Mothers. It is not known whether this drug is excretedin human milk. Because many drugs are excreted in human milk, cautionshould be exercised when iopamidol is administered to nursing woman.. Pediatric Use. Safety and effectiveness in childrenhas been established in pediatric angiocardiography, computed tomography(head and body) and excretory urography. Pediatric patients at higherrisk of experiencing adverse events during contrast medium administrationmay include those having asthma, sensitivity to medication and/orallergens, cyanotic heart disease, congestive heart failure, serumcreatinine greater than 1.5 mg/dL or those less than 12 months ofage.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse reactions following the useof iopamidol are usually mild to moderate, self-limited, and transient.In angiocardiography (597 patients),the adverse reactions with an estimated incidence of one percent orhigher are: hot flashes 3.4%; angina pectoris 3.0%; flushing 1.8%;bradycardia 1.3%; hypotension 1.0%; hives 1.0%.In clinical trial with 76 pediatric patients undergoingangiocardiography, adverse reactions (2.6%) both remotely attributedto the contrast media were reported. Both patients were less than2 years of age, both had cyanotic heart disease with underlying rightventricular abnormalities and abnormal pulmonary circulation. In onepatient preexisting cyanosis was transiently intensified followingcontrast media administration. In the second patient preexisting decreasedperipheral perfusion was intensified for 24 hours following the examination.(See PRECAUTIONS Section forinformation on high risk nature of these patients.)Intravascular injection of contrast media is frequentlyassociated with the sensation of warmth and pain especially in peripheralarteriography and venography; pain and warmth are less frequent andless severe with ISOVUE (lopamidol Injection) than with diatrizoatemeglumine and diatrizoate sodium injection.The following table of incidence of reactions is basedon clinical studies with ISOVUE in about 2246 patients.Adverse ReactionsEstimated Overall IncidenceSystem> 1%<= 1%Cardiovascularnonetachycardiahypotensionhypertensionmyocardial ischemiacirculatory collapseS-Tsegment depressionbigeminyextrasystolesventricular fibrillationangina pectorisbradycardiatransient ischemic attackthrombophlebitisNervouspain (2.8%)burning sensation (1.4%)vasovagal reactiontingling in armsgrimacefaintnessDigestivenausea (1.2%)vomitinganorexiaRespiratorynonethroat constrictiondyspneapulmonary edemaSkin and AppendagesnonerashurticariapruritusflushingBody as Wholehot flashes (1.5%)headachefeverchillsexcessivesweatingback spasmSpecial Senseswarmth (1.1%)taste alterationsnasal congestionvisualdisturbancesUrogenitalnoneurinary retentionRegardless of the contrast agentemployed, the overall estimated incidence of serious adverse reactionsis higher with coronary arteriography than with otherprocedures. Cardiac decompensation, serious arrhythmias, or myocardialischemia or infarction have been reported with Isovue and may occurduring coronary arteriography and left ventriculography.Following coronary andventricular injections, certain electrocardiographic changes (increasedQTc, increased R-R, T-wave amplitude) and certain hemodynamic changes(decreased systolic pressure) occurred less frequently with ISOVUE(lopamidol Injection) than with diatrizoate meglumine and diatrizoatesodium injection; increased LVEDP occurred less frequently after ventriculariopamidol injections.In aortography, the risks of procedures also include injuryto the aorta and neighboring organs, pleural puncture, renal damageincluding infarction and acute tabular necrosis with oliguria andanuria, accidental selective filling of the right renal artery duringthe translumbar procedure in the presence of preexisting renal disease,retroperitoneal hemorrhage from the translumbar approach, and spinalcord injury and pathology associated with the syndrome of transversemyelitis.The following adversereactions have been reported for lopamidol: Cardiovascular: arrhythmia, arterial spasms, flushing, vasodilation, chest pain,cardiopulmonary arrest; Nervous: confusion,paresthesia, dizziness, temporary cortical blindness, temporary amnesia,convulsions, paralysis, coma; Respiratory:increased cough, sneezing, asthma, apnea, laryngeal edema, chest tightness,rhinitis; Skin and Appendages: injection sitepain usually due to extravasation and/or erythematous swelling, pallor,periorbital edema, facial edema; Urogenital: pain, hematuria; Special Senses: wateryitchy eyes, lacrimation, conjunctivitis; Musculoskeletal: