ULTRAVIST

Iopromide is a low osmolar, non-ionic X-ray contrast agent for intravascular administration.

It functions as a contrast agent by opacifying blood vessels in the flow path of the contrast agent, permitting radiographic visualization of the internal structures until significant hemodilution occurs.

Although iopromide can cause several serious adverse effects, including cardiac events, thromboembolism, hypersensitivity reaction, and even death if administered intrathecally inadvertently, it is still deemed to have a favorable safety profile, with only 0.7% of patients in a 2 years study experiencing adverse events.

Although the mechanism is unclear, women and outpatients tend to have a higher incidence of adverse events compared to other population groups.

Approved by the FDA in and Health Canada in 1994 under the brand name ULTRAVIST, iopromide is used in radiological diagnosis, including, but not limited to, intra-arterial digital subtraction angiography (IA-DSA), cerebral and peripheral arteriography, peripheral venography, excretory urography, brain computer tomography (CT), coronary arteriography, left ventriculography, visceral angiography, and orthography. 3, 6.

Iopromide, as the product IOVIST, is approved by the FDA for use as an intra-arterial or intravenous X-ray contrast agent.

For intra-arterial administration, iopromide is indicated for cerebral arteriography, peripheral arteriography, coronary arteriography, left ventriculography, visceral angiography, and aortography in adults and radiographic evaluation of cardiac chambers and related arteries in pediatric patients aged 2 years and older.

For intravenous administration, iopromide is indicated for excretory urography in adults and pediatric patients aged 2 years and older, contrast Computed Tomography (CT) of the head and body (intrathoracic, intra-abdominal, and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions in adults and pediatric patients aged 2 years and older, and contrast mammography to visualize known or suspected lesions of the breast in adults, as an adjunct following mammography and/or ultrasound.

Iopromide is also approved by Health

Canada as an intravascular contrasting agent, although the indications differ depending on the dosage.

At 300 mg I/mL, iopromide is indicated for computed tomography (CT), excretory urography, pediatric excretory urography, renal arteriography, peripheral arteriography (bifemoral pelvis/leg), cerebral arteriography, phlebography of the extremities, and arthrography.

After intravenous injection, opacification of the renal parenchyma begins within 1 minute.

Excretion of the contrast agent becomes apparent in 1-3 minutes with optimal contrast in the calyces and collecting system occurring between and 15 minutes.

In nephropathic conditions, particularly when excretory capacity has been altered, the excretion rate varies unpredictably and opacification may be delayed for several hours after injection. 6 the degree of contrast enhancement is related to the iodine concentration in the tissue of interest.

Iopromide is a nonionic iodinated, water-soluble, radiographic contrast medium that is available in two stable, ready-to-use solutions of different concentrations (i.e., 300 mg I/mL and 370 mg I/mL).

Following intravascular injection, iopromide provides radiographic opacification of the vasculature and extracellular space in the path of flow of the agent, allowing diagnostic assessment of the limbs and internal organs until significant dilution occurs.

Immediately following intravascular injection, iopromide reaches peak plasma concentrations and is then rapidly distributed throughout the extracellular fluid compartment.

It displays little tendency to bind to serum or plasma proteins.

Iodinated contrast agents cross a disrupted blood-brain barrier.

The total volume of distribution at steady state is about 16 L, suggesting distribution into extracellular space.

Iopromide does not undergo significant metabolism, deiodination, or biotransformation.

The amounts excreted unchanged in urine represent 97% of the dose in adult healthy subjects.

Only 2% of the dose is recovered in the feces.

Similar recoveries in urine and feces are observed in middle-aged and elderly patients.

This finding suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide.

During the slower terminal phase, only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the largest part of which occurs during the main elimination phase.

The ratio of the renal clearance of iopromide to the creatinine clearance is 0.82, suggesting that iopromide is mainly excreted by glomerular filtration.

After intravenous administration to healthy adult subjects, the plasma iopromide concentration-time profile shows an initial distribution phase with a half-life of 0.24 hours; a main elimination phase with a half-life of 2 hours; and a terminal elimination phase with a half-life of 6.2 hours.

The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively.

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There are no data on iopromide use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Iopromide crosses the placenta and reaches fetal tissues in small amounts.

In animal reproduction studies, intravenous administration of iopromide to pregnant rats and rabbits during organogenesis at doses up to 0.35 and 0.7 times, respectively, the maximum recommended human dose based on body surface area resulted in no relevant adverse developmental effects.

The safety and efficacy of iopromide have been established in pediatric patients aged 2 years and older for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of the head and body.

The use of iopromide in these age groups for these indications is supported by evidence from adequate and well-controlled studies in adults and additional safety data in pediatric patients aged 2 years and older, including data from published studies.

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

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 0-3 years of age based on underlying risk factors, especially in term and preterm neonates.

The clearance of iopromide decreases with increasing degree of renal impairment and results in delayed opacification of the urinary system.

In addition, preexisting renal impairment increases the risk of acute kidney injury.

Iopromide can be removed by dialysis.

Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on fertility.

Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse micronucleus assay, and an in vivo mouse dominant lethal assay.

The manifestations of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems.

