Omnipaque

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks Associated with Inadvertent Intrathecal Administration [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] Contrast-Induced Kidney Injury [see Warnings and Precautions (5.3) ] Cardiovascular Adverse Reactions [see Warnings and Precautions (5.4) ] Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions 5.7 ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.10) ] Most common adverse reactions in adult patients:(incidence ≥ 1%) pain, vision abnormalities (including blurred vision and photomas), headache, taste perversion, arrhythmias including premature ventricular contractions (PVCs) and premature atrial contractions (PACs), angina/chest pain, nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults : The following Adverse Reactions are listed in decreasing frequency within each subgroup. Cardiovascular System: arrhythmias including premature ventricular contractions (PVCs) and premature atrial contractions (PACs), angina/chest pain, hypotension, cardiac failure, asystole, bradycardia, tachycardia, and vasovagal reaction Nervous System: pain, vision abnormalities (including blurred vision and photomas), headache, taste perversion, vertigo, dizziness, lightheadedness, anxiety, fever, motor and speech dysfunction, convulsion, paresthesia, somnolence, stiff neck, hemiparesis, syncope, shivering, transient ischemic attack, cerebral infarction, and nystagmus. Respiratory System: dyspnea, rhinitis, coughing, and laryngitis Gastrointestinal System: nausea, vomiting, diarrhea, dyspepsia, cramp, and dry mouth Skin and Appendages: urticaria, purpura, abscess, and pruritus Pediatric Patients: In controlled clinical trials involving pediatric patients for CT head imaging, adverse reactions following the use of OMNIPAQUE (300 mg iodine/mL) were similar in quality and frequency to those seen with adults. 6.2 Post-Marketing Experience The following additional reactions have been identified during post-approval intravascular use of OMNIPAQUE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to exposure. Hemodynamic Reactions: vein cramp and thrombophlebitis following intravenous injection Blood and Lymphatic System Disorders: neutropenia Cardiovascular Disorders: cardiac arrest, shock, peripheral vasodilatation hypertension, myocardial infarction, spasm of coronary arteries, reflex tachycardia, cyanosis, pallor, flushing Eye Disorders: transient visual impairment including cortical blindness, eyelid edema, conjunctival symptoms, lacrimation Endocrine Reactions: hyperthyroidism, hypothyroidism Gastrointestinal Disorders: abdominal pain, pancreatitis aggravated, salivary gland enlargement General Disorders and Administration Site Conditions: chills, pyrexia, pain and discomfort, weakness, administration site conditions including extravasation, feeling hot Immune System Disorders: hypersensitivity reactions, anaphylactic or anaphylactoid shock including life-threatening or fatal anaphylaxis Musculoskeletal and Connective Tissue Disorders: back pain Nervous System Disorders: coma, disturbance in consciousness, transient contrast-induced encephalopathy caused by extravasation of contrast media (including amnesia, hallucination, paralysis, paresis, speech disorder, aphasia, dysarthria), restlessness, tremors, hypoesthesia Psychiatric Disorders: confusional state, agitation Renal Disorders: acute kidney injury, nephropathy toxic, transient proteinuria, oliguria or anuria, increased serum creatinine Respiratory; Thoracic, and Mediastinal Disorders: respiratory arrest, pulmonary or laryngeal edema, bronchospasm, sneezing, throat irritation, throat tightness, laryngeal edema, pharyngeal edema, asthmatic attack Skin and Subcutaneous Tissue Disorders: Reactions range from mild (e.g. pleomorphic rashes, drug eruption, erythema, pruritus, urticaria and skin discoloration, hyperhidrosis, angioedema, localized areas of edema) to severe: [e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS)]

