IOHEXOL

Iohexol, USP is a nonionic radiographic contrast agent available as: Iohexol injection for intrathecal, intra-arterial, intravenous, oral, rectal, intraarticular and body cavity use. The chemical name of iohexol, USP is N,N’ -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: Iohexol Injection, USP is a sterile, pyrogen-free, clear, colorless to pale yellow solution available in following concentrations of iodine: Iohexol Injection USP, 300 mg iodine/mL: Each mL contains 647 mg iohexol, USP (providing 300 mg organically bound iodine) and the following inactive ingredients: 0.1 mg edetate calcium disodium, USP; 1.21 mg tromethamine, USP and water for injection. Iohexol Injection USP 350 mg iodine/mL: Each mL contains 755 mg iohexol, USP (providing 350 mg organically bound iodine) and the following inactive ingredients: 0.1 mg edetate calcium disodium, USP; 1.21 mg tromethamine, USP and water for injection. The pH is adjusted between 6.8 and 7.7 with hydrochloric acid or sodium hydroxide. Iohexol injection contain no preservatives and no ingredient made from a gluten-containing grain (wheat, barley, or rye). Iohexol injection have the following physical properties: Table 21: Physicochemical Properties of Iohexol Injection Dosage Form Concentration (mg iodine/mL) Osmolality * (mOsmol/kg water) Absolute Viscosity (cP) Specific Gravity 20°C 37°C 37°C Injection 300 659 11.48 6.05 1.344 350 774 21.48 12.16 1.4054 * By Freezing Point Depression Osmometer. Iohexol injection has osmolalities from approximately 2.4 times that of plasma (285 mOsmol/kg water) or cerebrospinal fluid (301 mOsmol/kg water) as shown in the above table and are hypertonic. 1

Iohexol is a radiographic contrast agent indicated for intrathecal, intra-arterial, intravenous, oral, rectal, intraarticular and body cavity imaging procedures in adults and pediatric patients. ( 1 ) 1.1 Intrathecal Procedures ‡ Iohexol injection is indicated for: Myelography and computerized tomography (CT) myelography (lumbar, thoracic, cervical, total columnar) in adults and pediatric patients aged 2 weeks and older CT cisternography in adults and pediatric patients aged 2 weeks and older 1.2 Intra-arterial Procedures ‡ Iohexol injection is indicated for: Cardiac ventriculography in adults and pediatric patients Aortography including studies of aorta and its branches in adults and pediatric patients Selective coronary arteriography in adults Cerebral arteriography in adults Peripheral arteriography in adults Intra-arterial digital subtraction angiography (IA-DSA) of the head, neck, abdominal, renal and peripheral vessels in adults Pulmonary angiography in pediatric patients 1.3 Intravenous Procedures ‡ Iohexol injection is indicated for: Excretory urography in adults and pediatric patients CT of the head and body in adults and pediatric patients Peripheral venography (phlebography) in adults Intravenous digital subtraction angiography (IV-DSA) of the head, neck, abdominal, renal and peripheral vessels in adults 1.4 Oral or Rectal Procedures ‡ Iohexol injection is indicated for: Radiographic examination of the gastrointestinal (GI) tract in adults and pediatric patients CT of the abdomen and pelvis in conjunction with intravenous administration of iohexol injection in adults and pediatric patients 1.5 Intraarticular Procedures ‡ Iohexol injection is indicated for: Arthrography in adults 1.6 Body Cavity Procedures ‡ Iohexol injection is indicated for: Endoscopic retrograde pancreatography (ERP) and cholangiopancreatography (ERCP) in adults Herniography in adults Hysterosalpingography in adults Voiding cystourethrography (VCU) in pediatric patients ‡ Specific dosage forms, concentrations and presentations of iohexol are recommended for each type of imaging procedure [see Dosage and Administrations (2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) and Warnings and Precautions (5.1 , 5.2) ].