muscle spasm, involuntary leg movement; Body as whole: tremors, malaise, anaphylactoid reaction (characterized by cardiovascular,respiratory and cutaneous symptoms), pain; Digestive: severe retching and choking, abdominal cramps. Some of these mayoccur as consequence of the procedure. Other reactions may alsooccur with the use of any contrast agent as consequence of the proceduralhazard; these include hemorrhage or pseudoaneurysms at the puncturesite, brachial plexus palsy following axillary artery injections,chest pain, myocardial infarction, and transient changes in hepatorenalchemistry tests. Arterial thrombosis, displacement of arterial plaques,venous thrombosis, dissection of the coronary vessels and transientsinus arrest are rare complications.. General Adverse ReactionsTo Contrast Media. Reactionsknown to occur with parenteral administration of iodinated ionic contrastagents (see the listing below) are possible with any nonionic agent.Approximately 95 percent of adverse reactions accompanying the useof other water-soluble intravascularly administered contrast agentsare mild to moderate in degree. However, life-threatening reactionsand fatalities, mostly of cardiovascular origin, have occurred. Reportedincidences of death from the administration of other iodinated contrastmedia range from 6.6 per million (0.00066 percent) to in 10,000patients (0.01 percent). Most deaths occur during injection or to10 minutes later, the main feature being cardiac arrest with cardiovasculardisease as the main aggravating factor. Isolated reports of hypotensivecollapse and shock are found in the literature. The incidence of shockis estimated to be out of 20,000 (0.005 percent) patients.Adverse reactions to injectable contrastmedia fall into two categories: chemotoxic reactions and idiosyncraticreactions. Chemotoxic reactions result from the physicochemical propertiesof the contrast medium, the dose, and the speed of injection. Allhemodynamic disturbances and injuries to organs or vessels perfusedby the contrast medium are included in this category.Experience with iopamidol suggests there is much lessdiscomfort (e.g. pain and/or warmth) with peripheral arteriography.Fewer changes are noted in ventricular function after ventriculographyand coronary arteriography.Idiosyncraticreactions include all other reactions. They occur more frequentlyin patients 20 to 40 years old. Idiosyncratic reactions may or maynot be dependent on the amount of drug injected, the speed of injection,the mode of injection, and the radiographic procedure.Idiosyncratic reactions are subdivided intominor, intermediate, and severe. The minor reactions are self-limitedand of short duration; the severe reactions are life-threatening andtreatment is urgent and mandatory.The reported incidence of adverse reactions to contrast media inpatients with history of allergy is twice that for the general population.Patients with history of previous reactions to contrast mediumare three times more susceptible than other patients. However, sensitivityto contrast media does not appear to increase with repeated examinations.Most adverse reactions to intravascular contrast agents appear withinone to three minutes after the start of injection, but delayed reactionsmay occur. Delayed reactions, usually involving the skin, may uncommonlyoccur within 2-3 days (range 1-7 days) after the administration ofcontrast (see PRECAUTIONS-General). Delayed allergic reactions are more frequent in patients treatedwith immunostimulants, such as interleukin-2.In addition to the adverse drug reactions reported foriopamidol, the following additional adverse reactions have been reportedwith the use of other intravascular contrast agents and are possiblewith the use of any water-soluble iodinated contrast agent:Cardiovascular: cerebralhematomas, petechiae; Hematologic: neutropenia; Urogenital: osmotic nephrosis of proximal tubular cells,renal failure; Special Senses: conjunctivalchemosis with infection; Endocrine: Thyroidfunction tests indicative of hypothyroidism or transient thyroid suppressionhave been uncommonly reported following iodinated contrast media administrationto adult and pediatric patients, including infants. Some patientswere treated for hypothyroidism. Skin and SubcutaneousTissue Disorders: Skin necrosis; Reactions range frommild (e.g. rash, erythema, pruritus, urticaria and skin discoloration)to severe: [e.g. Stevens-Johnson syndrome and toxic epidermal necrolysis(SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drugreaction with eosinophilia and systemic symptoms (DRESS)].

