GENERAL

Iodixanol is a dimeric, isosmolar, nonionic, water soluble, iodinated x-ray contrast agent for intravascular administration.

Intravascular injection of iodixanol opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant dilution and elimination occurs.

PHARMACOKINETICS

PHARMACODYNAMICS

As with other iodinated contrast agents, following administration of VISIPAQUE Injection, the degree of enhancement is directly related to the iodine content in an administered dose; peak iodine plasma levels occur immediately following rapid intravascular injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments.

INTRA-ARTERIAL ADMINISTRATION

Angiocardiography, cerebral arteriography, peripheral arteriography, and visceral arteriography were studied with either one or both concentrations of VISIPAQUE Injection (270 mgI/mL or 320 mgI/mL). In these intra-arterial studies, diagnostic visualization ratings were good or excellent in 100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given VISIPAQUE Injection. In additional intra-arterial studies, overall quality of diagnostic visualization was rated optimal in the majority of patients and a radiologic diagnosis was made in all (100%) of the patients administered VISIPAQUE Injection. Results were compared to those of active controls (ioxaglate, iohexol, iopromide). The number of patients studied in each indication is provided below.

Angiocardiography was evaluated in two randomized, double-blind clinical trials in 101 adult patients given VISIPAQUE Injection 320 mgI/mL and 97 given iohexol 350 mgI/mL. Seven additional angiocardiography studies were performed in 217 adult patients given VISIPAQUE Injection 320 mgI/mL, 37 given iohexol 350 mgI/mL, 40 given meglumine-sodium diatrizoate 370 mgI/mL, and 96 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given VISIPAQUE; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Cerebral arteriography was evaluated in two randomized, double-blind clinical trials in 51 adult patients given VISIPAQUE Injection 320 mgI/mL and 48 given iohexol 300 mgI/mL. Two additional cerebral arteriography studies were performed in 15 adult patients given VISIPAQUE Injection 270 mgI/mL, 40 patients given VISIPAQUE Injection 320 mgI/mL, and 40 patients given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given VISIPAQUE a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Peripheral arteriography was evaluated in two randomized, double-blind clinical trials in 49 adult patients given VISIPAQUE Injection 320 mgI/mL, 25 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Four additional peripheral arteriography studies were performed in 41 adult patients given VISIPAQUE Injection 270 mgI/mL, 85 patients given VISIPAQUE Injection 320 mgI/mL, 37 given iohexol 300 mgI/mL, and 47 given iopromide 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given VISIPAQUE; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Visceral arteriography was evaluated in two randomized, double-blind clinical trials in 55 adult patients given VISIPAQUE Injection 320 mgI/mL, 26 given iohexol 350 mgI/mL, and 25 given ioxaglate 320 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given VISIPAQUE; a radiologic diagnosis was made in the majority of the patients. The results were similar to iohexol. Confirmation of the radiologic findings by other diagnostic methods was not obtained. The risk added to renal arteriography by giving VISIPAQUE could not be analyzed.

Similar studies with digital subtraction angiography (DSA) were completed with comparable findings noted in cerebral arteriography, peripheral arteriography, and visceral arteriography. Studies have not been conducted to determine the lowest effective concentration.

INTRAVENOUS ADMINISTRATION

Excretory urography, contrast-enhanced computed tomography (CECT) of the head, CECT of the body, and peripheral venography were studied with either one or both VISIPAQUE Injection concentrations (270 mgI/mL or 320 mgI/mL). In these intravenous studies, diagnostic visualization ratings were good or excellent in 96-100% of the patients and a radiologic diagnosis was made in all (100%) of the patients given VISIPAQUE Injection. Results were compared to those of the active control. The number of patients studied in each indication is provided below.