For each imaging procedure, specific dosage forms, concentrations and presentations are recommended. Individualize the concentration and volume according to the specific dosing tables and accounting for factors such as age, body weight, and condition of the patient, and the equipment and imaging technique used. ( 2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) See full prescribing information for complete dosing and administration information. ( 2 ) 2.1 Important Dosage and Administration Instructions Specific dosage forms, concentrations and presentations of iohexol are recommended for each type of imaging procedure [see Dosage and Administration (2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9 ) and Warnings and Precautions (5.1 , 5.2) ]. Individualize the volume, strength and rate of administration of iohexol injection according to the specific dosing tables [see Dosage and Administration (2.2 , 2.3 , 2.4 , 2.5 , 2.6 , 2.7 , 2.8 , 2.9) ] . 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. Hydrate patients before and after administration of iohexol injection [see Warnings and Precautions (5.4) ]. Use aseptic technique for all handling and administration of iohexol injection. Administer iohexol injection at either body (37°C, 98.6°F) or room temperature (20° to 25°C, 68° to 77°F). Do not mix iohexol injection with, or inject in intravenous lines containing, other drugs or total nutritional admixtures. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Each container of iohexol injection in single-dose container is intended for one procedure only. Discard any unused portion. 2.2 Recommended Dosage for Intrathecal Procedures in Adults The recommended doses for intrathecal procedures in adults are shown in Table 1. Administer over 1 minute to 2 minutes. If sequential or repeat examinations are required, allow at least 48 hours for clearance of the drug from the body before repeat administration; however, whenever possible, 5 days to 7 days is recommended. If CT myelography is performed, delay imaging by several hours to reduce the degree of contrast. Table 1: Recommended Concentrations and Volumes of Iohexol Injection for Intrathecal Procedures in Adults Imaging Procedure Injection Type Concentration (mg Iodine/mL) Volume to Administer Lumbar Myelography Lumbar 180 * 10 mL to 17 mL 240 * 7 mL to 12.5 mL Thoracic Myelography Lumbar Cervical 240 * 6 mL to 12.5 mL 300 * 6 mL to 10 mL Cervical Myelography Lumbar 240 * 6 mL to 12.5 mL 300 * 6 mL to 10 mL C1-2 180 * 7 mL to 10 mL 240 * 6 mL to 12.5 mL 300 * 4 mL to 10 mL Total Columnar Myelography Lumbar 240 * 6 mL to 12.5 mL 300 * 6 mL to 10 mL CT Cisternography Lumbar 180 * 10 mL to 17 mL 240 * 7 mL to 12.5 mL * Use single-dose containers. 2.3 Recommended Dosage for Intra-arterial Procedures in Adults The recommended doses for intra-arterial procedures in adults are shown in Table 2. Table 2: Recommended Concentrations and Volumes of Iohexol Injection for Intra-arterial Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer per Single Injection for Selective Injection Sites Maximum Cumulative Total Dose Cardiac Ventriculography 350 * 40 mL (Range of 30 mL to 60 mL) may be combined with selective coronary arteriography 250 mL Aortography and Selective Visceral Arteriography 300 * Aorta (aortic arch, ascending aorta): 50 mL to 80 mL Abdominal aorta and its branches (celiac, mesenteric, hepatic and splenic arteries): 30 mL to 60 mL Renal arteries: 5 mL to 15 mL 290 mL 350 * 250 mL Aortic root and arch study when used alone 350 * 50 mL (Range of 20 mL to 75 mL) 250 mL Selective Coronary Arteriography 350 * 5 mL (Range of 3 mL to 14 mL) 250 mL Cerebral Arteriography 300 * Common carotid artery: 6 mL to 12 mL Internal carotid artery: 8 mL to 10 mL External carotid artery: 6 mL to 9 mL Vertebral artery: 6 mL to 10 mL 290 mL Peripheral Arteriography