4 CONTRAINDICATIONS None. None

11 DESCRIPTION 11.1 Chemical Characteristics OMNIPAQUE (iohexol) is a nonionic, radiographic contrast agent for intravenous use. OMNIPAQUE is provided as a sterile, pyrogen-free, colorless to pale-yellow solution. The chemical name of iohexol is Bis(2,3-dihydroxypropyl)-5-[ N -(2,3-dihydroxypropyl)-acetamido]-2,4,6- triiodoisophthalamide with a molecular weight of 821.14 (iodine content 46.36%). Iohexol has the following structural formula: OMNIPAQUE 300 mg iodine/mL (647 mg of iohexol/mL): Each mL contains 300 mg organically bound iodine, 1.21 mg tromethamine, 0.1 mg edetate calcium disodium OMNIPAQUE 350 mg iodine/mL (755 mg of iohexol/mL): Each mL contains 350 mg organically bound iodine, 1.21 mg tromethamine, 0.1 mg edetate calcium disodium The pH is adjusted between 6.8 and 7.7 with hydrochloric acid or sodium hydroxide. All solutions are sterile and contain no preservatives. Chemical Structure 11.2 Physical Characteristics Table 3 summarizes the physical properties of the two concentrations of OMNIPAQUE Imaging Bulk Package. TABLE 3 Concentration (mg iodine/mL) Osmolality By vapor-pressure osmometry. (mOsm/kg water) Absolute Viscosity (cp) Specific Gravity 20°C 37°C 37°C 300 672 11.8 6.3 1.349 350 844 20.4 10.4 1.406 OMNIPAQUE 300 mg iodine/mL and OMNIPAQUE 350 mg iodine/mL have osmolalities from approximately 2.2 to 3 times those of plasma (285 mOsm/kg water) or cerebrospinal fluid (301 mOsm/kg water) and are hypertonic under conditions of use.

2 DOSAGE AND ADMINISTRATION The concentration and volume required will depend on the equipment and imaging technique used. See full prescribing information for full dosing information. ( 2.2 ) 2.1 Important Administration Instructions OMNIPAQUE is for intravenous use only [see Boxed Warning , Contraindications (4) , and Warnings and Precautions (5.1) ] OMNIPAQUE may be administered at body (37°C) or room temperature. Do not warm the container beyond 37°C. Inspect OMNIPAQUE for particulate matter or discoloration before administration, whenever solution and container permit. Do not administer if OMNIPAQUE contains particulate matter or is discolored. Do not mix OMNIPAQUE with, or inject in intravenous lines containing, other drugs or total nutritional admixtures. Use sterile technique for all handling and administration of OMNIPAQUE. Hydrate patients before and after OMNIPAQUE administration [see Warnings and Precautions (5.3) ]. Avoid extravasation when injecting OMNIPAQUE, especially in patients with severe arterial or venous disease [see Warnings and Precautions (5.5) ] 2.2 Recommended Dosage The dosing recommendations for OMNIPAQUE Imaging Bulk Package are summarized below for adult (Table 1) and pediatric (Table 2) patients. The maximum recommended total dose of iodine for adults is 60 grams. Use the lowest dose necessary to obtain adequate visualization. Individualize the volume, strength, and rate of administration of OMNIPAQUE Imaging Bulk Package. Consider factors such as age, body