VISIPAQUE

Iodixanol is a nonionic hydrophilic compound commonly used as a contrast agent during coronary angiography, particularly in individuals with renal dysfunction, as it is believed to be less toxic to the kidneys than most other intravascular contrast agents.

Iodixanol is a contrast agent during coronary angiography.

Iodixanol is a contrast agent commonly used during coronary angiography, particularly in individuals with renal dysfunction, as it is believed to be less toxic to the kidneys than most other intravascular contrast agents.

It is an imaging contrast agent with the same osmolality as blood (290mOsm/kg H20).

Organic iodine compounds attenuate x-rays as they pass through the body, thereby allowing the body structures containing iodine to be delineated in contrast to those structures that do not contain iodine.

The degree of opacity produced by these compounds is directly proportional to the total amount (concentration and volume) of the iodinated contrast agent in the path of the x-rays.

After intravascular administration, iodixanol makes opaque those internal structures in its path of flow, allowing their visualization until significant hemodilution and elimination occur.

In adults, approximately 97% of the injected dose of iodixanol is excreted unchanged in urine within 24 hours, with less than 2% excreted in feces within five days post-injection.

In patients with significantly impaired renal function (mean creatinine clearance rate, 9.91 mL per minute), the plasma half-life is increased to 23 hours.

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Non-ionic radiocontrast agents like iodixanol are cytotoxic to renal cells.

The toxic effects include apoptosis, cellular energy failure, disruption of calcium homeostasis, and disturbance of tubular cell polarity, and are thought to be linked to oxidative stress.

Iodixanol is contraindicated for intrathecal use

Not indicated for intrathecal use.

Individualize the combination of volume and concentration of iodixanol injection considering age, body weight, size of the vessel, rate of blood flow within the vessel, and other applicable factors.

CT of the head and body, iodixanol injection may be used with an automated contrast injection system or contrast media management system cleared for use with iodixanol injection.

For the adult patients, the maximum recommended total dose of iodine is 80 grams.

Patients should be adequately hydrated prior to and following the intravascular administration of iodinated contrast agents.

See full prescribing information for complete dosing and administration information. 2.1 Important Dosage and Administration Instructions Iodixanol injection is for intravascular use only Use sterile technique for all handling and administration of iodixanol injection.

Do not use if tamper-evident ring is broken or missing.

Warm iodixanol injection and administer at body or room temperature.

Inspect iodixanol injection for particulate matter or discoloration before administration, whenever solution and container permit.

Do not administer if iodixanol injection contains particulate matter or is discolored.

Do not mix iodixanol injection with, or inject in intravenous lines containing, other drugs or total nutritional admixtures.

Use the lowest dose necessary to obtain adequate visualization.

Individualize the volume, strength, and rate of administration of iodixanol injection.

Consider factors such as age, bodyweight, vessel size, blood flow rate within the vessel, anticipated pathology, degree and extent of opacification required, structures or area to be examined, disease processes affecting the patient, and equipment and technique to be employed.

The maximum recommended total dose of iodine for adults is 80 grams.

Avoid extravasation when injecting iodixanol injection; especially in patients with severe arterial or venous disease.

Hydrate patients before and after iodixanol injection administration. 2.2 Intra-arterial Dosage and Administration Intra-arterial digital subtraction angiography (IA-DSA) (270 mg Iodine/mL and 320 mg Iodine/mL) Angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography (320 mg Iodine/mL) Use injection rates approximately equal to the flow rate in the vessel being injected.

The usual single injection volumes or total dose per patient (mL/kg) for adults and adolescents over 12 years of age are listed in Table 1: TABLE 1 ADULTS and PEDIATRIC PATIENTS 12 YEARS OF AGE AND OLDER IODIXANOL INJECTION SINGLE DOSE RECOMMENDATIONS FOR INJECTION INTO SELECTED ARTERIES ARTERIOGRAPHY IA-DSA 1 Maximum Total Dose Intra-arterial Injection Sites 320 mg Iodine/mL 270 mg Iodine/mL 320 mg Iodine/mL Carotid Arteries 10 mL to 14 mL 5 mL to 8 mL Usually Not to Exceed 175 mL Vertebral Arteries 10 mL to 12 mL 5 mL to 8 mL Right Coronary Artery 3 mL to 8 mL Usually Not to Exceed 200 mL Left Coronary Artery 3 mL to 10 mL Left Ventricle 20 mL to 45 mL Renal Arteries 8 mL to 18 mL 10 mL to 25 mL -