Aortofemoral Runoffs 300 * 30 mL to 90 mL 290 mL 350 * 20 mL to 70 mL 250 mL Selective Arteriogram 300 * 10 mL to 60 mL 290 mL 350 * 10 mL to 30 mL 250 mL IA-DSA (head, neck, abdominal, renal and peripheral vessels) 140 * Aorta: 20 mL to 45 mL at 8 mL/sec to 20 mL/sec Carotid artery: 5 mL to 10 mL at 3 mL/sec to 6 mL/sec Femoral artery: 9 mL to 20 mL at 3 mL/sec to 6 mL/sec Vertebral artery: 4 mL to 10 mL at 2 mL/sec to 8 mL/sec Renal arteries: 6 mL to 12 mL at 3 mL/sec to 6 mL/sec Other branches of aorta (includes subclavian, axillary, innominate and iliac): 8 mL to 25 mL at 3 mL/sec to 10 mL/sec 250 mL * Use single-dose containers. 2.4 Recommended Dosage for Intravenous Procedures in Adults The recommended doses for intravenous procedures in adults are shown in Table 3. Table 3: Recommended Concentrations and Volumes of Iohexol Injection for Intravenous Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer Excretory Urography 300 * 0.6 mL/kg to 1.2 mL/kg body weight (maximum dose is 102 mL) 350 * CT Head 240 * 120 mL to 250 mL by infusion 300 ** 70 mL to 150 mL by rapid injection 350 ** 80 mL by rapid injection Body 300 ** 50 mL to 200 mL by rapid injection 350 ** 60 mL to 100 mL by rapid injection Peripheral Venography (phlebography) 240 * 20 mL to 150 mL per leg 300 * 40 mL to 100 mL per leg IV-DSA (head, neck, abdominal, renal and peripheral vessels) 350 * 30 mL to 50 mL at 7.5 mL/sec to 30 mL/sec using a pressure injector Frequently three or more doses may be required; the maximum cumulative total dose is 250 mL * Use single-dose containers. ** Use single-dose containers. 2.5 Recommended Dosage for Oral Procedures in Adults Recommended Dosage for Radiographic Examination of the GI Tract in Adults The recommended dose for radiographic examination of the GI tract in adults is 50 mL to 100 mL of iohexol injection 350 mg iodine/mL administered undiluted orally. Recommended Dosage for CT of the Abdomen and Pelvis in Conjunction with Intravenous Administration of Iohexol Injection in Adults The recommended oral dose using diluted iohexol injection and concurrent intravenous doses for CT of the abdomen and pelvis in adults are shown in Table 4. Table 4: Recommended Concentrations and Volumes of Diluted Iohexol Injection and Concurrent Intravenous Iohexol Injection for CT of the Abdomen and Pelvis in Adults Concentration (mg Iodine/mL) Volume to Administer Administration Instructions Oral Dose Using Diluted Iohexol Injection 6 mg Iodine/mL to 12 mg Iodine/mL of Diluted Iohexol Injection § § See Table 5 for dilution instructions of Iohexol injection 500 mL to 1,000 mL Administer the oral dose all at once or over a period of up to 45 minutes if there is difficulty in consuming the required volume. Use a higher iodine concentration of the diluted product if a smaller volume needs to be administered (see Table 5). Intravenous Dose of Iohexol Injection in Conjunction with Oral Administration 300 ** 100 mL to 150 mL Administer up to 40 minutes AFTER consumption of the oral dose. ** Use single-dose containers. Preparation of Diluted Iohexol Injection for Oral Administration for CT of the Abdomen and Pelvis in Adults Prepare the diluted iohexol injection in water, carbonated beverage, milk, infant formula, or juice just prior to administration according to Table 5. Discard any unused portion after the procedure. Table 5: Volumes of Iohexol Injection and Added Liquid to Dilute Iohexol Injection for Oral Administration for CT of the Abdomen in Adults Concentration of Diluted Iohexol Injection (mg Iodine/mL) Dilution Method 1 Dilution Method 2 Dilution Method 3 Volume of Iohexol Injection 240 mg Iodine/mL (mL) Volume of Added Liquid † (mL) Volume of Iohexol Injection 300 mg Iodine/mL (mL) Volume of Added Liquid † (mL) Volume of Iohexol Injection 350 mg Iodine/mL (mL) Volume of Added Liquid † (mL) 6 25 975 20 980 17 983 9 38 962 30 970 26 974 12 50 950 40 960 35 965 15 63 937 50 950 43 957 18 75 925 60 940 52 948 21 88 912 70 930 60 940 † Use water, carbonated beverage, milk, infant formula, or juice. 