weight, 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. Table 1 Adult Dosing Recommendations: Intravenous Administration STUDY TYPE 300 mg iodine/mL 350 mg iodine/mL CT Imaging – Head 70 to 150 mL (21 to 45 grams iodine) 80 mL (28 grams iodine) CT Imaging – Body 50 to 200 mL (15 to 60 grams iodine) 60 to 100 mL (21 to 35 grams iodine) Table 2 Pediatric Patients The concentration and volume required will depend on the equipment and imaging technique used. Dosing Recommendations: Intravenous Administration STUDY TYPE 300 mg iodine/mL Dosage for infants and children should be administered in proportion to age and body weight. CT Imaging – Head and Body 1 to 2 mL/kg Maximum single dose = 3mL/kg 35 grams iodine (116 mL) 2.3 Imaging Bulk Package Preparation Instructions OMNIPAQUE Imaging Bulk Package is for use only with an automated contrast injection system, contrast management system, or contrast media transfer set cleared for use with this contrast agent in this Imaging Bulk Package. See device labeling for information on devices indicated for use with this Imaging Bulk Package and techniques to help assure safe use. Use OMNIPAQUE Imaging Bulk Package and 0.9% Sodium Chloride Injection only in a room designated for radiological procedures that involve intravascular administration of a contrast agent. Utilize sterile technique for penetrating the container closure of the OMNIPAQUE Imaging Bulk Package and transferring OMNIPAQUE solution. The container closure may be penetrated only one time with a suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set cleared for use with this Imaging Bulk Package. Do not use if tamper-evident ring is broken or missing. If 0.9% Sodium Chloride Injection USP is used, prepare the 0.9% Sodium Chloride Injection USP sterile port in accordance with the dosage and administration section of its approved prescribing information. The intravenous administration port of the 0.9% Sodium Chloride Injection USP container may be penetrated only one time with a suitable sterile component of the contrast management system approved for use with the OMNIPAQUE Imaging Bulk Package. Affix the saline tag provided with the OMNIPAQUE Imaging Bulk Package on the 0.9% Sodium Chloride Injection USP container. Once the OMNIPAQUE Imaging Bulk Package and 0.9% Sodium Chloride Injection are punctured do not remove them from the work area during the entire period of use. Maintain the OMNIPAQUE Imaging Bulk Package 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 OMNIPAQUE Imaging Bulk Package, the 0.9% Sodium Chloride, and the delivery system cannot be assured through direct continuous supervision, discard the OMNIPAQUE Imaging Bulk Package, 0.9% Sodium Chloride, and all associated disposables for the iodinated contrast media transfer set. A maximum time of 8 hours from initial puncture is permitted to complete fluid transfer. Discard any unused OMNIPAQUE solution and 0.9% Sodium Chloride 8 hours after initial puncture of the OMNIPAQUE Imaging Bulk Package.

