Optiray

Warnings and Precautions, Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age ( 5.8 ) 2/2023

1 INDICATIONS AND USAGE OPTIRAY is indicated for: OPTIRAY is a radiographic contrast agent indicated for the following: Intra-arterial Procedures ( 1.1 ) Adults: Cerebral Arteriography (300, 320 mg iodine/mL) Peripheral Arteriography (300, 320, 350 mg iodine/mL ) Visceral and Renal Arteriography, Aortography (320 mg iodine/mL) Coronary Arteriography and Left Ventriculography (320, 350 mg iodine/mL) Pediatric Patients: Angiocardiography (320, 350 mg iodine/mL) Intravenous Procedures ( 1.2 ) Adults: Computed tomography (CT) Imaging of Head and Body (300, 320, 350 mg iodine/mL) Venography (300, 320, 350 mg iodine/mL) Intravenous Excretory Urography (300, 320, 350 mg iodine/mL) Intravenous Digital Subtraction Angiography (350 mg iodine/mL) Pediatric Patients: CT Imaging of the Head and Body, and Intravenous Excretory Urography (320 mg iodine/mL) 1.1 Intra-arterial In adults OPTIRAY 300: cerebral arteriography and peripheral arteriography. OPTIRAY 320: cerebral arteriography, peripheral arteriography, visceral and renal arteriography, aortography, coronary arteriography, and left ventriculography. OPTIRAY 350: peripheral arteriography coronary arteriography, and left ventriculography. In pediatric patients OPTIRAY 320 and OPTIRAY 350: angiocardiography. 1.2 Intra-venous In adults OPTIRAY 300: CT imaging of the head and body, venography, and intravenous excretory urography. OPTIRAY 320: CT imaging of the head and body, venography, and intravenous excretory urography. OPTIRAY 350: CT imaging of the head and body, venography, intravenous excretory urography, and intravenous digital subtraction angiography (IV-DSA). In pediatric patients OPTIRAY 320: CT imaging of the head and body, and intravenous excretory urography.