2.6 Recommended Dosage for Intraarticular Procedures in Adults The recommended doses for intraarticular procedures in adults are shown in Table 6. Use passive or active manipulation to disperse the medium throughout the joint space. Table 6: Recommended Concentrations and Volumes of Iohexol Injection for Intraarticular Procedures in Adults Imaging Procedure Location Concentration (mg Iodine/mL) Volume to Administer Double Contrast/Single Contrast Arthrography Knee 240 * 5 mL to 15 mL Lower volumes recommended for double-contrast examinations; higher volumes recommended for single-contrast examinations. 300 * 5 mL to 15 mL 350 * 5 mL to 10 mL Shoulder 300 * 10 mL Temporomandibular 300 * 0.5 mL to 1 mL * Use single-dose containers. 2.7 Recommended Dosage for Body Cavity Procedures in Adults The recommended doses for body cavity procedures in adults are shown in Table 7. Volume to administer may vary depending on individual anatomy and/or disease state. Table 7: Recommended Concentrations and Volumes of Iohexol Injection for Body Cavity Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume to Administer Route of Administration Endoscopic retrograde pancreatography (ERP) and cholangiopancreatography (ERCP) 240 * 10 mL to 50 mL Intraductal Herniography 240 * 15 mL to 20 mL Intraperitoneal 300 * Hysterosalpingography 240 * 50 mL Intrauterine * Use single-dose containers. 2.8 Recommended Dosage for Intrathecal, Intra-arterial, and Intravenous Procedures in Pediatric Patients Recommended Dosage for Intrathecal Procedures in Pediatric Patients Aged 2 Weeks and Older Recommended doses based on age for intrathecal procedures in pediatric patients aged 2 weeks and older are shown in Table 8. Administer over 1 minute to 2 minutes. If sequential or repeat examinations are required, allow at least 48 hours for clearance of the drug from the body before repeat administration; however, whenever possible, 5 days to 7 days is recommended. If CT myelography is performed, delay imaging by several hours to reduce the degree of contrast. Table 8: Recommended Concentrations and Volumes of Iohexol Injection Based on Age for Intrathecal Procedure in Pediatric Patients Aged 2 Weeks and Older Imaging Procedure Injection Type Age Concentration (mg Iodine/mL) Volume to Administer Myelography Lumbar Thoracic Cervical Total Columnar CT cisternography Lumbar 2 weeks up to 3 months 180 * 2 mL to 4 mL 3 months up to 36 months 4 mL to 8 mL 3 years up to 7 years 5 mL to 10 mL 7 years up to 13 years 5 mL to 12 mL 13 years to 18 years 6 mL to 15 mL * Use single-dose containers . Recommended Dosage for Intra-arterial Procedures in Pediatric Patients The recommended doses for intra-arterial procedures in pediatric patients are shown in Table 9. Table 9: Recommended Concentrations and Volumes of Iohexol Injection per Body Weight for Intra-arterial Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume per Body Weight to Administer per Single Injection Maximum Cumulative Volume Cardiac Ventriculography 300 * 1.75 mL/kg (Range of 1.5 mL/kg to 2 mL/kg) 6 mL/kg up to a total volume of 290 mL 350 * 1.25 mL/kg (Range of 1 mL/kg to 1.5 mL/kg) 5 mL/kg up to a total volume of 250 mL Aortography (aortic root, aortic arch and descending aorta) 350 * 1 mL/kg 5 mL/kg up to a total volume of 250 mL Pulmonary Angiography 350 * 1 mL/kg 5 mL/kg up to a total volume of 250 mL * Use single-dose containers. Recommended Dosage for Intravenous Procedures in Pediatric Patients The recommended doses for intravenous procedures in pediatric patients are shown in Table 10. Table 10: Recommended Concentrations and Volumes of Iohexol Injection per Body Weight for Intravenous Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume per Body Weight to Administer Excretory Urography 300 * 0.5 mL/kg to 3 mL/kg (Maximum single dose: 116 mL) CT of the Head and Body 240 * 1 mL/kg to 2 mL/kg (with maximum 3 mL/kg) (Maximum single dose: 116 mL) 300 ** * Use single-dose containers. ** Use single-dose containers. 