1 INDICATIONS AND USAGE OMNIPAQUE Imaging Bulk Package is indicated for Computed tomographic (CT) imaging of the head and body by intravenous administration in: adults (300 and 350 mg iodine/mL) pediatric patients (300 mg iodine/mL) For use only with an automated contrast injection system, contrast management system, or contrast media transfer set cleared for use with OMNIPAQUE Imaging Bulk Package. OMNIPAQUE Imaging Bulk Package is a radiographic contrast agent indicated for intravenous computed tomographic (CT) imaging of the head and body in adult and pediatric patients. ( 2.1 ) For use only with an automated contrast injection system, contrast management system, or contrast media transfer set cleared for use with OMNIPAQUE Imaging Bulk Package.

10 OVERDOSAGE The adverse reactions to overdosage are life-threatening and affect mainly the pulmonary and cardiovascular systems. Treatment of an overdosage is directed toward the support of all vital functions, and prompt institution of symptomatic therapy. Iohexol displays a low affinity for serum or plasma proteins and is poorly bound to serum albumin and, therefore, can be dialyzed.

7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Metformin In patients with renal impairment, metformin can cause lactic acidosis. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. Stop metformin at the time of, or prior to, OMNIPAQUE administration in patients with an estimated Glomerular Filtration Rate (eGFR) between 30 and 60 mL/min/1.73 m 2 ; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and reinstitute metformin only after renal function is stable. Radioactive Iodine Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6 to 8 weeks. Beta-adrenergic Blocking Agents The use of beta-adrenergic blocking agents lowers the threshold for and increases the severity of contrast reactions and reduces the responsiveness of treatment of hypersensitivity reactions with epinephrine. Because of the risk of hypersensitivity reactions, use caution when administering OMNIPAQUE to patients taking beta-blockers. 7.2 Drug-Laboratory Test Interactions Effect on Thyroid Tests If iodine-containing isotopes are to be administered for the diagnosis of thyroid disease, the iodine-binding capacity of thyroid tissue may be reduced for up to 2 weeks after contrast agent administration. Thyroid function tests which do not depend on iodine estimation, e.g., T 3 resin uptake or direct thyroxine assays, are not affected.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Intravascular injection of iohexol opacifies vessels in the path of flow through attenuation of X-rays permitting visualization of the internal structures. Iohexol diffuses from the vascular into the extravascular space. Vessels feeding tumors are less of a barrier to iohexol diffusion than are normal vessels, resulting in increased accumulation in the extravascular space around tumors and thus contrast enhancement. However, iohexol does not accumulate in normal brain tissue due to the presence of the intact blood-brain barrier. A disruption in the blood-brain barrier allows for the accumulation of contrast agent within the interstitial space in the region of disruption. 12.2 Pharmacodynamics Following administration of OMNIPAQUE, the degree of contrast enhancement is directly related to the iodine content in an administered dose; peak iodine blood concentrations occur immediately following rapid intravenous injection. The time to maximum contrast enhancement can vary, depending on the organ, from the time that peak blood iodine concentrations are reached to one hour after intravenous bolus administration. When a delay between peak blood iodine concentrations and peak contrast is present, it suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing agent within the lesion and outside the blood pool. Renal accumulation is sufficiently rapid that the period of maximal opacification of the renal collecting system may begin as early as 1 minute after intravenous injection. Urograms become apparent in about 1 to 3 minutes with optimal contrast occurring between 5 to 15 minutes. 12.3 Pharmacokinetics Following the intravenous administration of iohexol (between 500 mg iodine/kg to 1500 mg iodine/kg) to 16 adult human subjects, apparent first-order terminal elimination half-life was 12.6 hrs and total body clearance was 131 (98 to 165) mL/min. Clearance does not appear to be dose dependent. Distribution In 16 adult subjects (receiving between 500 mg iodine/kg to 1500 mg iodine/kg intravenous iohexol) the volume of distribution was 165 (108 to 219) mL/kg. Elimination Metabolism No significant metabolism, deiodination or biotransformation occurs. Excretion Following intravascular injection, iohexol is excreted unchanged by glomerular filtration. 90% or more of the injected iohexol dose is excreted within the first 24 hours, with the peak urine concentrations occurring in the first hour after administration. Specific Populations Renal Impairment In patients with renal impairment, greater plasma iohexol exposure may be anticipated due to slowed elimination of iohexol. In these patients, as well as in infants with immature kidneys, fecal excretion of iohexol may occur.

12.1 Mechanism of Action Intravascular injection of iohexol opacifies vessels in the path of flow through attenuation of X-rays permitting visualization of the internal structures. Iohexol diffuses from the vascular into the extravascular space. Vessels feeding tumors are less of a barrier to iohexol diffusion than are normal vessels, resulting in increased accumulation in the extravascular space around tumors and thus contrast enhancement. However, iohexol does not accumulate in normal brain tissue due to the presence of the intact blood-brain barrier. A disruption in the blood-brain barrier allows for the accumulation of contrast agent within the interstitial space in the region of disruption.

12.2 Pharmacodynamics Following administration of OMNIPAQUE, the degree of contrast enhancement is directly related to the iodine content in an administered dose; peak iodine blood concentrations occur immediately following rapid intravenous injection. The time to maximum contrast enhancement can vary, depending on the organ, from the time that peak blood iodine concentrations are reached to one hour after intravenous bolus administration. When a delay between peak blood iodine concentrations and peak contrast is present, it suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing agent within the lesion and outside the blood pool. Renal accumulation is sufficiently rapid that the period of maximal opacification of the renal collecting system may begin as early as 1 minute after intravenous injection. Urograms become apparent in about 1 to 3 minutes with optimal contrast occurring between 5 to 15 minutes.

