ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Adverse reactions following the use of iopamidol are usually mild to moderate, self-limited, and transient.In angiocardiography (597 patients), the adversereactions with an estimated incidence of one percent or higher are:hot flashes 3.4%; angina pectoris 3.0%; flushing 1.8%; bradycardia1.3%; hypotension 1.0%; hives 1.0%.In clinical trial with 76 pediatric patients undergoing angiocardiography,2 adverse reactions (2.6%) both remotely attributed to the contrastmedia were reported. Both patients were less than years of age,both had cyanotic heart disease with underlying right ventricularabnormalities and abnormal pulmonary circulation. In one patient pre-existingcyanosis was transiently intensified following contrast media administration.In the second patient pre-existing decreased peripheral perfusionwas intensified for 24 hours following the examination. (See PRECAUTIONS Section for informationon 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 (Iopamidol 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 Reactions Estimated Overall Incidence System> 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 agent employed,the overall estimated incidence of serious adverse reactions is higherwith coronary arteriography than with other procedures.Cardiac decompensation, serious arrhythmias, or myocardial ischemiaor infarction have been reported with Isovue and may occur during coronary arteriography and left ventriculography.Following coronary and ventricularinjections, certain electrocardiographic changes (increased QTc, increasedR-R, T-wave amplitude) and certain hemodynamic changes (decreasedsystolic pressure) occurred less frequently with ISOVUE (IopamidolInjection) than with diatrizoate meglumine and diatrizoate sodiuminjection; 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 Iopamidol: Cardiovascular: arrhythmia, arterial spasms, flushing, vasodilation, chest pain,cardiopulmonary arrest; Nervous System: 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 withiopamidol suggests there is much less discomfort (e.g. pain and/orwarmth) with peripheral arteriography. Fewer changes are noted inventricular function after ventriculography and coronary arteriography.Idiosyncratic reactions include allother reactions. They occur more frequently in patients 20 to 40 yearsold. Idiosyncratic reactions may or may not be dependent on the amountof drug injected, the speed of injection, the mode of injection, andthe radiographic procedure. Idiosyncratic reactions are subdividedinto minor, 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: cerebral hematomas, petechiae; Hematologic: neutropenia; Urogenital: osmotic nephrosis of proximal tubular cells, renal failure; Special Senses: conjunctival chemosis with infection; Endocrine: Thyroid function tests indicative of hypothyroidismor transient thyroid suppression have been uncommonly reported followingiodinated contrast media administration to adult and pediatric patients,including infants. Some patients were treated for hypothyroidism.; Skin and Subcutaneous Tissue Disorders: Skin necrosis;Reactions range from mild (e.g. rash, erythema, pruritus, urticariaand skin discoloration) to severe: [e.g. Stevens-Johnson syndromeand toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematouspustulosis (AGEP) and drug reaction with eosinophilia and systemicsymptoms (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 renalparenchyma within 30-60 seconds following rapid intravenous administration.Opacification of the calyces and pelves in patients with normal renalfunction becomes apparent within to minutes, with optimum contrastoccurring between and 15 minutes. In patients with renal impairment,contrast visualization may be delayed.Iopamidol displays little tendency to bind to serumor plasma proteins.No evidenceof in vivo complement activation has been found in normal subjects.Animal studies indicate that iopamidoldoes not cross the blood-brain barrier to any significant extent followingintravascular administration.ISOVUE (Iopamidol Injection) enhances computed tomographic brainimaging through augmentation of radiographic efficiency. The degreeof enhancement of visualization of tissue density is directly relatedto the iodine content in an administered dose; peak iodine blood levelsoccur immediately following rapid injection of the dose. These levelsfall rapidly within five to ten minutes. This can be accounted forby the dilution in the vascular and extracellular fluid compartmentswhich causes an initial sharp fall in plasma concentration. Equilibrationwith the extracellular compartments is reached in about ten minutes;thereafter, the fall becomes exponential. Maximum contrast enhancementfrequently occurs after peak blood iodine levels are reached. Thedelay 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 (IopamidolInjection) does not accumulate in normal brain tissue due to the presenceof the blood-brain barrier. The increase in x-ray absorption innormal brain is due to the presence of contrast agent within the bloodpool. break in the blood-brain barrier such as occurs in malignanttumors of the brain allows the accumulation of the contrast mediumwithin the interstitial tissue of the tumor. Adjacent normal braintissue does 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 inboth normal 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.Itis desirable 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.The transferring of ISOVUE from ISOVUE Pharmacy BulkPackage should be performed in suitable work area, such as laminarflow hood, utilizing