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Intravascular injection of radiopaque diagnostic agent opacifiesthose vessels in the path of flow of the contrast medium, permittingradiographic visualization of the internal structures of the humanbody until significant hemodilution occurs.Following intravascular injection, radiopaque diagnosticagents are immediately diluted in the circulating plasma. Calculationsof apparent volume of distribution at steady-state indicate that iopamidolis distributed between the circulating blood volume and other extracellularfluid; there appears to be no significant deposition of iopamidolin tissues. Uniform distribution of iopamidol in extracellular fluidis reflected by its demonstrated utility in contrast enhancement ofcomputed tomographic imaging of the head and body following intravenousadministration.The pharmacokineticsof intravenously administered iopamidol in normal subjects conformto an open two-compartment model with first order elimination (a rapidalpha phase for drug distribution and slow beta phase for drug elimination).The elimination serum or plasma half-life is approximately two hours;the half-life is not dose dependent. No significant metabolism, deiodination,or biotransformation occurs.Iopamidolis excreted mainly through the kidneys following intravascular administration.In patients with impaired renal function, the elimination half-lifeis prolonged dependent upon the degree of impairment. In the absenceof renal dysfunction, the cumulative urinary excretion for Iopamidol,expressed as percentage of administered intravenous dose is approximately35 to 40 percent at 60 minutes, 80 to 90 percent at hours, and 90percent or more in the 72- to 96-hour period after administration.In normal subjects, approximately one percent or less of the administereddose appears in cumulative 72- to 96-hour fecal specimens.ISOVUE may be visualized in the renal parenchymawithin 30-60 seconds following rapid intravenous administration. Opacificationof the calyces and pelves in patients with normal renal function becomesapparent within to minutes, with optimum contrast occurring between5 and 15 minutes. In patients with renal impairment, contrast visualizationmay be delayed.Iopamidol displayslittle tendency to bind to serum or plasma proteins.No evidence of in vivo complement activation has been foundin normal subjects.Animal studiesindicate that iopamidol does not cross the blood-brain barrier toany significant extent following intravascular administration.ISOVUE (lopamidol Injection) enhancescomputed tomographic brain imaging through augmentation of radiographicefficiency. The degree of enhancement of visualization of tissue densityis directly related to the iodine content in an administered dose;peak iodine blood levels occur immediately following rapid injectionof the dose. These levels fall rapidly within five to ten minutes.This can be accounted for by the dilution in the vascular and extracellularfluid compartments which causes an initial sharp fall in plasma concentration.Equilibration with the extracellular compartments is reached in aboutten minutes, thereafter the fall becomes exponential. Maximum contrastenhancement frequently occurs after peak blood iodine levels are reached.The delay in maximum contrast enhancement can range from five to fortyminutes depending on the peak iodine levels achieved and the celltype of the lesion. This lag suggests that radiographic contrast enhancementis at least in part dependent on the accumulation of iodine withinthe lesion and outside the blood pool, although the mechanism by whichthis occurs is not clear. The radiographic enhancement of nontumorallesions, such as arteriovenous malformations and aneurysms, is probablydependent on the iodine content of the circulating blood pool.In CECT head imaging, ISOVUE (lopamidolInjection) does not accumulate in normal brain tissue due to the presenceof the blood-brain barrier. The increase in x-ray absorption in normalbrain is due to the presence of contrast agent within the blood pool.A break in the blood-brain barrier such as occurs in malignant tumorsof the brain allows the accumulation of the contrast medium withinthe interstitial tissue of the tumor. Adjacent normal brain tissuedoes not contain the contrast medium.In nonneural tissues (during computed tomography ofthe body), iopamidol diffuses rapidly from the vascular into the extravascularspace. Increase in x-ray absorption is related to blood flow, concentrationof the contrast medium, and extraction of the contrast medium by interstitialtissue of tumors since no barrier exists. Contrast enhancement isthus due to the relative differences in extravascular diffusion betweennormal and abnormal tissue, quite different from that in the brain.The pharmacokinetics of iopamidol in bothnormal and abnormal tissue have been shown to be variable. Contrastenhancement appears to be greatest soon after administration of thecontrast medium, and following intraarterial rather than intravenousadministration. Thus, greatest enhancement can be detected by seriesof consecutive two- to three-second scans performed just after injection(within 30 to 90 seconds), i.e., dynamic computed tomographic imaging.