Visipaque

1 INDICATIONS AND USAGE VISIPAQUE is indicated for: VISIPAQUE 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 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 and 320 mg Iodine/mL). Excretory urography (270 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 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 and 320 mg Iodine/mL) CT imaging of the head and body. (270 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.

2 DOSAGE AND ADMINISTRATION Individualize the combination of volume and concentration of VISIPAQUE Injection considering age, body weight, size of the vessel, rate of blood flow within the vessel, and other applicable factors. ( 2.1 , 2.2 , 2.3 , 2.4 ) For CT of the head and body, VISIPAQUE may be used with an automated contrast injection system or contrast media management system cleared for use with VISIPAQUE. ( 2.5 ) For the adult patients, the maximum recommended total dose of iodine is 80 grams. ( 2.1 ) Patients should be adequately hydrated prior to and following the intravascular administration of iodinated contrast agents. ( 2.1 , 5.3 ) See full prescribing information for complete dosing and administration information. ( 2 ) 2.1 Important Dosage and Administration Instructions VISIPAQUE is for intravascular use only [see Boxed Warning , Contraindications (4) , and Warnings and Precautions (5.1) ] Use sterile technique for all handling and administration of VISIPAQUE. Do not use if tamper-evident ring is broken or missing. Warm VISIPAQUE and administer at body or room temperature. Inspect VISIPAQUE for particulate matter or discoloration before administration, whenever solution and container permit. Do not administer if VISIPAQUE contains particulate matter or is discolored. Do not mix VISIPAQUE 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 VISIPAQUE. 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 VISIPAQUE; especially in patients with severe arterial or venous disease [see Warnings and Precautions (5.6) ]. Hydrate patients before and after VISIPAQUE administration [see Warnings and Precautions (5.3) ]. 2.2 Intra-Arterial Dosage and Administration Intra-arterial digital subtraction angiography (IA-DSA) (270 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 VISIPAQUE SINGLE DOSE RECOMMENDATIONS FOR INJECTION INTO SELECTED ARTERIES ARTERIOGRAPHY IA-DSA IA-DSA = Intra-Arterial Digital Subtraction Angiography Maximum Total Dose Intra-Arterial Injection Sites 320 mg Iodine/mL 270 mg Iodine/mL 320 mg Iodine/mL Carotid Arteries 10 to 14 mL 5 to 8 mL Usually Not to Exceed 175 mL Vertebral Arteries 10 to 12 mL 5 to 8 mL Right Coronary Artery 3 to 8 mL Usually Not to Exceed 200 mL Left Coronary Artery 3 to 10 mL Left Ventricle 20 to 45 mL Renal Arteries 8 to 18 mL 10 to 25 mL -- Usually Not to Exceed 250 mL Aortography 30 to 70 mL 20 to 50 mL 10 to 50 mL Major Branches of Aorta 10 to 70 mL 5 to 30 mL 2 to 10 mL Aortofemoral Runoffs 20 to 90 mL -- 6 to 15 mL Peripheral Arteries 15 to 30 mL -- 3 to 15 mL 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 VISIPAQUE 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 coi …

3 DOSAGE FORMS AND STRENGTHS Injection: Non-ionic, isotonic, water-soluble, sterile, pyrogen-free, colorless to pale yellow solution in the following strengths: 270 mg of organically bound iodine per mL (550 mg Iodixanol per mL). 320 mg of organically bound iodine per mL (652 mg Iodixanol per mL). Available in the following formats: Multiple-dose polymer bottle (+ PLUS PAKTM) and Single-dose polymer bottle (+ PLUS PAKTM). Injection: In concentrations of 270 and 320 mg of organically bound iodine per mL (550 mg and 652 mg of Iodixanol per mL). ( 3 )

4 CONTRAINDICATIONS VISIPAQUE is contraindicated for Intrathecal use [see Warnings and Precautions (5.1) ] . Not indicated for intrathecal use. ( 4 )

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 VISIPAQUE 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 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. VISIPAQUE is often associated with sensations of discomfort, warmth or pain. In a subgroup of 1259 patients; 30% who received VISIPAQUE or a comparator had application site discomfort, pain, warmth or cold. VISIPAQUE had a trend toward fewer patient reports of moderate or severe pain or warmth. Pain was reported in 2% of patients receiving VISIPAQUE and 10% of patients receiving a comparator. Heat was reported in 29% of patients receiving VISIPAQUE and 51% of patients receiving a comparator. Table 3 shows the incidence of events reported in blinded, controlled clinical studies of VISIPAQUE in a total of 1244 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 1244 ADULT PATIENTS RECEIVING VISIPAQUE OR OTHER IODINATED CONTRAST AGENTS NUMBER OF PATIENTS EXPOSED VISIPAQUE N (%) = 1244 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 1244 patients. Body as …