2.9 Recommended Dosage for Oral or Rectal and Body Cavity Procedures in Pediatric Patients Recommended Dosage for Radiographic Examination of the GI Tract in Pediatric Patients The recommended doses for radiographic examination of the GI tract are shown in Table 11. Administer orally or rectally. Table 11: Recommended Concentrations and Volumes of Iohexol Injection Based on Age for Radiographic Examination of the GI Tract in Pediatric Patients Age Concentration (mg iodine/mL) Oral Volume Rectal Volume Less than 3 months 180 * 5 mL to 30 mL May be a larger volume than the volume given orally (up to 300 mL) 3 months to 3 years 180 * , 240 * , or 300 * Up to 60 mL 4 years to 10 years Up to 80 mL Greater than 10 years Up to 100 mL *Use single-dose containers. Recommended Dosage for CT of the Abdomen and Pelvis in Conjunction with Intravenous Administration of Iohexol Injection in Pediatric Patients The recommended oral dose using diluted iohexol injection and concurrent intravenous dose for CT of the abdomen and pelvis in pediatric patients are shown in Table 12. Table 12: Recommended Concentrations and Volumes of Diluted Iohexol Injection and Concurrent Intravenous Iohexol Injection for CT of the Abdomen and Pelvis in Pediatric Patients Concentration (mg Iodine/mL) Volume to Administer Administration Instructions Maximum Dose by Age or Body Weight Oral Dose Using Diluted Iohexol Injection 9 mg Iodine/mL to 21 mg Iodine/mL of Diluted Iohexol Injection § § See Table 13 for Dilution Instructions of Iohexol injection 180 mL to 750 mL Administer the oral dose all at once or over a period of up to 45 minutes if there is difficulty in consuming the required volume. Use a higher iodine concentration of the diluted product if a smaller volume needs to be administered (see Table 13). less than 3 years old: 5 grams iodine 3 years old to 18 years old: 10 grams iodine Intravenous Dose in Conjunction with Oral Administration 240 ** or 300 ** 2 mL/kg body weight (with a range of 1 mL/kg to 2 mL/kg) Administer up to 60 minutes AFTER consumption of the oral dose. 3 mL/kg (maximum single dose: 116 mL) ** Use single-dose containers. Preparation of Diluted Iohexol Injection for Oral Administration for CT of the Abdomen and Pelvis in Pediatric Patients Prepare the diluted iohexol injection in water, carbonated beverage, milk, infant formula, or juice just prior to administration according to Table 13. Discard any unused portion after the procedure. Table 13: Volumes of Iohexol Injection and Added Liquid to Dilute Iohexol Injection for Oral Administration for CT of the Abdomen and Pelvis in Pediatric Patients Concentration of Diluted Iohexol Injection (mg Iodine/mL) Dilution Method 1 Dilution Method 2 Dilution Method 3 Volume of Iohexol Injection 240 mg Iodine/mL (mL) Volume of Added Liquid † (mL) Volume of Iohexol Injection 300 mg Iodine/mL (mL) Volume of Added Liquid † (mL) Volume of Iohexol Injection 350 mg Iodine/mL (mL) Volume of Added Liquid † (mL) 6 25 975 20 980 17 983 9 38 962 30 970 26 974 12 50 950 40 960 35 965 15 63 937 50 950 43 957 18 75 925 60 940 52 948 21 88 912 70 930 60 940 † Use water, carbonated beverage, milk, infant formula, or juice. Recommended Dosage for Voiding Cystourethrography in Pediatric Patients Voiding cystourethrography (VCU) can be performed in conjunction with excretory urography [see Dosage and Administration (2.8) ] . The concentration of diluted iohexol injection may vary depending upon the patient’s size and age and with the technique and equipment used. Volume ranges of diluted