2 DOSAGE AND ADMINISTRATION The Imaging Bulk Package is not for direct infusion. Adjust the volume and concentration of OPTIRAY. Modify the dose accounting for factors such as age, body weight, vessel size, blood flow rate within the vessel. Please see details in full Prescribing Information. ( 2 ) 2.1 Important Administration Instructions OPTIRAY is for intravascular use only [see Boxed Warning, Contraindications (4), Warnings and Precautions ( 5.1 )] . Use sterile technique for all handling and administration of OPTIRAY. Inspect glass container prior to use for breakage or other damage and do not use damaged containers. Warm OPTIRAY and administer at body or room temperature. Inspect OPTIRAY for particulate matter or discoloration before administration. Do not administer if OPTIRAY contains particulate matter or is discolored. Do not mix OPTIRAY with other drugs, solutions or total parenteral nutrition mixtures. Use the lowest dose necessary to obtain adequate visualization. Adjust the volume and concentration of OPTIRAY. Modify the dose accounting for factors such as age, body weight, vessel size, blood flow rate within the vessel, anticipated pathology, degree and extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed. Avoid extravasation when injecting OPTIRAY; especially in patients with severe arterial or venous disease [see Warnings and Precautions ( 5.6 )] . Hydrate patients before and after OPTIRAY administration [see Warnings and Precautions ( 5.3 )]. 2.2 Intra-arterial Procedures in Adults Cerebral Arteriography Use OPTIRAY 320. The recommended dose for visualization of cerebral arteries is shown below (may repeat as necessary): Diagnostic area Dose Maximum Cumulative Dose carotid or vertebral arteries 2 to 12 mL 200 mL aortic arch injection (four vessel study) 20 to 50 mL 200 mL Peripheral Arteriography Use OPTIRAY 320 or OPTIRAY 350. The recommended dose for visualization of peripheral arteries is shown below (may repeat as necessary): Diagnostic area Dose Maximum Cumulative Dose aorta-iliac runoff 60 mL (range 20 to 90 mL) 250 mL common iliac, femoral 40 mL (range 10 to 50 mL) 250 mL subclavian, brachial 20 mL (range 15 to 30 mL) 250 mL Visceral and Renal Arteriography and Aortography Use OPTIRAY 320. The recommended dose for visualization for the aorta and visceral arteries is shown below (may repeat as necessary): Diagnostic area Dose Maximum Cumulative Dose aorta 45 mL (range 10 to 80 mL) 250 mL celiac 45 mL (range 12 to 60 mL) 250 mL superior mesenteric 45 mL (range 15 to 60 mL) 250 mL renal or inferior mesenteric 9 mL (range 6 to 15 mL) 250 mL Coronary Arteriography and Left Ventriculography Use OPTIRAY 320 or OPTIRAY 350. The recommended dose for visualization of the coronary arteries and left ventricle is shown below (may repeat as necessary): Diagnostic area Dose Maximum Cumulative Dose left coronary 8 mL (range 2 to 10 mL) 250 mL right coronary 6 mL (range 1 to 10 mL) 250 mL left ventricle 40 mL (range 30 to 50 mL) 250 mL 2.3 Intravenous Procedures in Adults Computed Tomography Use OPTIRAY 320 or OPTIRAY 350 for head and body imaging. Head Imaging The recommended dosing is shown below: Scan immediately after completion of the intravenous administration. Infusion OPTIRAY 320 50 to 150 mL OPTIRAY 350 50 to 150 mL Body Imaging OPTIRAY may be administered by bolus injection, by rapid infusion, or by a combination of both. The recommended dosing is shown below: Scanning interval will vary with indication and target organ Bolus Injection Infusion OPTIRAY 320 25 to 75mL 50 to 150 mL OPTIRAY 350 25 to 75mL 50 to 150 mL Venography Use OPTIRAY 320 or OPTIRAY 350. The recommended dose is 50 to 100 mL per extremity; with a maximum cumulative dose of 250 mL. Intravenous Urography Use OPTIRAY 350 or OPTIRAY 320. The recommended dose is shown below: Usual Dose High Dose Urography Maximum Dose OPTIRAY 320 50 to 75mL 1.5 …

3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless to pale yellow solutions containing no undissolved solids, available in the following strengths and single-dose containers: Imaging Product mg of ioversol per mL mg of organically boundiodine per mL Presentations Vials Bottles Hand-held syringes Power injector syringes OPTIRAY 300 (Ioversol 64%) 636 300 No Yes Yes Yes OPTIRAY 320 (Ioversol 68%) 678 320 Yes Yes Yes Yes OPTIRAY 350 (Ioversol 74%) 741 350 No Yes Yes Yes OPTIRAY (ioversol) Injection comes in three strengths: 300 mg iodine/mL (ioversol 64%), 320 mg iodine/mL (ioversol 68%), 350 mg iodine/mL (ioversol 74%) in single-dose vials, bottles, or syringes. ( 3 )