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. General. Parenteral drug products should be inspectedvisually for particulate matter and discoloration prior to administration,whenever solution and container permit. Iopamidol solutions shouldbe used only if clear and within the normal colorless to pale yellowrange. Discard any product which shows signs of crystallization ordamage to the container-closure system, which includes the glass container,stopper and/or crimp.It isdesirable that solutions of radiopaque diagnostic agents for intravascularuse be at body temperature when injected. Withdrawal of contrast agentsfrom their containers should be accomplished under aseptic conditionswith sterile syringes. Sterile techniques must be used with any intravascularinjection, and with catheters and guidewires.Patients should be well hydrated priorto and following ISOVUE (lopamidol Injection) administration.As with all radiopaquecontrast agents, only the lowest dose of ISOVUE necessary to obtainadequate visualization should be used. lower dose reduces the possibilityof an adverse reaction. Most procedures do not require use of eithera maximum dose or the highest available concentration of ISOVUE; thecombination of dose and ISOVUE concentration to be used should becarefully individualized, and factors such as age, body size, sizeof the vessel and its blood flow rate, anticipated pathology and degreeand extent of opacification required, structure(s) or area to be examined,disease processes affecting the patient, and equipment and techniqueto be employed should be considered.. Cerebral Arteriography. ISOVUE-300 (lopamidol Injection, 300 mgl/mL)should be used. The usual individual injection by carotid punctureor transfemoral catheterization is to 12 mL, with total multipledoses ranging to 90 mL.. Peripheral Arteriography. ISOVUE-300 usually provides adequate visualization.For injection into the femoral artery or subclavian artery, to 40mL may be used; for injection into the aorta for distal runoff,25 to 50 mL may be used. Doses up to total of 250 mL of ISOVUE-300have been administered during peripheral arteriography.. Peripheral Venography(Phlebography). ISOVUE-200(lopamidol Injection, 200 mgl/mL) should be used. The usual dose is25 to 150 mL per lower extremity. The combined total dose for multipleinjections has not exceeded 350 mL.. Selective Visceral Arteriographyand Aortography. ISOVUE-370(lopamidol Injection, 370 mgl/mL) should be used. Doses up to 50 mLmay be required for injection into the larger vessels such as theaorta or celiac artery; doses up to 10 mL may be required for injectioninto the renal arteries. Often, lower doses will be sufficient. Thecombined total dose for multiple injections has not exceeded 225 mL.. Pediatric Angiocardiography. ISOVUE-370 should be used. Pediatricangiocardiography may be performed by injection into large peripheralvein or by direct catheterization of the heart.The usual dose range for single injections isprovided in the following table:Single InjectionUsual Dose RangeAgemL< years10-152-9 years15-3010-18 years20-50The usual recommended dose forcumulative injections is provided in the following table:Cumulative Injection Usual Recommended DoseAgemL< years402-4 years505-9 years10010-18 years125. Coronary Arteriographyand Ventriculography. ISOVUE-370 should be used. The usual dose forselective coronary artery injections is to 10 mL. The usual dosefor ventriculography, or for nonselective opacification of multiplecoronary arteries following injection at the aortic root is 25 to50 mL. The total dose for combined procedures has not exceeded 200mL. EKG monitoring is essential.. Excretory Urography. ISOVUE-250 ISOVUE-300 or ISOVUE-370may be used. The usual adult dose for ISOVUE-250 is 50 to 100 mL,for ISOVUE-300 is 50 mL and for ISOVUE-370 is 40 mL administered byrapid intravenous injection.. Pediatric Excretory Urography. ISOVUE-250 or ISOVUE-300 may be used. Thedosage recommended for use in children for excretory urography is1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and 1.0 mL/kg to 3.0 mL/kg forISOVUE-300. It should not be necessary to exceed total dose of 30grams of iodine.. Computed Tomography. ISOVUE-250 or ISOVUE-300 may be used.CECT OF THE HEAD: The suggested dose forISOVUE-250 is 130 to 240 mL and for ISOVUE-300 is 100 to 200 mL byintravenous administration. Imaging may be performed immediately aftercompletion of administration.CECT OF THE BODY: The usual adult dose range for ISOVUE-250 is 130to 240 mL and for ISOVUE-300 is 100 to 200 mL administered by rapidintravenous infusion or bolus injection. Equivalent doses of ISOVUE-370based on organically bound iodine content may also be used. The totaldose for either CECT procedure should not exceed 60 grams of iodine.. Pediatric Computed Tomography. ISOVUE-250 or ISOVUE-300 may be used.The dosage recommended for use in children for contrast enhanced computedtomography is 1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and 1.0 mL/kgto 3.0 mL/kg for ISOVUE-300. It should not be necessary to exceeda total dose of 30 grams of iodine.. Drug Incompatibilities. Many radiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs;therefore, no other pharmaceuticals should be admixed with contrastagents.

