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.

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.

5.1 Risks with Inadvertent Intrathecal Administration

OMNIPAQUE is for intravenous use only [see Dosage and Administration (2.1)]. Inadvertent Intrathecal administration can cause death, convulsions/seizures, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, rhabdomyolysis, hyperthermia, and brain edema.

5.2 Hypersensitivity Reactions

OMNIPAQUE, can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock. Most severe reactions develop shortly after the start of the injection (within 3 minutes), but reactions can occur up to hours later. There is an increased risk in patients with a history of a previous reaction to contrast agent, and known allergies (i.e., bronchial asthma, drug, or food allergies) or other hypersensitivities. Premedication with antihistamines or corticosteroids does not prevent serious life-threatening reactions, but may reduce both their incidence and severity.

Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and always have emergency resuscitation equipment and trained personnel available prior to OMNIPAQUE administration. Monitor all patients for hypersensitivity reactions.

5.3 Contrast-Induced Acute Kidney Injury

Acute kidney injury, including renal failure, may occur after OMNIPAQUE administration. Risk factors include: pre-existing renal impairment, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma/paraproteinaceous diseases, repetitive and/or large doses of an iodinated contrast agent.

Use the lowest necessary dose of OMNIPAQUE in patients with renal impairment. Adequately hydrate patients prior to and following OMNIPAQUE administration. Do not use laxatives, diuretics, or preparatory dehydration prior to OMNIPAQUE administration.

5.4 Cardiovascular Adverse Reactions

Life-threatening or fatal cardiovascular reactions including hypotension, shock, cardiac arrest have occurred with the use of OMNIPAQUE. Based upon clinical literature, reported deaths from the administration of iodinated contrast agents range from 6.6 per million (0.00066%) to 1 per 10,000 (0.01%). Most deaths occur during injection or 5 to 10 minutes later; the main feature being cardiac arrest with cardiovascular disease as the main aggravating factor.

OMNIPAQUE has the potential to transiently increase in the circulatory osmotic load in patients with congestive heart failure. Use the lowest necessary dose of OMNIPAQUE in patients with congestive heart failure and observe these patients for several hours following the procedure to detect delayed hemodynamic disturbances. Monitor all patients for severe cardiovascular reactions always have emergency resuscitation equipment and trained personnel available.

5.5 Extravasation and Injection Site Reactions

Extravasation of intravenously administered OMNIPAQUE may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or venous disease. Ensure intravenous placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.

5.6 Thyroid Storm in Patients with Hyperthyroidism

Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism, or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of OMNIPAQUE.

5.7 Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age

Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media in pediatric patients 0 to 3 years of age.

Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after ICM exposure. Pediatric patients with congenital cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures.

An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to iodinated contrast media, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates.

5.8 Hypertensive Crisis in Patients with Pheochromocytoma

Hypertensive crisis has occurred after the use of iodinated contrast agents in patients with pheochromocytoma. Monitor patients when administering OMNIPAQUE if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of contrast necessary, assess the blood pressure throughout the procedure, and have measures for treatment of a hypertensive crisis readily available.

5.9 Sickle Cell Crisis in Patients with Sickle Cell Disease

Iodinated contrast agents when administered intravascularly may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following OMNIPAQUE administration and use OMNIPAQUE only if the necessary imaging information cannot be obtained with alternative imaging modalities.

5.10 Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Reaction severity may increase and time to onset may decrease with repeat administration of contrast agents; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering OMNIPAQUE to patients with a history of a severe cutaneous adverse reaction to OMNIPAQUE.

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.

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)]

7.1 Drug-Drug Interactions

7.2 Drug-Laboratory Test Interactions

8.1 Pregnancy

8.2 Lactation

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.

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.

11.2 Physical Characteristics

Table 3 summarizes the physical properties of the two concentrations of OMNIPAQUE Imaging Bulk Package.

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.

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.

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.

14.1 Intravenous Administration Studies

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:

OMNIPAQUE Imaging Bulk Package (iohexol) Injection 350 mg iodine/mL:

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.

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)].