12.3 Pharmacokinetics Following the intravenous administration of iohexol (between 500 mg iodine/kg to 1500 mg iodine/kg) to 16 adult human subjects, apparent first-order terminal elimination half-life was 12.6 hrs and total body clearance was 131 (98 to 165) mL/min. Clearance does not appear to be dose dependent. Distribution In 16 adult subjects (receiving between 500 mg iodine/kg to 1500 mg iodine/kg intravenous iohexol) the volume of distribution was 165 (108 to 219) mL/kg. Elimination Metabolism No significant metabolism, deiodination or biotransformation occurs. Excretion Following intravascular injection, iohexol is excreted unchanged by glomerular filtration. 90% or more of the injected iohexol dose is excreted within the first 24 hours, with the peak urine concentrations occurring in the first hour after administration. Specific Populations Renal Impairment In patients with renal impairment, greater plasma iohexol exposure may be anticipated due to slowed elimination of iohexol. In these patients, as well as in infants with immature kidneys, fecal excretion of iohexol may occur.

20230425

7

3 DOSAGE FORMS AND STRENGTHS Injection: Non-ionic, sterile, pyrogen-free, colorless to pale yellow solution in an imaging bulk package in the following strengths: 300 mg of organically bound iodine per mL (647 mg of iohexol/mL) 350 mg of organically bound iodine per mL (755 mg of iohexol/mL) Imaging Bulk Package is available in the following format: 500 mL polymer bottle ( PLUS PAK™) Injection: 500 mL Imaging Bulk Package available in two strengths: 300 mg of iodine per mL (647 mg of iohexol/mL) and 350 mg of iodine per mL (755 mg of iohexol/mL) ( 3 )

Omnipaque Iohexol TROMETHAMINE EDETATE CALCIUM DISODIUM HYDROCHLORIC ACID SODIUM HYDROXIDE IOHEXOL IOHEXOL IODINE colorless to pale yellow Omnipaque Iohexol TROMETHAMINE EDETATE CALCIUM DISODIUM HYDROCHLORIC ACID SODIUM HYDROXIDE IOHEXOL IOHEXOL IODINE colorless to pale yellow

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed with iohexol to evaluate carcinogenic potential. Iohexol was not genotoxic by the Ames test, the mouse lymphoma TK locus forward mutation assay, and a mouse micronucleus assay. Iohexol did not impair the fertility of male or female rats when repeatedly administered at intravenous dosages up to 4 g iodine/kg.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed with iohexol to evaluate carcinogenic potential. Iohexol was not genotoxic by the Ames test, the mouse lymphoma TK locus forward mutation assay, and a mouse micronucleus assay. Iohexol did not impair the fertility of male or female rats when repeatedly administered at intravenous dosages up to 4 g iodine/kg.

NDA020608

Omnipaque

Iohexol

0407-1414

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PRINCIPAL DISPLAY PANEL - 300 mL Bottle Box Label I538 Contains 10 x 500 mL Bottles NDC 0407-1413-48 Omnipaque™ (iohexol) Injection 300 mg Iodine/mL 500 mL NOVAPLUS ® IMAGING BULK PACKAGE For Intravenous Use Only For use only with an automated contrast injection system, contrast management system or contrast media transfer set cleared for use with OMNIPAQUE Imaging Bulk Package. Sterile Aqueous Solution See drug and device labeling for information on devices cleared for use with this Imaging Bulk Package. Each 1 mL contains 647.1 mg of iohexol (300 mg organically bound iodine), 1.21 mg tromethamine, and 0.1 mg edetate calcium disodium. The pH is adjusted between 6.8 and 7.7 with hydrochloric acid or sodium hydroxide. No preservative added. Not for Intrathecal Use. +PLUSPAK™ (polymer bottle) Provided the container is held under the labeled storage conditions the maximum use time is 8 hours after initial entry. Discard unused Omnipaque 8 hours after initial puncture. Protect from light. Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP]. Do not freeze. For indications, dosage and further information on the use of the Imaging Bulk Package, see package insert. R x ONLY Distributed by GE Healthcare Inc. Marlborough, MA 01752 U.S.A. For inquiries call (800) 654-0118. Omnipaque is a registered trademark of GE Healthcare. N+ and NOVAPLUS are registered trademarks of Vizient, Inc. Product of Norwegian Origin. (01)20304071413481 Exp.: Lot: Qty.: 1 1196544 USA NP omnipaque-02