GENERAL PRECAUTIONS SECTION.

General. Diagnostic procedureswhich involve the use of any radiopaque agent should be carried outunder the direction of personnel with the prerequisite training andwith thorough knowledge of the particular procedure to be performed.Appropriate facilities should be available for coping with any complicationof the procedure, as well as for emergency treatment of severe reactionto the contrast agent itself. After parenteral administration of aradiopaque agent, competent personnel and emergency facilities shouldbe available for at least 30 to 60 minutes since severe delayed reactionsmay occur. Caution should be exercised in hydrating patients withunderlying conditions that may be worsened by fluid overload, suchas congestive heart failure.Diabetic nephropathy may predispose to acute renal impairment followingintravascular contrast media administration. Acute renal impairmentfollowing contrast media administration may precipitate lactic acidosisin patients who are taking biguanides.The administration of iodinated contrast media mayaggravate the symptoms of myasthenia gravis.Preparatory dehydration is dangerous and may contributeto acute renal failure in patients with advanced vascular disease,diabetic patients, and in susceptible nondiabetic patients (oftenelderly with preexisting renal disease). Patients should bewell hydrated prior to and following iopamidol administration. The possibility of reaction, including serious, life-threatening,fatal, anaphylactoid or cardiovascular reactions, should always beconsidered (see ADVERSE REACTIONS). Patients at increased risk include those with history of previousreaction to contrast medium, patients with known sensitivity toiodine per se, and patients with known clinical hypersensitivity(bronchial asthma, hay fever, and food allergies). The occurrenceof severe idiosyncratic reactions has prompted the use of severalpretesting methods. However, pretesting cannot be relied upon to predictsevere reactions and may itself be hazardous for the patient. It issuggested that thorough medical history with emphasis on allergyand hypersensitivity, prior to the injection of any contrast medium,may be more accurate than pretesting in predicting potential adversereactions. positive history of allergies or hypersensitivity doesnot arbitrarily contraindicate the use of contrast agent where adiagnostic procedure is thought essential, but caution should be exercised.Premedication with antihistamines or corticosteroids to avoid or minimizepossible allergic reactions in such patients should be considered.Recent reports indicate that such pretreatment does not prevent seriouslife-threatening reactions but may reduce both their incidence andseverity.Pre-existing conditions,such as pacemakers or cardiac medications, specifically beta-blockers,may mask or alter the signs or symptoms of an anaphylactoid reaction,as well as masking or altering the response to particular medicationsused for treatment. For example, beta-blockers inhibit tachycardiacresponse, and can lead to the incorrect diagnosis of vasovagal ratherthan an anaphylactoid reaction. Special attention to this possibilityis particularly critical in patients suffering from serious, life-threateningreactions.General anesthesiamay be indicated in the performance of some procedures in selectedpatients; however, higher incidence of adverse reactions has beenreported with radiopaque media in anesthetized patients, which maybe attributable to the inability of the patient to identify untowardsymptoms, or to the hypotensive effect of anesthesia which can reducecardiac output and increase the duration of exposure to the contrastagent.Even though the osmolalityof iopamidol is low compared to diatrizoate or iothalamate based ionicagents of comparable iodine concentration, the potential transitoryincrease in the circulatory osmotic load in patients with congestiveheart failure requires caution during injection. These patients shouldbe observed for several hours following the procedure to detect delayedhemodynamic disturbances. Injection site pain and swelling may occur.In the majority of cases it is due to extravasation of contrast medium.Reactions are usually transient and recover without sequelae. However,inflammation and even skin necrosis have been seen on very rare occasions.In angiographic procedures, the possibilityof dislodging plaques or damaging or perforating the vessel wall,or inducing vasospasm, and or subsequent ischemic events, should beborne in mind during catheter manipulations and contrast medium injection.Test injections to ensure proper catheter placement are suggested.Selective coronary arteriography shouldbe performed only in selected patients and those in whom the expectedbenefits outweigh the procedural risk. The inherent risks of angiocardiographyin patients with pulmonary hypertension must be weighed against thenecessity for performing this procedure. Angiography should be avoidedwhenever possible in patients with homocystinuria, because of therisk of inducing thrombosis and embolism. See also Pediatric Use.In addition to the general precautions previously described,special care is required when venography is performed in patientswith suspected thrombosis, phlebitis, severe ischemic disease, localinfection or totally obstructed venous system. Extreme caution duringinjection of contrast media is necessary to avoid extravasation andfluoroscopy is recommended. This is especially important in patientswith severe arterial or venous disease.