Excretory urography was evaluated in one uncontrolled, unblinded clinical trial in 40 patients, 20 given VISIPAQUE Injection 270 mgI/mL and 20 given VISIPAQUE Injection 320 mgI/mL, and in two randomized, double-blind clinical trials in 50 adult patients given VISIPAQUE Injection 270 mgI/mL, 50 patients given VISIPAQUE Injection 320 mgI/mL, and 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given VISIPAQUE; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

CECT of the head was evaluated in two randomized, double-blind clinical trials in 49 adult patients given VISIPAQUE Injection 270 mgI/mL, in 50 patients given VISIPAQUE Injection 320 mgI/mL, and in 49 patients given iohexol 300 mgI/mL. CECT of the body was evaluated in three randomized, double-blind clinical trials in 104 adult patients given VISIPAQUE Injection 270 mgI/mL, in 109 patients given VISIPAQUE Injection 320 mgI/mL, and in 101 patients given iohexol 300 mgI/mL. In both CECT of the head and body, visualization ratings were good or excellent in 100% of the patients given VISIPAQUE; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of active controls. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

Peripheral venography was evaluated in two randomized, double-blind clinical trials in 46 adult patients given VISIPAQUE Injection 270 mgI/mL and in 50 patients given iohexol 300 mgI/mL. Visualization ratings were good or excellent in 100% of the patients given VISIPAQUE; a radiologic diagnosis was made in the majority of the patients. The results were similar to those of the active control. Confirmation of the radiologic findings by other diagnostic methods was not obtained.

INTRA-ARTERIAL1

VISIPAQUE Injection (270 mgI/mL) is indicated for intra-arterial digital subtraction angiography.

VISIPAQUE Injection (320 mgI/mL) is indicated for angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography.

INTRAVENOUS1

VISIPAQUE Injection (270 mgI/mL) is indicated for CECT imaging of the head and body, excretory urography, and peripheral venography.

VISIPAQUE Injection (320 mgI/mL) is indicated for CECT imaging of the head and body, and excretory urography.

1

For information on the concentrations and doses for the pediatric population see the Precautions–Pediatric Use, Clinical Pharmacology–Special Populations, and Dosage and Administration sections.

SERIOUS ADVERSE EVENTS—INADVERTENT INTRATHECAL ADMINISTRATION

Serious adverse reactions have been reported due to the inadvertent intrathecal administration of iodinated contrast media that are not indicated 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 this drug product is not administered intrathecally.

Nonionic, iodinated contrast media inhibit blood coagulation in vitro less than ionic contrast media. Clotting has been reported when blood remains in contact with syringes containing nonionic contrast media. The use of plastic syringes in place of glass syringes has been reported to decrease but not eliminate the likelihood of in vitro clotting.

Serious, rarely fatal, thromboembolic events causing myocardial infarction and stroke have been reported during angiocardiographic procedures with both ionic and nonionic contrast media. Therefore, meticulous intravascular administration technique is necessary, particularly during angiographic procedures, to minimize thromboembolic events. Numerous factors, including length of procedure, catheter and syringe material, underlying disease state, and concomitant medications, may contribute to the development of thromboembolic events. For these reasons, meticulous angiographic techniques are recommended, including close attention to guidewire and catheter manipulation, use of manifold systems and/or three-way stopcocks, frequent catheter flushing with heparinized saline solutions, and minimizing the length of the procedure.

Serious or rare fatal reactions have been associated with the administration of iodine-containing radiopaque media. It is of utmost importance to be completely prepared to treat any reaction associated with the use of any contrast agent.

Caution must be exercised in patients with severely impaired renal function, combined renal and hepatic disease, combined renal and cardiac disease, severe thyrotoxicosis, myelomatosis, or anuria, particularly when large doses are administered. (See PRECAUTIONS.)

Intravascularly administered iodine-containing radiopaque media are potentially hazardous in patients with multiple myeloma or other paraproteinaceous diseases, who are prone to disease induced renal insufficiency and/or renal failure. Although neither the contrast agent nor dehydration has been proven to be the cause of renal insufficiency (or worsening renal insufficiency) in myelomatous patients, it has been speculated that the combination of both may be causative. Special precautions, including maintenance of normal hydration and close monitoring, are required. Partial dehydration in the preparation of these patients is not recommended since it may predispose the patient to precipitation of the myeloma protein.

Reports of thyroid storm following the intravascular use of iodinated radiopaque contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule, suggest that this additional risk be evaluated in such patients before use of any contrast agent.