RECENT MAJOR CHANGES Warnings and Precautions, Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age ( 5.7 ) 4/2023

Distributed by GE Healthcare Inc., Marlborough, MA 01752 U.S.A. Product of Norwegian Origin. OMNIPAQUE is a trademark of GE HealthCare or one of its subsidiaries. GE is a trademark of General Electric Company used under trademark license. NOVAPLUS is a registered trademark of Vizient, Inc. © 2023 GE HealthCare

17 PATIENT COUNSELING INFORMATION Hypersensitivity Reactions Advise the patient concerning the risk of hypersensitivity reactions that can occur both during and after OMNIPAQUE administration. Advise the patient to report any signs or symptoms of hypersensitivity reactions during the procedure and to seek immediate medical attention for any signs or symptoms experienced after discharge [see Warnings and Precautions (5.2) ]. Advise patients to inform their physician if they develop a rash after receiving OMNIPAQUE [see Warnings and Precautions (5.10)) ]. Contrast-Induced Acute Kidney Injury Advise the patient concerning appropriate hydration to decrease the risk of contrast induced acute kidney injury [see Warnings and Precautions (5.3) ]. Extravasation If extravasation occurs during injection, advise patients to seek medical care for progression of symptoms [see Warnings and Precautions (5.5) ]. Lactation Advise a lactating woman that interruption of breastfeeding is not necessary, however, to avoid any exposure a lactating woman may consider pumping and discarding breast milk for 10 hours after OMNIPAQUE administration [see Use in Specific Populations (8.2) ]. Thyroid Dysfunction Advise parents/caregivers about the risk of developing thyroid dysfunction after OMNIPAQUE administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function [see Warnings and Precautions (5.7) ] .

14 CLINICAL STUDIES 14.1 Intravenous Administration Studies OMNIPAQUE Clinical Studies for CT The safety and efficacy of intravenously administered OMNIPAQUE for CT of the head and body were evaluated in six clinical studies (Table 4). Each study also used an ionic high-osmolar iodinated contrast agent as a comparator (Table 4). Patients were randomized to administration of either OMNIPAQUE or the comparator. OMNIPAQUE patients had a mean age of 53 years (range 16 to 85), were 44% women, had a mean weight of 67 kg (range 36 to 134), and were administered a mean of 572 mg iodine/kg (range 176 to 1250); comparator patients had a mean age of 51 years (range 14 to 80), were 43% women, had a mean weight of 70 kg (range 40 to 136), and were administered a mean of 484 mg iodine/kg (range 135 to 1500). In three studies, efficacy was determined from investigator ratings of quality of contrast enhancement (none, poor, good, or excellent; only scans rated as good or excellent were considered diagnostic); in the remaining three studies, efficacy was assessed quantitatively through X-ray attenuation, measured pre-contrast and at various time points post-contrast. The percentage of scans rated as good or excellent was 100% for both OMNIPAQUE and the comparator in each of the two studies, and 79% for OMNIPAQUE and 74% for the comparator in the third study. In the studies that measured X-ray attenuation, there were no clinically significant differences between OMNIPAQUE and the comparator regarding contrast over time or time to maximal attenuation. Overall, the incidence of discomfort (heat, pain, cold, tingling, pressure, chest heaviness, or cramp) was lower in the patients receiving OMNIPAQUE, with 115 (38%) of 300 patients receiving OMNIPAQUE vs. 177 (60%) of 295 comparator patients reporting discomfort ionic media (p<0.001). Similarly, fewer patients receiving OMNIPAQUE than comparator patients reported adverse events (7% versus 19%, respectively, p<0.001). Table 4 Study Indication OMNIPAQUE (mg iodine/mL) No. of Patients Receiving OMNIPAQUE Comparator (mg iodine/mL) Patients Receiving Comparator 1 Intracranial 300 26 Diatrizoate (282) 23 2 300 16 Iothalamate (282) 15 3 350 30 Metrizoate (350) 30 4 240 100 Diatrizoate (168) 100 5 Abdominal 350 28 Metrizoate (350) 27 6 300 100 Metrizoate (280) 100 TOTAL 300 295