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, VISIPAQUE administration in patients with an 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 VISIPAQUE to patients taking beta-blockers. Oral Cholecystographic Contrast Agents Renal toxicity has been reported in patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular iodinated contrast agents. Postpone the administration of VISIPAQUE in patients who have recently received an oral cholecystographic contrast agent. 7.2 Drug-Laboratory Test Interactions Effect on Thyroid Tests The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine estimations (e.g., T3 resin uptake and total or free thyroxine T4 assays) are not affected. Effect on Urine Tests As reported with other contrast agents, VISIPAQUE may produce a false-positive result for protein in the urine using urine dip tests. However, the Coomassie blue method has been shown to give accurate results for the measurement of urine protein in the presence of VISIPAQUE. In addition, care should be used in interpreting the results of urine specific gravity measurements in the presence of high levels of VISIPAQUE and other contrast agents in the urine. Refractometry or urine osmolality may be substituted.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating woman may pump and discard breast milk for 10 hours after VISIPAQUE administration. ( 8.2 ) Geriatrics: Exercise caution in dose selection for elderly patients. ( 8.5 ) 8.1 Pregnancy Risk Summary 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 ( see Data ). 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. Data Animal Data 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 7 in rat; 6 in rabbit) through closure of the hard palate (gestation day 17 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. 8.2 Lactation Risk Summary There are no data on the presence of iodixanol in human milk, the effects on the breastfed infant or the effects on milk production. Iodinated contrast agents are poorly excreted into human milk and are poorly absorbed by the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for VISIPAQUE and any potential adverse effects on the breastfed infant from VISIPAQUE 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 VISIPAQUE administration in order to minimize drug exposure to a breast fed infant. 8.4 Pediatric Use The safety and efficacy of VISIPAQUE 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 VISIPAQUE 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 VISIPAQUE is supported by evidence from adequate and well controlled studies of VISIPAQUE 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 VISIPAQUE [see Adverse Events (6.3) ] . The elimination of VISIPAQUE is slower in this age group [see Clinical Pharmacology (12.3) ] . 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 (5.8) and Adverse Reactions (6.2) ] . 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 othe …

12.1 Mechanism of Action Intravascular injection of iodixanol opacifies vessels in the path of flow of the contrast agent, permitting visualization of internal structures. In imaging of the body, iodinated contrast agents diffuse from the vascular into the extravascular space. In a normal brain with an intact blood-brain barrier, contrast does not diffuse into the extravascular space. In patients with a disrupted blood- brain barrier, contrast agent accumulates in the interstitial space in the region of disruption.

11 DESCRIPTION 11.1 Chemical Characteristics VISIPAQUE (iodixanol) injection is a dimeric, iso-osmolar, nonionic, water-soluble, radiographic contrast medium for intravascular (intravenous and intra-arterial) use. It is provided as a ready-to-use sterile, pyrogen-free, and preservative free, colorless to pale yellow solution. The chemical formula is 5,5 ́-[(2-hydroxy-1,3-propanediyl) bis(acetylimino)] bis[N,N ́-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3- benzenedicarboxamide] with a molecular weight of 1550.20 (iodine content 49.1%). VISIPAQUE (C 35 H 44 I 6 N 6 O 15 ) has the following structural formula: VISIPAQUE is available in two strengths: VISIPAQUE 270 mg Iodine/mL (550 mg Iodixanol/mL), 0.074 mg calcium chloride dihydrate, 1.87 mg sodium chloride, 1.2 mg tromethamine, and 0.1 mg edetate calcium disodium. VISIPAQUE 320 mg Iodine/mL (652 mg Iodixanol/mL), 0.044 mg calcium chloride dihydrate, 1.11 mg sodium chloride, 1.2 mg tromethamine and 0.1 mg edetate calcium disodium. Sodium chloride and calcium chloride have been added, resulting in an isotonic solution for injection providing for both concentrations a sodium/calcium ratio equivalent to blood. The pH is adjusted to 7.4 with hydrochloric acid and/or sodium hydroxide to achieve a range between pH 6.8 and 7.7 at 22°C. Chemical Structure 11.2 Physical Characteristics The two concentrations of VISIPAQUE Injection (270 mg Iodine/mL and 320 mg Iodine/mL) have the following physical properties: TABLE 4 Physical Properties of VISIPAQUE Parameter Concentration (mg Iodine/mL) 320 270 Osmolality (mOsmol/kg water) 290 290 Viscosity (cP) @ 20°C 26.6 12.7 @ 37°C 11.8 6.3 Density (g/mL) @ 20°C 1.369 1.314 @ 37°C 1.356 1.303

10 OVERDOSAGE The adverse effects of overdosage of any contrast agent may be 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. VISIPAQUE Injection does not bind to plasma or serum protein and can be dialyzed.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied VISIPAQUE injection is a ready-to-use sterile, pyrogen-free, preservative free, colorless to pale yellow solution available in two (2) strengths. It is supplied in the following configurations: PHARMACY BULK PACKAGE CONTAINING VISIPAQUE (iodixanol) Injection 320 mg Iodine/mL: 500 mL in multiple-dose + PLUS PAK TM (polymer bottle), boxes of 10 (NDC 0407-2223-23) SINGLE-DOSE BOTTLE CONTAINING VISIPAQUE (iodixanol) Injection 270 mg Iodine/mL: 50 mL in single-dose + PLUS PAK TM (polymer bottle), boxes of 10 (NDC 0407-2222-16) 100 mL in single-dose + PLUS PAK TM (polymer bottle), boxes of 10 (NDC 0407-2222-17) 150 mL in single-dose + PLUS PAK TM (polymer bottle), boxes of 10 (NDC 0407-2222-19) 200 mL in single-dose + PLUS PAK TM (polymer bottle), boxes of 10 (NDC 0407-2222-21) 16.2 Storage and Handling Protect VISIPAQUE from direct exposure to sunlight. Store VISIPAQUE 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) [see USP Controlled Room Temperature]. VISIPAQUE 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. DIRECTIONS FOR PROPER USE OF VISIPAQUE PHARMACY BULK PACKAGE Restrict the transfer of VISIPAQUE (iodixanol) Injection from the Pharmacy Bulk Package to a suitable work area, such as a laminar flow hood. Penetrate the container closure only one time, utilizing a suitable transfer device and aseptic technique. Perform the withdrawal of container contents without delay. However, a maximum time of 8 hours from initial closure entry is permitted to complete fluid transfer operations. Do not remove the container from the aseptic area during the entire 8-hour period. After the closure has been entered, the temperature of the container should not exceed 37°C.