iohexol injection 50 mg iodine/mL and 100 mg iodine/mL are shown in Table 14. Dilute iohexol injection with Sterile Water for Injection according to Table 15, utilizing aseptic technique, just prior to use. Discard any unused portion after the procedure. Table 14: Volume Ranges of Diluted Iohexol Injection for VCU in Pediatric Patients Concentration of Diluted Iohexol Injection § (mg Iodine/mL) Volume to Administer 50 50 mL to 600 mL by intravesical administration 100 50 mL to 300 mL by intravesical administration § See Table 15 below for dilution instructions of iohexol injection. Table 15: Volumes of Iohexol Injection and Sterile Water for Injection to Dilute Iohexol Injection for VCU in Pediatric Patients Concentration of Diluted Iohexol Injection (mg Iodine/mL) Dilution Method 1 Dilution Method 2 Dilution Method 3 Volume of Iohexol Injection 240 mg Iodine/mL (mL) Volume of Sterile Water for Injection (mL) Volume of Iohexol Injection 300 mg Iodine/mL (mL) Volume of Sterile Water for Injection (mL) Volume of Iohexol Injection 350 mg Iodine/mL (mL) Volume of Sterile Water for Injection (mL) 50 100 380 100 500 100 600 60 100 300 100 400 100 483 70 100 243 100 330 100 400 80 100 200 100 275 100 338 90 100 167 100 233 100 289 100 100 140 100 200 100 250

Iohexol for hysterosalpingography is contraindicated during pregnancy or suspected pregnancy, menstruation or when menstruation is imminent, within 6 months after termination of pregnancy, within 30 days after conization or curettage, when signs of infection are present in any portion of the genital tract including the external genitalia, and when reproductive tract neoplasia is known or suspected because of the risk of peritoneal spread of neoplasm. Hysterosalpingography during pregnancy (or suspected pregnancy), menstruation (or when menstruation is imminent), within 6 months after termination of pregnancy, within 30 days after conization or curettage, when signs of infection are present in any portion of the genital tract, including the external genitalia and when reproductive tract neoplasia is known or suspected. ( 4 )

The following clinically significant adverse reactions are described elsewhere in the labeling: Risks Associated with Intrathecal Administration of Iohexol Injection 140 mg Iodine/mL and 350 mg Iodine/mL [see Warnings and Precautions (5.1) ] Risks Associated with Parenteral Administration of Iohexol Oral Solution [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Warnings and Precautions (5.3) ] Acute Kidney Injury [see Warnings and Precautions (5.4) ] Cardiovascular Adverse Reactions [see Warnings and Precautions (5.5) ] Thromboembolic Events [see Warnings and Precautions (5.6) ] Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age [see Warnings and Precautions (5.9) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.12) ] Most common adverse reactions (incidence ≥ 1%) in adult patients Intrathecal: Headaches, pain including backache, neckache, stiffness and neuralgia, nausea, vomiting, dizziness. Intra-arterial or intravenous: 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. Oral: Diarrhea, nausea, vomiting, abdominal pain, flatulence, headache. Body Cavity: Pain, swelling, heat sensation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals LLC at 1-877-835-5472 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. Intrathecal Administration Adults Adverse reactions (≥ 1%) in 1,531 adult patients following intrathecal administration of iohexol injection in clinical trials are presented in Table 16. Table 16: Adverse Reactions (≥ 1%) in Adult Patients Following Intrathecal Administration of Iohexol Injection in Clinical Trials System Organ Class Adverse Reaction Incidence N = 1,531 Nervous system disorders Headaches 18% Musculoskeletal and connective tissue disorders Pain including backache, neckache, stiffness, neuralgia 