8.5 Geriatric Use In clinical studies of OMNIPAQUE in computed tomography, 52/299 (17%) of patients were 70 years and older. 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, 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.

8.4 Pediatric Use The safety and efficacy of OMNIPAQUE 300 mg iodine/mL have been established in pediatric patients birth to 17 years of age for CT imaging of the head and body. Use of OMNIPAQUE 300 mg iodine/mL is supported by controlled clinical trials in pediatric patients undergoing head CT and evidence of effectiveness from well-controlled studies of OMNIPAQUE in adults for head and body CT. The safety and efficacy of OMNIPAQUE 350 mg iodine/mL have not been established in pediatric patients birth to 17 years of age for CT imaging of the head and body. In general, the frequency of adverse reactions in pediatric patients was similar to that seen in adults [see Adverse Reactions (6.1) ] . Pediatric patients at higher risk of experiencing adverse events during contrast agent administration may include those having asthma, sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine greater than 1.5 mg/dL or those less than 12 months of age. 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 to 3 years of age based on underlying risk factors, especially in term and preterm neonates [see Warnings and Precautions (5.7) and Adverse Reactions (6.2) ] .

8.1 Pregnancy Risk Summary Postmarketing data with OMNIPAQUE use in pregnant women are insufficient to determine if there is a drug-associated risk of adverse developmental outcomes. Iohexol crosses the placenta and reaches fetal tissues in small amounts (see Data ). In animal reproduction studies, no adverse developmental effects were observed following intravenous iohexol administration to pregnant rats and rabbits during organogenesis at doses up to 0.4 (rat) and 0.5 (rabbit) times the maximum recommended human intravenous dose ( see Data ). 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. Data Human Data Literature reports show that iohexol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Reproduction studies were performed in rats and rabbits with intravenous administration of iohexol at the following dose levels: 1.0, 2.0, 4.0 g iodine/kg in rats, in 3 groups of 25 dams once daily during days 6 through 15 of pregnancy; 0.3, 1.0, 2.5 g iodine/kg in rabbits, in 3 groups of 18 doses once a day during days 6 through 18 of pregnancy. Iohexol was not embryotoxic or teratogenic in either species at the dose levels tested.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating woman may pump and discard breast milk for 10 hours after OMNIPAQUE administration. ( 8.2 ) 8.1 Pregnancy Risk Summary Postmarketing data with OMNIPAQUE use in pregnant women are insufficient to determine if there is a drug-associated risk of adverse developmental outcomes. Iohexol crosses the placenta and reaches fetal tissues in small amounts (see Data ). In animal reproduction studies, no adverse developmental effects were observed following intravenous iohexol administration to pregnant rats and rabbits during organogenesis at doses up to 0.4 (rat) and 0.5 (rabbit) times the maximum recommended human intravenous dose ( see Data ). 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. Data Human Data Literature reports show that iohexol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Reproduction studies were performed in rats and rabbits with intravenous administration of iohexol at the following dose levels: 1.0, 2.0, 4.0 g iodine/kg in rats, in 3 groups of 25 dams once daily during days 6 through 15 of pregnancy; 0.3, 1.0, 2.5 g iodine/kg in rabbits, in 3 groups of 18 doses once a day during days 6 through 18 of pregnancy. Iohexol was not embryotoxic or teratogenic in either species at the dose levels tested. 