• Usually Not to Exceed 250 mL Aortography 30 mL to 70 mL 20 mL to 50 mL 10 mL to 50 mL Major Branches of Aorta 10 mL to 70 mL 5 mL to 30 mL 2 mL to 10 mL Aortofemoral Runoffs 20 mL to 90 mL -

• 6 mL to 15 mL Peripheral Arteries 15 mL to 30 mL -

• 3 mL to 15 mL 1 IA-DSA = Intra-arterial Digital Subtraction Angiography 2.3 Intravenous Dosage and Administration Computed Tomography of the Head or Body (270 mg Iodine/mL and 320 mg Iodine/mL) Excretory Urography (270 mg Iodine/mL and 320 mg Iodine/mL) Peripheral Venography (270 mg Iodine/mL) Coronary Computed Tomography Angiography (CCTA) (320 mg Iodine/mL) Recommended dosage of iodixanol injection is dependent on: the administration procedure, patient weight, and CT device factors, as detailed in Table 2.

Calibrate the intravenous injection rate so that image acquisition coincides with peak arterial concentration.

The time between iodixanol injection and peak arterial concentration varies between patients.

Selected dosing for different indications in adults and pediatric patients over 12 years of age are shown in Table 2.

TABLE 2 ADULTS and PEDIATRIC PATIENTS 12 YEARS OF AGE AND OLDER IODIXANOL INJECTION DOSING RECOMMENDATIONS FOR INTRAVENOUS CONTRAST ADMINISTRATION Study Type Comment 270 mg Iodine/mL 320 mg Iodine/mL Maximum Total Volume CT of Head or Body 1 Bolus 75 mL to 150 mL 75 mL to 150 mL 150 mL Infusion 100 mL to 150 mL 100 mL to 150 mL Excretory Urography Normal Renal Function 1 mL/kg 1 mL/kg 100 mL Venography Per lower extremity 50 mL to 150 mL 250 mL CCTA 1,2 Bolus injection with test bolus 3 or bolus tracking 50 mL to 150 mL 4 (4 mL to 7 mL per second) 150 mL For CT of the head and body, iodixanol injection may be used with an automated contrast injection system or contrast media management system cleared for use with iodixanol injection.

For pediatric patients aged to 17, recommended dose is 1 mL/kg to 2 mL/kg.

The main iodixanol injection volume may be preceded by a test bolus consisting of 20 mL iodixanol injection, immediately followed by a 20 mL saline flush, both injected at rate of 4 mL/sec to 7 mL/sec.

Injection of iodixanol injection with saline can be either biphasic (without dilution phase) or triphasic (with dilution phase).

Alternatively, a dose of 1 mL/kg may be used to calculate total iodixanol injection dose (excluding any test bolus).

CCTA acquired at < 120 kVp, the dose of iodixanol injection may be reduced by up to 15% in patients < 85 kg and BMI < 30 kg/m 2.

CCTA acquired on a scanner with more than 64 detector rows, the dose of iodixanol injection may be reduced in proportion to the scan duration. 2.4 Dosage in Pediatric Patients Less Than 12 Years of Age Intra-arterial Dosage and Administration Angiocardiography, cerebral arteriography, or visceral arteriography (320 mg Iodine/mL): The recommended dosage is 1 mL/kg to 2 mL/kg. The maximum dose should not exceed 4 mL/kg. Intravenous Dosage and Administration Computerized Tomography or Excretory Urography (270 mg Iodine/mL): The recommended dosage is 1 mL/kg to 2 mL/kg. The maximum dose should not exceed 2 mL/kg. 2.5 Instructions for Use with an Automated Contrast Injection System or Contrast Management System for CT of the Head and Body Iodixanol injection may be used with an automated contrast injection system cleared for use with contrast media. ◦ See above Important Dosage and Administration Instructions for iodixanol injection. ◦ See device labeling for information on device indications, instructions for use, and techniques to help assure safe use.

Iodixanol injection 320 mg Iodine/mL in 100 mL and 150 mL bottles may be used with a contrast media management system cleared for use with iodixanol injection 320 mg Iodine/mL in 100 mL and 150 mL bottles. ◦ See device labeling for information on device indications, instructions for use, and techniques to help assure safe use. ◦ Use sterile technique for penetrating the container closure of iodixanol injection 320 mg Iodine/mL and transferring iodixanol injection solution.