8% Gastrointestinal disorders Nausea 6% Vomiting 3% Nervous System disorders Dizziness 2% Other adverse reactions (< 1%) were: Ear and labyrinth disorders : tinnitus, vertigo Eye disorders : photophobia General disorders and administration site conditions : sensation of heat Metabolism and nutrition disorders : loss of appetite Musculoskeletal and connective tissue disorders : feeling of heaviness Nervous system disorders : drowsiness, hypertonia, neuralgia, neurological changes, paresthesia, syncope Renal and urinary disorders : difficulty in micturition Skin and subcutaneous tissue disorders : sweating Vascular disorders : hypertension, hypotension Pediatric Patients The adverse reactions reported in pediatric patients following intrathecal administration of iohexol injection were generally similar to those reported in adults. A total of 152 pediatric patients were administered iohexol injection 180 mg iodine/mL intrathecally by lumbar puncture for pediatric myelography in clinical trials. Adverse reactions (≥ 1%) are presented in Table 17. Table 17: Adverse Reactions (≥ 1%) in Pediatric Patients Following Intrathecal Administration of Iohexol Injection 180 mg iodine/mL by Lumbar Puncture for Myelography in Clinical Trials System Organ Class Adverse Reaction Incidence N = 152 Nervous system disorders Headache 9% Gastrointestinal disorders Vomiting 6% Musculoskeletal and connective tissue disorders Backache 1.3% Other adverse reactions (< 1%) were: Gastrointestinal disorders: stomachache General disorders and administration site conditions: fever Nervous system disorders : neurological changes Psychiatric disorders : visual hallucination Skin and subcutaneous tissue disorders : hives Intra-arterial or Intravenous Administration Adults Adverse reactions (≥ 1%) in 1,485 adult patients following intra-arterial or intravenous administration of iohexol injection in clinical trials are presented in Table 18. Table 18: Adverse Reactions (≥ 1%) in Adult Patients Following Intra-arterial or Intravenous Administration of Iohexol Injection in Clinical Trials System Organ Class Adverse Reaction Incidence (N = 1,485) Cardiac disorders Arrhythmias including PVCs and PACs 2% Nervous system disorders Pain 3% Vision abnormalities including blurred vision and photomas 2% Taste perversion 1% Gastrointestinal disorders Nausea 2% Other adverse reactions (< 1%) were: Cardiac disorders: hypotension, cardiac failure, asystole, bradycardia, tachycardia, vasovagal reaction Respiratory, thoracic and mediastinal disorders: dyspnea, rhinitis, coughing, laryngitis Gastrointestinal disorders : vomiting, diarrhea, dyspepsia, cramp, dry mouth General disorders and administration site conditions: fever, shivering Nervous system disorders: cerebral infarction, convulsion, hemiparesis, motor and speech dysfunction, nystagmus, paresthesia, somnolence, transient ischemic attack, vertigo including dizziness and lightheadedness Musculoskeletal and connective tissue disorders: still neck Skin and subcutaneous tissue disorders : urticaria, abscess, pruritus, purpura Psychiatric disorders : anxiety, syncope Pediatric Patients Adverse reactions reported in pediatric patients following intra-arterial or intravenous administration of iohexol injection were generally similar in quality and frequency to those reported in adults. A total of 391 pediatric patients in clinical trials were administered iohexol injection 240 mg iodine/mL, 300 mg iodine/mL, or 350 mg iodine/mL by intra-arterial or intravenous injection for pediatric cardiac ventriculography, excretory urography, and CT head imaging. Adverse reactions (≥ 1%) were vomiting (2%) and nausea (1%). Other adverse reactions (< 1%) were: Cardiac disorders: Ventricular tachycardia, 2:1 heart block, hypertension, anemia General disorders and administration site conditions: Pain, fever Nervous