Treatment of overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy.

The most common adverse reactions (>1%) are headache, nausea, injection site and infusion site reactions, vasodilatation, vomiting, back pain, urinary urgency, chest pain, pain, dysgeusia, and abnormal vision.

Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.

• Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, size of the vessel, and the rate of blood flow within the vessel.

• For contrast mammography, use ULTRAVIST with a device that is cleared for dual-energy full field digital mammography.

• See full prescribing information for important dosage and administration instructions and directions for use of pharmacy bulk packages and imaging bulk packages. 2.1 Important Dosage and Administration Information.

• ULTRAVIST is for intra-arterial or intravenous use only and must not be administered intrathecally.

• Specific concentrations and presentations of ULTRAVIST are recommended for each type of imaging procedure.

• Hydrate patients, as appropriate, prior to and following the administration of ULTRAVIST.

• Individualize the volume, concentration, and injection rate of ULTRAVIST according to the specific dosing tables.

Consider factors such as age, body weight, size of the vessel, and the rate of blood flow within the vessel; also consider extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed.

• Visually inspect ULTRAVIST for particulate matter and/or discoloration, whenever solution and container permit.

Do not administer

ULTRAVIST if particulate matter (including crystals) and/or discoloration is observed or if containers are defective.

• Use aseptic technique for all handling and administration of ULTRAVIST.

• Warm ULTRAVIST to body temperature before administration.

• ULTRAVIST can be used with 0.9% Sodium Chloride Injection in a power injector suitable for simultaneous injection of contrast.

However, do not mix or inject ULTRAVIST in intravenous administration lines containing other drugs or total nutritional admixtures.

• Discard any unused portion remaining in the single-dose container following initial use. 2.2 Recommended Dosage for Intra-Arterial Procedures in Adults.

• The recommended doses for intra-arterial procedures in adults are shown in Table 1.

• Inject at rates approximately equal to the flow rate in the vessel being injected.

Table 1: Recommended Concentrations and Volume of ULTRAVIST to Administer per Single Injection for Selected Injection Sites of Intra-Arterial Procedures in Adults Imaging Procedure Cerebral Arteriography Peripheral Arteriography Coronary Arteriography and Left Ventriculography Visceral Angiography and Aortography Concentration (mg Iodine per mL) 300 300 370 370 Intra-Arterial Injection Sites Carotid Arteries 3 mL to 12 mL.

• Vertebral Arteries 4 mL to 12 mL Aortic Arch Injection (four vessel study) 20 mL to 50 mL Subclavian or Femoral Artery.

• 5 mL to 40 mL.

• Aortic Bifurcation (distal runoff) 25 mL to 50 mL Right Coronary Artery.

• 3 mL to 14 mL.

• Left Coronary Artery 3 mL to 14 mL Left Ventricle 30 mL to 60 mL Aorta and Major Abdominal Branches.

• Individualize a volume approximately equal to the blood flow and related to the vascular and pathological characteristics of the specific vessels being studied.

Dose 150 mL 250 mL 225 mL 225 mL *Use single-dose vials or pharmacy bulk package. 2.3 Recommended Dosage for Intravenous Procedures in Adults Recommended doses for intravenous procedures in adults are shown in Table 2.

Table 2: Recommended Concentrations and Volume of ULTRAVIST for Intravenous Procedures in Adults Imaging Procedure Excretory Urography Contrast Computed Tomography Contrast Mammography Concentration (mg Iodine per mL) 300 * 300 ‡ 370 ‡ 300 ‡ or 370 ‡ Excretory Urography 1 mL/kg body weight.

• 50 mL to 200 mL 41 mL to 162 mL.

• Single Phase Contrast Bolus Injection Rapid Infusion.

• 50 mL to 200 mL 100 mL to 200 mL 41 mL to 162 mL 81 mL to 162 mL.

• CT of Body – Multiple Phase Contrast.

• 50 mL to 200 mL total volume Phase 1: 100% contrast, Phase 2: 20% to 60% contrast, using a power injector suitable for simultaneous injection of contrast and 0.9% Sodium Chloride Injection 41 mL to 162 mL total volume Phase 1: 100% contrast, Phase 2: 20% to 60% contrast, using a power injector suitable for simultaneous injection of contrast and 0.9% Sodium Chloride Injection.

• 1.5 mL/kg body weight using a power injector at 2 mL/second to 4 mL/second Maximum Total Dose 100 mL 200 mL 162 mL 150 mL * Use single-dose vials or pharmacy bulk package. ‡ Use single-dose vials, pharmacy bulk package or imaging bulk package. 2.4 Recommended Dosage in Pediatric Patients Aged 2 Years and Older The recommended doses in pediatric patients aged 2 years and older are shown in Table 3.