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. ISOVUE (lopamidol Injection) is indicatedfor angiography throughout the cardiovascular system, including cerebraland peripheral arteriography, coronary arteriography and ventriculography,pediatric angiocardiography, selective visceral arteriography andaortography, peripheral venography (phlebography), and adult and pediatricintravenous excretory urography and intravenous adult and pediatriccontrast enhancement of computed tomographic (CECT) head and bodyimaging (see below).. CECT Head Imaging. ISOVUE may be used to refine diagnosticprecision in areas of the brain which may not otherwise have beensatisfactorily visualized.. Tumors. ISOVUE may be useful to investigate thepresence and extent of certain malignancies such as: gliomas includingmalignant gliomas, glioblastomas, astrocytomas, oligodendrogliomasand gangliomas, ependymomas, medulloblastomas, meningiomas, neuromas,pinealomas, pituitary adenomas, craniopharyngiomas, germinomas, andmetastatic lesions. The usefulness of contrast enhancement for theinvestigation of the retrobulbar space and in cases of low grade orinfiltrative glioma has not been demonstrated.In calcified lesions, there is less likelihood of enhancement.Following therapy, tumors may show decreased or no enhancement.The opacification of the inferior vermisfollowing contrast media administration has resulted in false-positivediagnosis in number of otherwise normal studies.. Nonneoplastic Conditions. ISOVUE may be beneficial in the image enhancementof nonneoplastic lesions. Cerebral infarctions of recent onset maybe better visualized with contrast enhancement, while some infarctionsare obscured if contrast media are used. The use of iodinated contrastmedia results in contrast enhancement in about 60 percent of cerebralinfarctions studied from one to four weeks from the onset of symptoms.Sites of active infection may alsobe enhanced following contrast media administration.Arteriovenous malformations and aneurysms will showcontrast enhancement. For these vascular lesions, the enhancementis probably dependent on the iodine content of the circulating bloodpool.Hematomas and intraparenchymalbleeders seldom demonstrate any contrast enhancement. However, incases of intraparenchymal clot, for which there is no obvious clinicalexplanation, contrast media administration may be helpful in rulingout the possibility of associated arteriovenous malformation.. CECT Body Imaging. ISOVUE (lopamidol Injection) may be usedfor enhancement of computed tomographic images for detection and evaluationof lesions in the liver, pancreas, kidneys, aorta, mediastinum, abdominalcavity, pelvis and retroperitoneal space.Enhancement of computed tomography with ISOVUE may beof benefit in establishing diagnoses of certain lesions in these siteswith greater assurance than is possible with CT alone, and in supplyingadditional features of the lesions (e.g., hepatic abscess delineationprior to percutaneous drainage). In other cases, the contrast agentmay allow visualization of lesions not seen with CT alone (e.g., tumorextension), or may help to define suspicious lesions seen with unenhancedCT (e.g., pancreatic cyst).Contrast enhancement appears to be greatest within 60 to 90 secondsafter bolus administration of contrast agent. Therefore, utilizationof continuous scanning technique (dynamic CT scanning) may improveenhancement and diagnostic assessment of tumor and other lesions suchas an abscess, occasionally revealing unsuspected or more extensivedisease. For example, cyst may be distinguished from vascularizedsolid lesion when precontrast and enhanced scans are compared; thenonperfused mass shows unchanged x-ray absorption (CT number). vascularizedlesion is characterized by an increase in CT number in the few minutesafter bolus of intravascular contrast agent; it may be malignant,benign, or normal tissue, but would probably not be cyst, hematoma,or other nonvascular lesion.Because unenhanced scanning may provide adequate diagnostic informationin the individual patient, the decision to employ contrast enhancement,which may be associated with risk and increased radiation exposure,should be based upon careful evaluation of clinical, other radiological,and unenhanced CT findings.