aseptic technique. The container closure maybe penetrated only one time, utilizing suitable transfer device.Patients should be well hydratedprior to and following ISOVUE (Iopamidol 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 (Iopamidol Injection, 300 mgI/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.. Selective Visceral Arteriographyand Aortography. ISOVUE-370(Iopamidol Injection, 370 mgI/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 is providedin 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 for selective coronaryartery injections is to 10 mL. The usual dose for ventriculography,or for nonselective opacification of multiple coronary arteries followinginjection at the aortic root is 25 to 50 mL. The total dose for combinedprocedures has not exceeded 200 mL. EKG monitoring is essential.. Excretory Urography. ISOVUE-250 ISOVUE-300 or ISOVUE-370 maybe used. The usual adult dose for ISOVUE-250 is 50 to 100 mL, forISOVUE-300 is 50 mL and for ISOVUE-370 is 40 mL administered by rapidintravenous injection.. PediatricExcretory Urography. ISOVUE-250or ISOVUE-300 may be used. The dosage recommended for use in childrenfor excretory urography is 1.2 mL/kg to 3.6 mL/kg for ISOVUE-250 and1.0 mL/kg to 3.0 mL/kg for ISOVUE-300. It should not be necessaryto exceed total dose of 30 grams of iodine.. DrugIncompatibilities. Manyradiopaque contrast agents are incompatible in vitro with some antihistamines and many other drugs; therefore, no otherpharmaceuticals should be admixed with contrast agents.

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.Preparatorydehydration is dangerous and may contribute to acute renal failurein patients with advanced vascular disease, diabetic patients, andin susceptible nondiabetic patients (often elderly with pre-existingrenal disease). Patients should be well hydratedprior to and following iopamidol administration. The possibility of reaction,including serious, life-threatening, fatal, anaphylactoid or cardiovascularreactions, should always be considered (see ADVERSE REACTIONS). Patients atincreased risk include those with history of previous reactionto contrast medium, patients with known sensitivity to iodineper se, and patients with known clinical hypersensitivity (bronchialasthma, hay fever, and food allergies). The occurrence of severe idiosyncraticreactions has prompted the use of several pretesting methods. However,pretesting cannot be relied upon to predict severe reactions and mayitself be hazardous for the patient. It is suggested that thoroughmedical history with emphasis on allergy and hypersensitivity, priorto the injection of any contrast medium, may be more accurate thanpretesting in predicting potential adverse reactions. positive historyof allergies or hypersensitivity does not arbitrarily contraindicatethe use of contrast agent where diagnostic procedure is thoughtessential, but caution should be exercised. Premedication with antihistaminesor corticosteroids to avoid or minimize possible allergic reactionsin such patients should be considered. Recent reports indicate thatsuch pretreatment does not prevent serious life-threatening reactionsbut may reduce both their incidence and severity.Pre-existing conditions, such as pacemakers or cardiacmedications, specifically beta-blockers, may mask or alter the signsor symptoms of an anaphylactoid reaction, as well as masking or alteringthe response to particular medications used for treatment. For example,beta-blockers inhibit tachycardiac response, and can lead to theincorrect diagnosis of vasovagal rather than an anaphylactoid reaction.Special attention to this possibility is particularly critical inpatients suffering from serious, life-threatening reactions.General anesthesia may be indicated in theperformance of some procedures in selected patients; however, higherincidence of adverse reactions has been reported with radiopaque mediain anesthetized patients, which may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensiveeffect of anesthesia which can reduce cardiac output and increasethe duration of exposure to the contrast agent.Even though the osmolality of iopamidol is low comparedto diatrizoate or iothalamate based ionic agents of comparable iodineconcentration, the potential transitory increase in the circulatoryosmotic load in patients with congestive heart failure requires cautionduring injection. These patients should be observed for several hoursfollowing the procedure to detect delayed hemodynamic disturbances.Injection site pain and swelling may occur. In the majority of casesit is due to extravasation of contrast medium. Reactions are usuallytransient and recover without sequelae. However, inflammation andeven 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 should be performed only in selected patients and those in whomthe expected benefits outweigh the procedural risk. The inherent risksof angiocardiography in patients with chronic pulmonaryemphysema must be weighed against the necessity for performing thisprocedure. Angiography should be avoided whenever possible in patientswith homocystinuria, because of the risk of inducing thrombosis andembolism. See also Pediatric Use.In addition to the generalprecautions previously described, special care is required when venographyis performed in patients with suspected thrombosis, phlebitis, severeischemic disease, local infection or totally obstructed venous system.Extreme caution during injection of contrastmedia is necessary to avoid extravasation and fluoroscopy is recommended.This is especially important in patients with severe arterial or venousdisease.