4 CONTRAINDICATIONS Symptomatic hyperthyroidism. Symptomatic Hyperthyroidism ( 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 Acute 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 )] The most common reaction is nausea, occurring at a rate of 1 percent. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact LIEBEL-FLARSHEIM COMPANY LLC at 855-266-5037 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Adult Patients 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. The following listing shows adverse reactions based upon clinical trials with OPTIRAY (ioversol) in 4,187 patients. Adverse reactions are listed by organ system according to clinical importance. More severe reactions are listed before others in a system regardless of incidence. The most common reaction is nausea, occurring at a rate of 1 percent. Cardiac disorders Cardiac arrest, myocardial infarction, arrhythmia, atrioventricular block complete, atrioventricular block, nodal rhythm, bradycardia, angina pectoris, palpitations Ear and labyrinth disorders Vertigo, tinnitus Eye disorders Vision blurred, periorbital edema, conjunctivitis Gastrointestinal disorders Nausea, vomiting, abdominal pain, dysphagia, dry mouth General disorders and administration site conditions Chest pain, pain, injection site pain, injection site hematoma, extravasation, pyrexia, swelling, asthenia, malaise, fatigue, chills Infections and infestations Rhinitis Injury, poisoning, and procedural complications Heart injury, vascular pseudoaneurysm Investigations Electrocardiogram ST segment depression, blood pressure decreased Metabolism and nutrition disorders Acidosis Musculoskeletal and connective tissue disorders Muscular weakness, muscle spasms, back pain Nervous system disorders Cerebral infarction, aphasia, tremor, dizziness, presyncope, headache, paraesthesia, dysgeusia Psychiatric disorders Hallucination, visual hallucination, disorientation, anxiety Renal and urinary disorders Urinary retention, renal pain, polyuria Respiratory, thoracic, and mediastinal disorders Laryngeal edema, hypoxia, pulmonary edema, dyspnea, hyperventilation, cough, sneezing, nasal congestion Skin and subcutaneous tissue disorders Urticaria, rash, pruritus, swelling face, hyperhidrosis, erythema Vascular disorders Hypertension, hypotension, arterial spasm, vasospasm, vasodilation, flushing Pediatric Patients In clinical studies involving 311 patients for pediatric angiocardiography, contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography; 6% of patients reported an adverse reaction, with the most common adverse reactions being nausea and fever. Adverse reactions reported were similar in quality and frequency to the adverse events reported by adults. 6.2 Postmarketing Experience The following additional adverse drug reactions have been reported during post-approval use of OPTIRAY. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure. Cardiac disorders: coronary artery spasm, cyanosis, arrhythmia (ventricular fibrillation, tachycardia, extrasystole), ECG abnormal. Endocrine disorders: hyperthyroidism, hypothyroidis …

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, OPTIRAY 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 agents. Re-evaluate eGFR 48 hours after the imaging procedure, and reinstitute only after renal function is stable. Radioactive Iodine Administration of iodinated contrast agents may interfere with thyroid uptake of radioactive iodine (I 131) and decrease therapeutic efficacy in patients with carcinoma of the thyroid. The decrease in efficacy lasts for 6-8 weeks. Oral Cholecystographic Contrast Agents Renal toxicity has been reported in patients with liver impairment who were given oral cholecystographic agents followed by intravascular contrast agents. Administration of OPTIRAY should be postponed in patients who have recently received a cholecystographic contrast agent. 7.2 Drug/Laboratory Test Interactions Protein-Bound Iodine, Radioactive Iodine Determinations The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for up to 16 days following administration of iodinated contrast agent. However, thyroid function tests that do not depend on iodine estimations, e.g., T3 resin uptake and total or free thyroxine (T4) assays are not affected.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating woman may pump and discard breast milk for 8 hours after OPTIRAY administration. ( 8.2 ) 8.1 Pregnancy Risk Summary Postmarketing data with OPTIRAY use in pregnant women are insufficient to determine if there is a risk of drug-associated adverse developmental outcomes. Ioversol crosses the placenta and reaches fetal tissues in small amounts [see Data]. In animal reproduction studies, no adverse developmental effects were observed following daily intravenous administrations of ioversol to pregnant rats (from Gestation Day 7 to 17) and rabbits (Gestation Day 6 to 18) at doses 0.35 and 0.71 times, respectively, the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data Literature reports show that ioversol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Developmental toxicity studies were conducted with ioversol given intravenously at doses of 0, 0.2, 0.8, and 3.2 g iodine/kg/day from Gestation Day7 to 17 and 6 to 18, in rats and rabbits, respectively. No adverse effects on embryo-fetal development were observed in either species at the maximum dose tested (3.2 g iodine/kg/day). Maternal toxicity was observed in rabbits at 0.8 and 3.2 g iodine/kg/day. 8.2 Lactation Risk Summary There is no information about the presence of ioversol in human or animal milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, iodinated contrast agents are excreted unchanged in human milk in very low amounts with poor absorption from the gastrointestinal tract of the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for OPTIRAY and any potential adverse effects on the breastfed infant from OPTIRAY 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 8 hours (approximately 5 elimination half-lives) after OPTIRAY administration in order to minimize drug exposure to a breast fed infant. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have been established for the use of OPTIRAY 350 and OPTIRAY 320 in angiocardiography; and for OPTIRAY 320 in contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography. Use of OPTIRAY 350 and OPTIRAY 320 in these age groups is based on controlled clinical trials involving 159 patients for pediatric angiocardiography; contrast enhanced computed tomographic imaging of the head and body, and intravenous excretory urography. In general, the types of adverse reactions reported are similar to those of adults [see Adverse Reactions ( 6.1 )] . Safety and effectiveness of OPTIRAY 350 and OPTIRAY 320 have not been established in pediatric patients less than 1 month of age. Pediatric patients at higher risk of experiencing adverse reactions to OPTIRAY include patients with: asthma, sensitivity to medication and/or allergens, congestive heart failure, serum creatinine greater than 1.5 mg/dL, or age less than 12 months. Thyroid function tests indicative of hypothyroidism or transient thyroid suppression have been uncommonly reported following iodinated contrast media administration in pediatric patients, including infants. Some patients were treated for hypothyroidism [See Adverse R …