Administration of radiopaque materials to patients known to have, or suspected of having, pheochromocytoma should be performed 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 radiopaque medium injected should be kept to an absolute minimum. The blood pressure should be assessed throughout the procedure, and measures for the treatment of hypertensive crisis should be readily available. These patients should be monitored very closely during contrast-enhanced procedures.

Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when the agents are administered intravascularly.

GENERAL

CONTRAST AGENTS ARE ASSOCIATED WITH RISK AND INCREASED RADIATION EXPOSURE, AND THE DECISION TO USE ENHANCEMENT SHOULD BE BASED UPON A CAREFUL EVALUATION OF CLINICAL, OTHER RADIOLOGIC DATA, AND THE RESULTS OF UNENHANCED CT FINDINGS.

Patients receiving contrast agents, and especially those who are medically unstable, must be closely supervised. Diagnostic procedures which involve the use of iodinated intravascular contrast agents should be carried out under the direction of personnel skilled and experienced in the particular procedure to be performed. A fully equipped emergency cart, or equivalent supplies and equipment, and personnel competent in recognizing and treating adverse reactions of all types should always be available. Since severe delayed reactions have been known to occur, emergency facilities and competent personnel should be available for at least 30 to 60 minutes.

GENERAL ADVERSE REACTIONS WITH CONTRAST AGENTS

The following adverse reactions are possible with any parenterally administered iodinated contrast agent. Severe life-threatening reactions and fatalities, mostly of cardiovascular origin, have occurred. Most deaths occur during injection or five to ten minutes later, the main feature being cardiac arrest, with cardiovascular disease as the main aggravating factor. Isolated reports of hypotensive collapse and shock are found in the literature. Based upon clinical literature reported deaths from the administration of other iodinated contrast agents range from 6.6 per million (0.00066%) to 1 in 10,000 (0.01%).

The reported incidence of adverse reactions to contrast agents in patients with a history of allergy is twice that of the general population. Patients with a history of a previous reaction to a contrast agent are three times more susceptible than other patients. However, sensitivity to contrast media does not appear to increase with repeated examinations.

Adverse reactions to injectable contrast agents fall into two categories: chemotoxic reactions and idiosyncratic reactions. Chemotoxic reactions result from the physicochemical properties of the contrast agent, the dose and the speed of injection. All hemodynamic disturbances and injuries to organs or vessels perfused by the contrast agent are included in this category.

Idiosyncratic reactions include all other reactions. They occur more frequently in patients 20 to 40 years old. Idiosyncratic reactions may or may not be dependent on the dose injected, the speed of injection, the mode of injection and the radiographic procedure. Idiosyncratic reactions are subdivided into minor, intermediate, and severe. The minor reactions are self-limited and of short duration; the severe reactions are life-threatening, and treatment is urgent and mandatory.

INFORMATION FOR PATIENTS

Patients receiving an iodinated intravascular contrast agent should be instructed to:

1. Inform your physician if you are pregnant (see PRECAUTIONS - Pregnancy Category B).
2. Inform your physician if you are diabetic or if you have multiple myeloma, pheochromocytoma, homozygous sickle cell disease, or known thyroid disorder (see WARNINGS).
3. Inform your physician if you are allergic to any drugs or food, or if you have immune, autoimmune or immune deficiency disorders. Also inform your physician if you had any reactions to previous injections of dyes used for x-ray procedures (see PRECAUTIONS, General).
4. Inform your physician about all medications you are currently taking, including nonprescription (over-the-counter) drugs, before you have this procedure.

DRUG INTERACTIONS

Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received an oral cholecystographic contrast agent.

Other drugs should not be mixed with VISIPAQUE Injection.

DRUG/LABORATORY TEST INTERACTIONS

The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine estimations (e.g., T3 resin uptake and total or free thyroxine T4 assays) are not affected.

As reported with other contrast agents, VISIPAQUE may produce a false-positive result for protein in the urine using Multistix®. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of VISIPAQUE. In addition, care should be used in interpreting the results of urine specific gravity measurements in the presence of high levels of VISIPAQUE and other contrast agents in the urine. Refractometry or urine osmolality may be substituted.