Clean the stopper with a pad soaked in sporicidal solution followed by a pad soaked in alcohol, then puncture the stopper.

The container closure may be penetrated only one time with a suitable sterile component of the contrast media management system cleared for use with iodixanol injection 320 mg Iodine/mL in 100 mL and 150 mL bottles. ◦ Once the iodixanol injection 320 mg Iodine/mL is punctured do not remove the bottle from the work area during the entire period of use. ◦ Maximum use time is 4 hours after initial puncture. ◦ Each bottle is for one procedure only.

Discard unused portion.

Iodixanol injection, USP is a ready-to-use sterile, pyrogen-free, preservative free, colorless to pale yellow solution available in two strengths.

It is supplied in the following configurations: Iodixanol Injection, USP, 270 mg Iodine/mL: Product Code Unit of Sale Each 381100 NDC 65219-381-10 Unit of 10 NDC 65219-381-03 100 mL single-dose polypropylene bottle 381150 NDC 65219-381-50 Unit of 10 NDC 65219-381-05 150 mL single-dose polypropylene bottle Iodixanol Injection, USP, 320 mg Iodine/mL: Product Code Unit of Sale Each 383105 NDC 65219-383-05 Unit of 10 NDC 65219-383-02 50 mL single-dose polypropylene bottle 383110 NDC 65219-383-10 Unit of 10 NDC 65219-383-04 100 mL single-dose polypropylene bottle 383150 NDC 65219-383-50 Unit of 10 NDC 65219-383-06 150 mL single-dose polypropylene bottle 383200 NDC 65219-383-70 Unit of 10 NDC 65219-383-08 200 mL single-dose polypropylene bottle 16.2 Storage and Handling Protect iodixanol injection, USP from direct exposure to sunlight.

Store iodixanol injection, USP at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Iodixanol injection, USP may be stored in a contrast media warmer for up to one month at 37°C (98.6°F).

Do not freeze.

Discard any product that is inadvertently frozen, as freezing may compromise the closure integrity of the immediate container.

DO NOT USE IF TAMPER-EVIDENT RING IS BROKEN OR MISSING.

Protect iodixanol injection, USP from direct exposure to sunlight.

Store iodixanol injection, USP at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Iodixanol injection, USP may be stored in a contrast media warmer for up to one month at 37°C (98.6°F).

Do not freeze.

Discard any product that is inadvertently frozen, as freezing may compromise the closure integrity of the immediate container.

DO NOT USE IF TAMPER-EVIDENT RING IS BROKEN OR MISSING.

There are no data with iodixanol use in pregnant women to inform any drug-associated risks.

In animal reproduction studies, no developmental toxicity occurred with intravenous iodixanol administration to rats and rabbits at doses up to 0.24 (rat) or 0.48 (rabbit) times the maximum recommended human intravenous dose.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Reproduction studies were performed in rats and rabbits with intravenous administration of iodixanol at doses up to 2 g Iodine/kg, daily, from implantation of the embryo (gestation day in rat; 6 in rabbit) through closure of the hard palate (gestation day in rats; 18 in rabbits).

No maternal toxicity occurred, and no adverse effects occurred on fetal survival, embryo-fetal development, or the ability of dams to rear a litter.

The safety and efficacy of iodixanol have been established in pediatric patients down to birth for angiocardiography, cerebral arteriography, visceral arteriography, CT imaging of the head and body, and excretory urography.

The safety and efficacy of iodixanol have also been established in pediatric patients 12 years and older for intra-arterial digital subtraction angiography, peripheral arteriography, peripheral venography and CCTA.

Use of iodixanol is supported by evidence from adequate and well controlled studies of iodixanol in adults and additional safety data obtained in 459 pediatric patients.

In general, the types of adverse reactions reported are similar to those of adults.

A higher number of adverse events in patients less than 1 year of age compared to older patients were observed in a study of iodixanol.

The elimination of iodixanol is slower in this.

Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates.

Some patients were treated for hypothyroidism.

After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients to 3 years of age based on underlying risk factors, especially in term and preterm neonates.

Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent may include those with asthma, hypersensitivity to other medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL.

Pediatric patients with immature renal function or dehydration may be at increased risk for adverse events due to slower elimination of iodinated contrast agents.

In clinical studies of iodixanol, 254/757 (34%) of patients were and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients.

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.