12.1 Mechanism of Action Intravascular injection of ioversol opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures until significant hemodilution occurs. Ioversol may be visualized in the renal parenchyma within 30 to 60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1 to 3 minutes, with optimum contrast occurring within 5 to 15 minutes. OPTIRAY enhances computed tomographic imaging through augmentation of radiographic efficiency. The degree of density enhancement is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid intravenous injection. Blood levels fall rapidly within 5 to 10 minutes and the vascular compartment half-life is approximately 20 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about 10 minutes; thereafter, the fall becomes exponential.

11 DESCRIPTION 11.1 Chemical Characteristics OPTIRAY (ioversol injection) is a non-ionic radiographic contrast agent. OPTIRAY formulations are sterile, nonpyrogenic, aqueous solutions intended for intravascular use. Ioversol is designated chemically as N,N '-Bis (2,3-dihydroxypropyl)-5-[ N -(2-hydroxyethyl) -glycolamido] -2,4,6-triiodoisophthalamide. The molecular weight of ioversol is 807.11 and the organically bound iodine content is 47.2%. The structural formula of ioversol is as follows: OPTIRAY is available in three strengths: OPTIRAY 300 (ioversol injection 64%): Each mL contains 300 mg organically bound iodine, 636 mg ioversol, 3.6 mg, tromethamine, 0.2 mg edetate calcium disodium. OPTIRAY 320 (ioversol injection 68%): Each mL contains 320 mg organically bound iodine, 678 mg of ioversol, 3.6 mg tromethamine, 0.2 mg edetate calcium disodium. OPTIRAY 350 (ioversol injection 74%): Each mL contains 350 mg organically bound iodine, 741 mg ioversol, 3.6 mg tromethamine, 0.2 mg edetate calcium disodium. The pH of the OPTIRAY formulations is adjusted to 6.0 to 7.4 with hydrochloric acid or sodium hydroxide. All solutions are sterilized by autoclaving and contain no preservatives. Ioversol does not dissociate in solution. structure 11.2 Physical Characteristics Some physical and chemical properties of these formulations are listed below: OPTIRAY 300 OPTIRAY 320 OPTIRAY 350 Ioversol content (mg/mL) 636 678 741 Iodine content (mg I/mL) 300 320 350 Osmolality (mOsm/kg water) 651 702 792 Viscosity (cps) at 25°C 8.2 9.9 14.3 at 37°C 5.5 5.8 9.0 Specific Gravity at 37°C 1.352 1.371 1.405 The OPTIRAY formulations are clear, colorless to pale yellow solutions containing no undissolved solids. Crystallization does not occur at room temperature. OPTIRAY solutions have osmolalities 1.8 to 2.8 times that of plasma (285 mOsm/kg water) as shown in the above table and are hypertonic under conditions of use.