LABORATORY TEST FINDINGS

Coagulation, platelets, erythrocytes and complement activation were evaluated with standard citrated human plasma or whole blood in the following assays: thrombin generation time, platelet aggregation and activation, red blood cell rigidification and aggregation, and complement activation. Data on reversibility, thrombin time, PTT and clotting factors are not available.

In vitro human blood studies showed that with 5 mL of iodixanol 320 mgI/mL, the thrombin generation time was increased to a mean of 46 minutes (saline control = 14 minutes). An in vitro study of platelet enriched plasma after incubation with iodixanol 320 mgI/mL, the platelet aggregation response to collagen was inhibited to 63% of normal (range 30-98% with iodixanol concentrations of 16 to 64 mgI/mL); these findings were comparable to those of a tested nonionic comparators; platelet degranulation did not occur. Erythrocyte rigidification (measured by half conductance of the Mynipore sieve with hematocrit adjusted to 8%) was comparable for iodixanol and the tested nonionic comparators. Also, the red cell aggregation decrease was comparable to that of other nonionic comparators. In a CH-50 hemolytic complement activation assay after 11 hours of incubation with 320 mgI/mL, the remaining complement activity was approximately 15 % (± 3) of normal.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Long-term animal studies have not been performed with iodixanol to evaluate carcinogenic potential. Iodixanol was not genotoxic in a series of studies including the Ames test, the CHO/HGPRT assay, a chromosome aberration assay in CHO cells, and a mouse micronucleus assay. Iodixanol did not impair the fertility of male or female rats when administered at doses up to 2.0 gI/kg (1.3 times the maximum recommended dose for a 50 kg human, or approximately 0.2 times the maximum recommended dose for a 50 kg human following normalization of the data to body surface area estimates).

PREGNANCY

NURSING MOTHERS

It is not known whether VISIPAQUE Injection is excreted in human milk. However, many injectable contrast agents are excreted unchanged in human milk. Although it has not been established that serious adverse reactions occur in nursing infants, caution should be exercised when intravascular contrast agents are administered to nursing women because of the potential for adverse reactions, and consideration should be given to temporarily discontinue nursing.

PEDIATRIC USE

The safety and efficacy of VISIPAQUE has been established in the pediatric population over 1 year of age for arterial studies and for intravenous procedures. Use of VISIPAQUE in these age groups is supported by evidence from adequate and well controlled studies of VISIPAQUE in adults and additional safety data obtained in pediatric studies. Although VISIPAQUE has been administered to pediatric patients less than 1 year of age, the relative safety of the volumes injected, the optimal concentrations, and the potential need for dose adjustment because of prolonged elimination half-lives have not been systematically studied. (See Clinical Pharmacology–Special Populations section).

VISIPAQUE (iodixanol) Injection was administered to 459 pediatric patients. There were 26 patients administered VISIPAQUE Injection in the birth to <29 day age range, 148 from 29 days to 2 years, 263 from 2 to <12 years, and 22 from 12 to 18 years. The mean age was 4.4 years (range <1 day to 17.4 years). Of the 459 patients, 252 (55%) were male and 207 (45%) were female. The racial distribution was: Caucasian-81%, Black-14%, Oriental-2%, and other or unknown-4%. The demographic information for the pool of patients who received a comparison contrast agent was similar.

In pediatric patients who received intravenous injection for computerized tomography or excretory urography, a concentration of 270 mgI/mL was used in 144 patients, and a concentration of 320 mgI/mL in 154 patients. All patients received one intravenous injection of 1-2 mL/kg.

In pediatric patients who received intra-arterial and intracardiac studies, a concentration of 320 mgI/mL was used in 161 patients. Of the 161 patients in the intra-arterial studies, the mean age was 2.6 years. Twenty-two patients were < 29 days of age; 78 were 29 days to 2 years of age; and 61 were over 2 years. Most of these pediatric patients received initial volumes of 1-2 mL/kg and most patients had a maximum of 3 injections.

Optimal volumes, concentrations or injection rates of VISIPAQUE have not been established because different injection volumes, concentrations, and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment to maximize efficacy of computerized tomography, or to minimize the toxicity to other immature body tissues, has not been studied in neonates or infants with immature renal function.

