1 INDICATIONS AND USAGE Iodixanol injection is indicated in for: Iodixanol injection is a radiographic contrast agent indicated for the following: Intra-arterial Procedures ( 1.1 ) Adults and pediatric patients 12 years of age and over Intra-arterial digital subtraction angiography (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).

Pediatric patients less than 12 years of age Angiocardiography, cerebral arteriography, and visceral arteriography (320 mg Iodine/mL).

Intravenous Procedures ( 1.2 ) Adults and pediatric patients 12 years of age and over Computed tomography (CT) imaging head and 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) to assist diagnostic evaluation of patients with suspected coronary artery disease (320 mg Iodine/mL).

Pediatric patients less than 12 years of age CT imaging of the head and body (270 mg Iodine/mL).

Excretory urography (270 mg Iodine/mL).

1.1 Intra-arterial Procedures Adult and pediatric patients 12 years of age and older (270 mg Iodine/mL and 320 mg Iodine/mL) intra-arterial digital subtraction angiography (IA-DSA).

(320 mg Iodine/mL) angiocardiography (left ventriculography and selective coronary arteriography), peripheral arteriography, visceral arteriography, and cerebral arteriography.

Pediatric patients less than 12 years of age (320 mg Iodine/mL) angiocardiography, cerebral arteriography, and visceral arteriography.

1.2 Intravenous Procedures Adult and pediatric patients 12 years of age and older (270 mg Iodine/mL and 320 mg Iodine/mL) CT imaging of the head and body.

(270 mg Iodine/mL and 320 mg Iodine/mL) excretory urography.

(270 mg Iodine/mL) peripheral venography.

(320 mg Iodine/mL) coronary computed tomography angiography (CCTA) to assist in the diagnostic evaluation of patients with suspected coronary artery disease.

Pediatric patients less than 12 years of age (270 mg Iodine/mL) CT imaging of the head and body.

(270 mg Iodine/mL) excretory urography.

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) ] Thromboembolic Events [see Warnings and Precautions (5.5) ] Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions (5.8) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence greater than 0.5%) in adult patients after iodixanol injection: Discomfort, warmth, pain; Cardiovascular: angina.

Gastrointestinal: diarrhea, nausea, vomiting.

Nervous System: agitation, anxiety, insomnia, nervousness, dizziness, headache, migraine, unusual skin sensations, sensory disturbance, fainting, sensation of spinning.

Skin: itchy rash, severe itching, hives.

Special Senses: Smell, taste, and vision alteration.

( 6.1 ) Pediatric patients experienced similar adverse reactions.

( 6.3 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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.

Iodixanol is often associated with sensations of discomfort, warmth or pain.

In a subgroup of 1,259 patients; 30% who received iodixanol or a comparator had application site discomfort, pain, warmth or cold.

Iodixanol had a trend toward fewer patient reports of moderate or severe pain or warmth.

Pain was reported in 2% of patients receiving iodixanol and 10% of patients receiving a comparator.

Heat was reported in 29% of patients receiving iodixanol and 51% of patients receiving a comparator.

Table 3 shows the incidence of events reported in blinded, controlled clinical studies of iodixanol in a total of 1,244 adult patients.

Adverse events (AEs) are listed by body system and in decreasing order of occurrence greater than 0.5% of patients.

One or more adverse events were reported in 20% of patients during the study period (24 to 72 hours).

In a 757 patient subgroup, the number of women reporting adverse events was 83/299 (28%) and the number of men was 77/458 (16%).

A total of 3% of women and 0.8% of men reported chest pain.

TABLE 3 ADVERSE EVENTS REPORTED IN CONTROLLED CLINICAL TRIALS IN GREATER THAN 0.5% OF 1,244 ADULT PATIENTS RECEIVING IODIXANOL OR OTHER IODINATED CONTRAST AGENTS NUMBER OF PATIENTS EXPOSED Iodixanol N (%)= 1,244 Pooled Comparators N (%) = 861 Number of Patients with Any Adverse Event 248 (19.9) 194 (22.5) Body As a Whole Patients With Any Event 41 (3.3) 22 (2.6) Edema (any location) 7 (0.6) 0 (0) Cardiovascular Patients With Any Event 37 (3.0) 39 (4.5) Angina Pectoris/Chest Pain 28 (2.2) 22 (2.6) Gastrointestinal Patients With Any Event 51 (4.1) 46 (5.3) Diarrhea 7 (0.6) 6 (0.7) Nausea 35 (2.8) 32 (3.7) Vomiting 10 (0.8) 11 (1.3) Nervous System Patients With Any Event 101 (8.1) 60 (7.0) Agitation, Anxiety, Insomnia, Nervousness 10 (0.8) 0 (0) Dizziness 8 (0.7) 8 (0.9) Headache/Migraine 31 (2.5) 15 (1.7) Paresthesia 12 (1.0) 1 (0.1) Sensory Disturbance 10 (0.8) 9 (1.0) Syncope 8 (0.6) 1 (0.1) Vertigo 30 (2.4) 20 (2.3) Skin (not including application site) Patients With Any Event 42 (4.6) 18 (2.1) Nonurticarial Rash or Erythema 26 (2.1) 4 (0.5) Pruritus 20 (1.6) 3 (0.3) Urticaria 6 (0.5) 10 (1.2) Special Senses Patients With Any Event 57 (4.6) 38 (4.4) Parosmia 6 (0.5) 4 (0.5) Taste Perversion 43 (3.5) 32 (3.7) Scotoma 14 (1.1) 2 (0.2) The following selected adverse events were reported in ≤0.5% of the 1,244 patients.