8.2 Lactation Risk Summary The literature reports that breast feeding after iohexol administration to the mother would result in the infant receiving an oral dose of approximately 0.7% of the maternal intravenous dose. There is no information on the effects of the drug on milk production. Iodinated contrast agents are excreted unchanged in human milk in very low amounts with poor absorption from the gastrointestinal tract of a breastfed infant. Exposure to iohexol to a breastfed infant can be minimized by temporary discontinuation of breastfeeding (see Clinical Considerations ). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for OMNIPAQUE and any potential adverse effects on the breastfed infant from OMNIPAQUE or from the underlying maternal condition. Clinical Considerations Interruption of breastfeeding after exposure to iodinated contrast agents is not necessary because the potential exposure of the breastfed infant to iodine is small. However, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 10 hours (approximately 5 elimination half-lives) after OMNIPAQUE administration to minimize drug exposure to a breastfed infant. 8.4 Pediatric Use The safety and efficacy of OMNIPAQUE 300 mg iodine/mL have been established in pediatric patients birth to 17 years of age for CT imaging of the head and body. Use of OMNIPAQUE 300 mg iodine/mL is supported by controlled clinical trials in pediatric patients undergoing head CT and evidence of effectiveness from well-controlled studies of OMNIPAQUE in adults for head and body CT. The safety and efficacy of OMNIPAQUE 350 mg iodine/mL have not been established in pediatric patients birth to 17 years of age for CT imaging of the head and body. In general, the frequency of adverse reactions in pediatric patients was similar to that seen in adults [see Adverse Reactions (6.1) ] . Pediatric patients at higher risk of experiencing adverse events during contrast agent administration may include those having asthma, sensitivity to medication and/or allergens, congestive heart failure, a serum creatinine greater than 1.5 mg/dL or those less than 12 months of age. 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 to 3 years of age based on underlying risk factors, especially in term and preterm neonates [see Warnings and Precautions (5.7) and Adverse Reactions (6.2) ] . 8.5 Geriatric Use In clinical studies of OMNIPAQUE in computed tomography, 52/299 (17%) of patients were 70 years and older. 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, 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied OMNIPAQUE injection is provided as a sterile, pyrogen-free, preservative free, colorless-to-pale yellow solution available in two strengths in an Imaging Bulk Package. It is supplied in the following configurations: OMNIPAQUE Imaging Bulk Package (iohexol) Injection 300 mg iodine/mL: 500 mL in + PLUS PAK™ (polymer bottle), boxes of 10 Imaging Bulk Packages (NDC 0407-1413-48) OMNIPAQUE Imaging Bulk Package (iohexol) Injection 350 mg iodine/mL: 500 mL in + PLUS PAK™ (polymer bottle), boxes of 10 Imaging Bulk Packages (NDC 0407-1414-48) 16.2 Storage and Handling Protect OMNIPAQUE Imaging Bulk Package from exposure to sunlight. Store OMNIPAQUE Imaging Bulk Package at controlled room temperature, 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. OMNIPAQUE Imaging Bulk Package 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.

16.2 Storage and Handling Protect OMNIPAQUE Imaging Bulk Package from exposure to sunlight. Store OMNIPAQUE Imaging Bulk Package at controlled room temperature, 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. OMNIPAQUE Imaging Bulk Package 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.

WARNING: RISKS WITH INADVERTENT INTRATHECAL ADMINISTRATION FOR INTRAVENOUS USE ONLY. Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema [see Warnings and Precautions (5.1) ] . WARNING: RISKS WITH INADVERTANT INTRATHECAL ADMINISTRATION See full prescribing information for complete boxed warning. FOR INTRAVENOUS USE ONLY. Inadvertent intrathecal administration may cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema ( 5.1 ) .