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.Preparatorydehydration is dangerous and may contribute to acute renal failurein patients with advanced vascular disease, diabetic patients, andin susceptible nondiabetic patients (often elderly with pre-existingrenal disease). Patients should be well hydratedprior to and following iopamidol administration. The possibility of reaction,including serious, life-threatening, fatal, anaphylactoid or cardiovascularreactions, should always be considered (see ADVERSE REACTIONS). Patients atincreased risk include those with history of previous reactionto contrast medium, patients with known sensitivity to iodineper se, and patients with known clinical hypersensitivity (bronchialasthma, hay fever, and food allergies). The occurrence of severe idiosyncraticreactions has prompted the use of several pretesting methods. However,pretesting cannot be relied upon to predict severe reactions and mayitself be hazardous for the patient. It is suggested that thoroughmedical history with emphasis on allergy and hypersensitivity, priorto the injection of any contrast medium, may be more accurate thanpretesting in predicting potential adverse reactions. positive historyof allergies or hypersensitivity does not arbitrarily contraindicatethe use of contrast agent where diagnostic procedure is thoughtessential, but caution should be exercised. Premedication with antihistaminesor corticosteroids to avoid or minimize possible allergic reactionsin such patients should be considered. Recent reports indicate thatsuch pretreatment does not prevent serious life-threatening reactionsbut may reduce both their incidence and severity.Pre-existing conditions, such as pacemakers or cardiacmedications, specifically beta-blockers, may mask or alter the signsor symptoms of an anaphylactoid reaction, as well as masking or alteringthe response to particular medications used for treatment. For example,beta-blockers inhibit tachycardiac response, and can lead to theincorrect diagnosis of vasovagal rather than an anaphylactoid reaction.Special attention to this possibility is particularly critical inpatients suffering from serious, life-threatening reactions.General anesthesia may be indicated in theperformance of some procedures in selected patients; however, higherincidence of adverse reactions has been reported with radiopaque mediain anesthetized patients, which may be attributable to the inability of the patient to identify untoward symptoms, or to the hypotensiveeffect of anesthesia which can reduce cardiac output and increasethe duration of exposure to the contrast agent.Even though the osmolality of iopamidol is low comparedto diatrizoate or iothalamate based ionic agents of comparable iodineconcentration, the potential transitory increase in the circulatoryosmotic load in patients with congestive heart failure requires cautionduring injection. These patients should be observed for several hoursfollowing the procedure to detect delayed hemodynamic disturbances.Injection site pain and swelling may occur. In the majority of casesit is due to extravasation of contrast medium. Reactions are usuallytransient and recover without sequelae. However, inflammation andeven 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 should be performed only in selected patients and those in whomthe expected benefits outweigh the procedural risk. The inherent risksof angiocardiography in patients with chronic pulmonaryemphysema must be weighed against the necessity for performing thisprocedure. Angiography should be avoided whenever possible in patientswith homocystinuria, because of the risk of inducing thrombosis andembolism. See also Pediatric Use.In addition to the generalprecautions previously described, special care is required when venographyis performed in patients with suspected thrombosis, phlebitis, severeischemic disease, local infection or totally obstructed venous system.Extreme caution during injection of contrastmedia is necessary to avoid extravasation and fluoroscopy is recommended.This is especially important in patients with severe arterial or venousdisease.. Information for Patients. Patients receiving injectable radiopaque diagnostic agents shouldbe 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 fewpatients 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 uptake studies,which depend on iodine estimations, will not accurately reflect thyroidfunction for up to 16 days following administration of iodinated contrastmedia. However, thyroid function tests not depending on iodine estimations,e.g., T3 resin uptake and total or free thyroxine (T4) assays arenot affected.Any test which mightbe affected by contrast media should be performed prior to administrationof the contrast medium.. Laboratory Test Findings. In vitro studies with animalblood showed that many radiopaque contrast agents, including iopamidol,produced slight depression of plasma coagulation factors includingprothrombin time, partial thromboplastin time, and fibrinogen, aswell as slight tendency to cause platelet and/or red blood cellaggregation (see PRECAUTIONS-General).Transitory changes mayoccur 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 Reproductionstudies have been performed in rats and rabbits at doses up to 2.7and 1.4 times the maximum recommended human dose (1.48 gI/kg in a50 kg individual), respectively, and have revealed no evidence ofimpaired fertility or harm to the fetus due to iopamidol. There are,however, no adequate and well-controlled studies in pregnant women.Because animal reproduction studies are not always predictive of humanresponse, this drug should be used during pregnancy only if clearlyneeded.. 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 children hasbeen established in pediatric angiocardiography and excretory urography.Pediatric patients at higher risk of experiencing adverse events duringcontrast medium administration may include those having asthma, asensitivity to medication and/or allergens, cyanotic heart disease,congestive heart failure, serum creatinine greater than 1.5 mg/dLor those less than 12 months of age.