Body as a Whole—General Disorders: back pain, fatigue, malaise Cardiovascular Disorders: arrhythmias, cardiac failure, conduction abnormalities, hypotension, myocardial infarction Gastrointestinal System Disorders: dyspepsia Hypersensitivity Disorders: pharyngeal edema Nervous System: cerebral vascular disorder, convulsions, hypoesthesia, stupor, confusion Peripheral Vascular Disorders: flushing, peripheral ischemia Renal System Disorders: abnormal renal function, acute renal failure, hematuria Respiratory System Disorders: asthma, bronchitis, dyspnea, pulmonary edema, rhinitis Skin and Appendage Disorders: hematoma, increased sweating Special Senses, Other Disorders: tinnitus Vision Disorders: abnormal vision 6.2 Post-marketing Experience The following additional adverse reactions have been identified during post approval use of iodixanol.

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.

Cardiovascular Disorders: Cardiac arrest, palpitations, spasms of coronary arteries, hypertension, and flushing Endocrine Disorders: Hyperthyroidism, hypothyroidism Eye Disorders: Transient visual impairment including cortical blindness, diplopia, and blurred vision Gastrointestinal Disorders: Abdominal pain, pancreatitis, salivary gland enlargement General Disorders and Administration Site Conditions: Chills, pyrexia, pain and discomfort, administration site reactions including extravasation Immune System Disorders: Hypersensitivity reactions, anaphylactic shock including, life-threatening or fatal anaphylaxis Nervous System Disorders: Tremor (transient), coma, disturbance in consciousness, transient contrast-induced encephalopathy caused by extravasation of contrast media (including amnesia, hallucination, paralysis, paresis, transient speech disorder, aphasia, dysarthria) Psychiatric Disorders: Anxiety, agitation Respiratory, Thoracic, and Mediastinal Disorders: Cough, sneezing, throat irritation or tightness, laryngeal edema, pharyngeal edema, bronchospasm Skin and subcutaneous tissue disorders: Reactions range from mild (e.g.

rash, erythema, pruritus, urticaria, and skin discoloration) 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)] 6.3 Pediatric Adverse Reactions The overall character, quality, and severity of adverse reactions in pediatric patients is similar to that reported in adult patients from post marketing surveillance and other information.

Additional safety data was obtained in studies of iodixanol in 459 pediatric patients.

A total of 26 patients ranged in age from birth to <29 days, 148 ranged from 29 days to 2 years, 263 from 2 to <12 years, and 22 from 12 to 18 years.

A total of 252 (55%) of the patients were male.

The racial distribution was: Caucasian-81%, Black-14%, Oriental-2%, and other or unknown-4%.

The proportion of patients undergoing an intra-arterial procedure by age was: 92 % (<29 days), 55% (29 days to 6 months), and 29 % (>6 months).

In these studies, adverse events were numerically higher in pediatric patients less than one year of age compared to older pediatric patients.

In pediatric patients who received intravenous injections of iodixanol for computerized tomography or excretory urography, a concentration of 270 mg Iodine/mL was used in 144 patients, and a concentration of 320 mg Iodine/mL in 154 patients.

All patients received one intravenous injection of 1 mL/kg to 2 mL/kg.

In pediatric patients who received intra-arterial and intracardiac studies, a concentration of 320 mg Iodine/mL was used in 161 patients.

Twenty-two patients were <29 days of age; 78 were 29 days to 2 years of age; and 61 were over 2 years.

Most of these pediatric patients received initial volumes of 1 mL/kg to 2 mL/kg and most patients received a maximum of 3 injections.