WARNINGS SECTION.

WARNINGS. Severe Adverse Events-lnadvertentIntrathecal AdministrationSerious adverse reactions have been reported due to the inadvertentintrathecal administration of iodinated contrast media that are notindicated for intrathecal use.These serious adverse reactions include: death,convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis,acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia,and brain edema. Special attention must be given to insure that thisdrug product is not inadvertently administered intrathecally.. General. Nonionic iodinated contrast media inhibitblood coagulation, in vitro, less than ionic contrastmedia. Clotting has been reported when blood remains in contact withsyringes containing nonionic contrast media.Serious, rarely fatal, thromboembolic events causingmyocardial infarction and stroke have been reported during angiographicprocedures with both ionic and nonionic contrast media. Therefore,meticulous intravascular administration technique is necessary, particularlyduring angiographic procedures, to minimize thromboembolic events.Numerous factors, including length of procedure, catheter and syringematerial, underlying disease state, and concomitant medications maycontribute to the development of thromboembolic events. For thesereasons, meticulous angiographic techniques are recommended includingclose attention to guidewire and catheter manipulation, use of manifoldsystems and/or three way stopcocks, frequent catheter flushing withheparinized saline solutions, and minimizing the length of the procedure.The use of plastic syringes in place of glass syringes has been reportedto decrease but not eliminate the likelihood of in vitro clotting.Caution must be exercisedin patients with severely impaired renal function, those with combinedrenal and hepatic disease, or anuria, particularly when larger orrepeat doses are administered.Radiopaque diagnostic contrast agents are potentially hazardous inpatients with multiple myeloma or other paraproteinemia, particularlyin those with therapeutically resistant anuria. Myeloma occurs mostcommonly in persons over age 40. Although neither the contrast agentnor dehydration has been proved separately to be the cause of anuriain myelomatous patients, it has been speculated that the combinationof both may be causative. The risk in myelomatous patients is nota contraindication; however, special precautions are required.Contrast media may promote sickling inindividuals who are homozygous for sickle cell disease when injectedintravenously or intraarterially.Administration of radiopaque materials to patients known or suspectedof having pheochromocytoma should be performed with extreme caution.If, in the opinion of the physician, the possible benefits of suchprocedures outweigh the considered risks, the procedures may be performed;however, the amount of radiopaque medium injected should be kept toan absolute minimum. The blood pressure should be assessed throughoutthe procedure and measures for treatment of hypertensive crisisshould be available. These patients should be monitored very closelyduring contrast enhanced procedures.Reports of thyroid storm following the use of iodinatedradiopaque diagnostic agents in patients with hyperthyroidism or withan autonomously functioning thyroid nodule suggest that this additionalrisk be evaluated in such patients before use of any contrast medium.Severe Cutaneous AdverseReactions: Severe cutaneous adverse reactions (SCAR) may developfrom hour to several weeks after intravascular contrast agent administration.These reactions include Stevens-Johnson syndrome and toxic epidermalnecrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP)and drug reaction with eosinophilia and systemic symptoms (DRESS).Reaction severity may increase and time to onset may decrease withrepeat administration of contrast agent; prophylactic medicationsmay not prevent or mitigate severe cutaneous adverse reactions. Avoidadministering Isovue to patients with history of severe cutaneousadverse reaction to Isovue.