STORAGE AND HANDLING SECTION.

DRUG HANDLING. 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.. Directions for ProperUse of ISOVUE Pharmacy Bulk Package. The Pharmacy Bulk Package is used as multiple dosecontainer with an appropriate transfer device to fill empty sterilesyringes.ISOVUE injection shouldbe drawn into the syringe and administered using sterile technique.Unused portions of the drug must be discarded.The transferring ISOVUE (Iopamidol Injection) from the PharmacyBulk Package should be performed in suitable work area, such asa laminar flow hood, utilizing aseptic technique.The container closure may be penetrated only one time, utilizinga suitable transfer device. Once the Pharmacy Bulk Package is punctured,it should not be removed from the aseptic work area during the entireperiod of use.The withdrawal of container contents should be accomplishedwithout delay. However, should this not be possible, maximum timeof 10 hours from initial closure entry is permitted to complete fluidtransfer operation. Any unused ISOVUE Pharmacy Bulk Package injectionmust be discarded 10 hours after initial punctureof the bulk package. Storage temperature of container after the closure has beenentered should not exceed 25 (77 F).. The transferring ISOVUE (Iopamidol Injection) from the PharmacyBulk Package should be performed in suitable work area, such asa laminar flow hood, utilizing aseptic technique.. The container closure may be penetrated only one time, utilizinga suitable transfer device. Once the Pharmacy Bulk Package is punctured,it should not be removed from the aseptic work area during the entireperiod of use.. The withdrawal of container contents should be accomplishedwithout delay. However, should this not be possible, maximum timeof 10 hours from initial closure entry is permitted to complete fluidtransfer operation. Any unused ISOVUE Pharmacy Bulk Package injectionmust be discarded 10 hours after initial punctureof the bulk package. Storage temperature of container after the closure has beenentered should not exceed 25 (77 F).

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 beexercised in patients with severely impaired renal function, thosewith combined renal and hepatic disease, or anuria, particularly whenlarger or repeat doses are administered.Radiopaque diagnostic contrast agents are potentiallyhazardous in patients with multiple myeloma or other paraproteinemia,particularly in those with therapeutically resistant anuria. Myelomaoccurs most commonly in persons over age 40. Although neither thecontrast agent nor dehydration has been proved separately to be thecause of anuria in myelomatous patients, it has been speculated thatthe combination of both may be causative. The risk in myelomatouspatients is not contraindication; however, special precautions arerequired.Contrast media maypromote sickling in individuals who are homozygous for sickle celldisease when injected intravenously or intraarterially.Administration of radiopaque materialsto patients known or suspected of having pheochromocytoma should beperformed with extreme caution. If, in the opinion of the physician,the possible benefits of such procedures outweigh the considered risks,the procedures may be performed; however, the amount of radiopaquemedium injected should be kept to an absolute minimum. The blood pressureshould be assessed throughout the procedure and measures for treatmentof hypertensive crisis should be available. These patients shouldbe monitored very closely during contrast enhanced procedures.Reports of thyroid storm following theuse of iodinated radiopaque diagnostic agents in patients with hyperthyroidismor with an autonomously functioning thyroid nodule suggest that thisadditional risk be evaluated in such patients before use of any contrastmedium.SevereCutaneous Adverse Reactions: Severe cutaneous adverse reactions(SCAR) may develop from hour to several weeks after intravascularcontrast agent administration. These reactions include Stevens-Johnsonsyndrome and toxic epidermal necrolysis (SJS/TEN), acute generalizedexanthematous pustulosis (AGEP) and drug reaction with eosinophiliaand systemic symptoms (DRESS). Reaction severity may increase andtime to onset may decrease with repeat administration of contrastagent; prophylactic medications may not prevent or mitigate severecutaneous adverse reactions. Avoid administering Isovue to patientswith history of severe cutaneous adverse reaction to Isovue.