In the above patients, adverse events were associated with decreasing age and intra-arterial procedures. In general the type of adverse events reported are similar to those of adults. Although the frequency of events appears to be comparable, the percentages cannot be confirmed because of the different ability of pediatric and adult patients to report adverse events.

GERIATRIC USE

Of the total number of patients in clinical studies of VISIPAQUE in the U.S., 254/757 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

GENERAL

The combination of volume and concentration of VISIPAQUE Injection to be used should be individualized, accounting for factors such as age, body weight, size of the vessel, and rate of blood flow within the vessel. Specific dose adjustment studies for age, gender, weight and renal function have not been conducted with VISIPAQUE. As with other iodinated contrast agents, lower doses may have less risk. The efficacy of VISIPAQUE Injection below doses recommended has not been established. Other factors, such as pathology anticipated, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed, should be considered.

The maximum recommended total dose of iodine is 80 grams.

If an adverse reaction occurs during injection, consider stopping the injection immediately if warranted by the nature and severity of the event.

Patients should be adequately hydrated prior to and following the intravascular administration of iodinated contrast agents (see WARNINGS and PRECAUTIONS).

INTRA-ARTERIAL ADMINISTRATION

VISIPAQUE 320mgI/mL is recommended for intra-arterial injection in the radiographic contrast evaluation of arterial lesions of the brain, the coronary arteries and left ventricle, and for intra-arterial injection in the radiographic contrast evaluation of peripheral arteries. VISIPAQUE is also recommended for intra-arterial digital subtraction angiography, as specified in the dosing chart below.

Injection rates should be approximately equal to the flow rate in the vessel being injected. The volume required will depend on the size, flow rate, and disease state of the injected vessel, on the size and condition of the patient, and on the imaging technique used. The usual single injection volumes or total dose per patient (mL/kg) for adults and adolescents over 12 years of age are listed in the tables below.

INTRAVENOUS ADMINISTRATION

PEDIATRIC DOSING

The recommended dose in children over 1 year of age for the evaluation of:

DRUG HANDLING

As with all contrast agents because of the potential for chemical incompatibility, VISIPAQUE Injection should not be mixed with, or injected in, intravenous administration lines containing other drugs, solutions or total nutritional admixtures.

Sterile technique must be used in all procedures involving vascular injections of contrast agents.

VISIPAQUE Injection may be administered at body temperature as well as at room temperature.

If nondisposable equipment is used, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents.

Withdrawal of contrast agents from their containers should be accomplished under strict aseptic conditions using only sterile syringes and transfer devices. Contrast agents which have been transferred into other delivery systems should be used immediately.

Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, and should not be used if particulates are observed or marked discoloration has occurred.

DIRECTIONS FOR PROPER USE OF VISIPAQUE PHARMACY BULK PACKAGE

1. The transfer of VISIPAQUE (iodixanol) Injection from the Pharmacy Bulk Package is restricted to a suitable work area, such as a laminar flow hood.
2. The container closure may be penetrated only one time, utilizing a suitable transfer device and aseptic technique.
3. The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operations. The container should not be removed from the aseptic area during the entire 8 hour period.
4. The temperature of the container should not exceed 30°C, after the closure has been entered.

FEDERAL GOVERNMENT CODES

VISIPAQUE (iodixanol) Injection 270 mgI/mL:

500 mL in +PLUSPAK (polymer bottle), boxes of 10 Pharmacy Bulk Packages (NDC 0407-2222-24)

VISIPAQUE (iodixanol) injection 320 mgI/mL:

500 mL in +PLUSPAK (polymer bottle), boxes of 10 Pharmacy Bulk Packages (NDC 0407-2223-58)

Protect polymer bottles of VISIPAQUE Injection from strong daylight and direct exposure to sunlight. VISIPAQUE should be stored at controlled room temperature, 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature].

VISIPAQUE Injection in all presentations may be stored in a contrast media warmer for up to one month at 37°C (98.6°F).

Do not freeze or use if the product is inadvertently frozen. Freezing may compromise the closure integrity of these packages.

SPECIAL HANDLING AND STORAGE FOR POLYMER BOTTLES:
DO NOT USE IF TAMPER-EVIDENT RING IS BROKEN OR MISSING.