Table 3: Recommended Concentrations and Volume per Body Weight of ULTRAVIST for Cardiac Chambers and Related Arteries, Excretory Urography, and Contrast Computed Tomography in Pediatric Patients Aged 2 Years and Older Imaging Procedure Intra-arterial Intravenous Cardiac Chambers and Related Arteries Excretory Urography Contrast Computerized Tomography Concentration (mg Iodine/mL) 370 300 300 ‡ Volume (mL/kg body weight) 1 to 2 1 to 2 1 to 2 Maximum Total Dose (mL/kg) 4 3 3 * Use single-dose vials or pharmacy bulk package. ‡ Use single-dose vials, pharmacy bulk package or imaging bulk package. 2.5 Imaging Instruction for Contrast Mammography For contrast mammography, use ULTRAVIST with a device that is cleared for dual-energy full field digital mammography. 2.6 Directions for Use of ULTRAVIST Pharmacy Bulk Package.

• ULTRAVIST Pharmacy Bulk Package (PBP) is not for direct infusion.

• Perform the transfer of the PBP in a suitable work area, such as a laminar flow hood, utilizing aseptic technique.

• Penetrate the container closure only one time, utilizing a suitable transfer device.

• After initial puncture, use the contents of the PBP within 10 hours.

Discard any unused portion 2.7 Directions for Use of ULTRAVIST Imaging Bulk Package.

• ULTRAVIST Imaging Bulk Package (IBP) is for intravenous use only.

• ULTRAVIST IBP is for use only with an automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this IBP.

Please see drug and device labeling for information on devices indicated for use with this IBP and techniques to help assure safe use.

• The IBP is to be used only in a room designated for radiological procedures that involve intravascular administration of a contrast agent.

• Using aseptic technique, penetrate the container closure of the IBP only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this IBP.

• Once the IBP is punctured, do not remove it from the work area during the entire period of use.

Maintain the bottle in an inverted position such that container contents are in continuous contact with the dispensing set.

• After the container closure is punctured, if the integrity of the IBP and the delivery system cannot be assured through direct continuous supervision, discard the IBP and all associated disposables for the automated contrast injection system, contrast management system, or contrast media transfer set.

• A maximum use time from initial puncture is 10 hours.

Discard any unused portion remaining in

IBP container.

• Storage temperature of IBP after the closure has been entered should not exceed 25°C (77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F); however, it is desirable that the contents be warmed to body temperature prior to injection.

ULTRAVIST injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in the following presentations: ULTRAVIST 300 mg Iodine per mL Package Type Volume Sale Unit NDC Single-Dose Vials 50 mL Carton of 10 50419-344-05 100 mL Carton of 10 50419-344-10 125 mL Carton of 10 50419-344-12 150 mL Carton of 10 50419-344-15 Pharmacy Bulk Package 200 mL Carton of 10 50419-344-21 500 mL Carton of 8 50419-344-58 Imaging Bulk Package 200 mL Carton of 10 50419-344-23 500 mL Carton of 8 50419-344-65 ULTRAVIST 370 mg Iodine per mL Package Type Volume Sale Unit NDC Single-Dose Vials 50 mL Carton of 10 50419-346-05 100 mL Carton of 10 50419-346-10 150 mL Carton of 10 50419-346-15 200 mL Carton of 10 50419-346-20 Pharmacy Bulk Package 200 mL Carton of 10 50419-346-26 500 mL Carton of 8 50419-346-58 Imaging Bulk Package 200 mL Carton of 10 50419-346-28 500 mL Carton of 8 50419-346-65 Storage and Handling Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Protect from light.

Risk Summary There are no data on ULTRAVIST use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Iopromide crosses the placenta and reaches fetal tissues in small amounts.

In animal reproduction studies, intravenous administration of iopromide to pregnant rats and rabbits during organogenesis at doses up to0.35 and 0.7 times, respectively, the maximum recommended human dose based on body surface area resulted in no relevant adverse developmental effects.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defects, 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.

Limited case reports demonstrate that intravenously administered iodinated contrast agents, including iopromide, cross the placenta and are visualized in the digestive tract of exposed infants after birth.

Reproduction studies were performed with intravenous iopromide in rats (day to 15 of gestation) and rabbits (day to 18 of gestation) at dose levels of 0, 0.37, 1.11, and 3.7 g iodine per kg, corresponding to doses up to 0.35 times (rats) and 0.7 times (rabbits) the maximum human recommended dose based on body surface area.

Iopromide was not teratogenic at any dose level in rats and rabbits and embryolethality was observed in rabbits that received 3.7 g iodine per kg, but this was considered to have been secondary to maternal toxicity.

The safety and efficacy of

ULTRAVIST have been established in pediatric patients aged 2 years and older for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of head and body.

Use of

ULTRAVIST in these age groups for these indications is supported by evidence from adequate and well-controlled studies in adults and additional safety data in pediatric patients aged 2 years and older, including data from published studies.

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

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.

Safety and effectiveness of

ULTRAVIST have not been established in pediatric patients younger than 2 years for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of head and body.

ULTRAVIST for cerebral arteriography, peripheral arteriography, coronary arteriography and left ventriculography, visceral angiography, aortography, and contrast mammography have not been established in pediatric patients.

In a clinical study of ULTRAVIST for CT, 96/434 (22.1%) of patients were and over.

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

Other reported clinical experience has not identified differences in response between the elderly and younger patients.

Iopromide is known to be substantially excreted by the kidney, and the risk of adverse reactions to iopromide 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.