10 OVERDOSAGE The adverse effects of overdosage are life-threatening and affect mainly the pulmonary and cardiovascular system. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Ioversol does not bind to plasma or serum protein and is, therefore, dialyzable.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied OPTIRAY is a clear, colorless to pale yellow, sterile, pyrogen-free, aqueous solution available in three strengths. The products are supplied in containers from which the air has been displaced by nitrogen. OPTIRAY is supplied in the following single-dose configurations: OPTIRAY 350 NDC Number Glass 25x50 mL bottles 0019-1333-06 12x100 mL bottles 0019-1333-11 12x150 mL bottles 0019-1333-16 12x200 mL fill/250 mL bottles 0019-1333-21 Plastic 20x50 mL hand held syringes 0019-1333-78 20x75 mL fill/125 mL power injector syringes 0019-1333-95 20x100 mL fill/125 mL power injector syringes 0019-1333-90 20x125 mL power injector syringes 0019-1333-87 RFID-Tagged Syringes* 20x100 mL fill/125 mL power injector syringes 0019-1333-00 20x125 mL power injector syringes 0019-1333-27 OPTIRAY 320 Glass 25x20 mL vials 0019-1323-02 25x50 mL bottles 0019-1323-06 12x100 mL bottles 0019-1323-11 12x150 mL bottles 0019-1323-16 12x200 mL fill/250 mL bottles 0019-1323-21 Plastic 20x50 mL hand held syringes 0019-1323-78 20x50 mL fill/125 mL power injector syringes 0019-1323-52 20x75 mL fill/125 mL power injector syringes 0019-1323-95 20x100 mL fill/125 mL power injector syringes 0019-1323-90 20x125 mL power injector syringes 0019-1323-87 RFID-Tagged Syringes* 20x75 mL fill/125 mL power injector syringes 0019-1323-85 20x100 mL fill/125 mL power injector syringes 0019-1323-00 20x125 mL power injector syringes 0019-1323-27 OPTIRAY 300 Glass 25x50 mL bottles 0019-1332-06 12x100 mL bottles 0019-1332-11 12x150 mL bottles 0019-1332-16 12x200 mL fill/250 mL bottles 0019-1332-21 Plastic 20x100 mL fill/125 mL power injector syringes 0019-1332-90 RFID-Tagged Syringes* 20x100 mL fill/125 mL power injector syringes 0019-1332-00 *Radio Frequency Identification (RFID) Technology RFID-Tagged Syringe Description This information is for UltrajectTM syringes containing OPTIRAY that have been labeled with a Radio Frequency Identification (RFID) tag. When used with an RFID-enabled OptivantageTM injector, this tag allows for the exchange of product information such as lot number, expiration, concentration, and identification of the syringe as being “unused” prior to use and “used” after product administrations. Patient information is not used in any form with this RFID technology. OPTIRAY product quality is not influenced by the use of this RFID tag. RFID-Tagged Syringe Directions for Use For the RFID Technology to function, the syringe must be used with an Optivantage Injector with RFID technology [see Dosage and Administration ( 2.2 )] . Function of the RFID technology is not dependent on syringe orientation as it is placed in the injector. Instructions for use of injector are provided on the injector interface screen and operator’s manual. If the RFID tag is damaged or otherwise non-functional, the injector will notify the user. Should this occur the OPTIRAY syringe with the non-functional RFID tag may still be used but no data will be transferred to the injector. Regarding interference with medical devices, the RFID tag and injector system meet the IEC 60601-1-2 requirements for emission and immunity standards for medical devices. Follow all manufacturers’ guidelines and do not operate any part of the Optivantage Injector System and RFID-tagged syringes within 6 inches (15 cm) of a pacemaker and/or defibrillator. 16.2 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from strong daylight or direct exposure to the sun. Store up to 40°C (104°F) for up to one month in a contrast media warmer utilizing circulating warm air. May store OPTIRAY for periods longer than one month. Store OPTIRAY RFID-tagged syringes at the same conditions listed for the drug product. Discard OPTIRAY syringes, glass bottles, and their contents if they are frozen or if crystallization occurs. 16.3 Handling Do not re-autoclave plastic container because of possible damage to syringe. RFID-tagged syringes requir …