system disorders: Convulsion, taste abnormality Respiratory, thoracic and mediastinal disorders: Congestion, apnea Endocrine disorders: Hypoglycemia Skin and subcutaneous tissue disorders: Rash Oral or Rectal Administration for Examination of the Gastrointestinal Tract Adults A total of 54 adult patients were administered undiluted iohexol injection 350 mg iodine/mL by oral route for radiographic examination of the gastrointestinal tract in clinical trials. Adverse reactions (≥ 1%) are presented in Table 19. Table 19: Adverse Reactions (≥ 1%) in Adult Patients Following Oral Administration of Undiluted Iohexol Injection 350 mg Iodine/mL in Clinical Trials System Organ Class Adverse Reaction Incidence N = 54 Gastrointestinal disorders Diarrhea 42% Nausea 15% Vomiting 11% Abdominal Pain 7% Flatulence 2% Nervous system disorders Headache 2% Pediatrics Patients A total of 58 pediatric patients were administered iohexol injection by oral or rectal administration in clinical trials. Adverse reactions (≥ 1%) are presented in Table 20. Table 20: Adverse Reactions (≥ 1%) in Pediatric Patients Following Oral or Rectal Administration of Iohexol Injection in Clinical Trials System Organ Class Adverse Reaction Incidence N = 58 Gastrointestinal disorders Diarrhea 36% Vomiting 9% Nausea 5% Abdominal pain 2% General disorders and administration site conditions Fever 5% Skin and subcutaneous tissue disorders Urticaria 2% Vascular disorders Hypotension 2% Oral Administration for CT of the Abdomen in Conjunction with Intravenous Administration Adults A total of 44 adult patients received diluted iohexol injection (4 mg iodine/mL to 9 mg iodine/mL) by oral route in conjunction with intravenously injected iohexol 300 mg iodine/mL for CT examination of the abdomen in clinical trials. Adverse reactions (≥ 1%) were limited to a single report of vomiting (2.3%). Pediatric Patients A total of 69 pediatric patients received diluted iohexol injection (9 mg iodine/mL to 29 mg iodine/mL) by oral route in conjunction with intravenously administered iohexol injection 240 mg iodine/mL or iohexol injection 300 mg iodine/mL for CT examination of the abdomen in clinical trials. Adverse reactions (≥ 1%) were limited to a single report of vomiting (1.4%). Intraarticular Administration Arthrography in Adults A total of 285 adult patients received iohexol injection 240 mg iodine/mL, 300 mg iodine/mL, or 350 mg iodine/mL for various body cavity examinations in clinical trials. The most frequent adverse reactions (≥ 1%) were administration site pain (26%) and swelling (22%) in arthrography. Patients also experienced heat (7%). Body Cavity Use VCU in Pediatric Patients No new adverse reactions associated with the use of iohexol injection for VCU procedures were reported in 51 pediatric patients studied. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of iohexol injection. 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 drug exposure. General Immune system disorders: Hypersensitivity reactions, anaphylactic or anaphylactoid reactions, anaphylactic or anaphylactoid shock including life-threatening or fatal anaphylaxis General disorders and administration site conditions: Pyrexia, chills, pain and discomfort, asthenia, administration site conditions including extravasation Intrathecal Administration Nervous system disorders: Meningism, aseptic meningitis, seizures or status epilepticus, disorientation, coma, depressed or loss of consciousness, transient contrast-induced toxic encephalopathy (including amnesia, hallucination, paralysis, paresis, speech disorder, aphasia, dysarthria), restlessness, tremors, hypoesthesia Musculoskeletal and connective tissue disorders : Pain, muscle spasms or spasticity Psychiatric disorders: Confusional state, agitation, anxiety Eye disorders: Transient visual impairment including cortical blindness Renal and urinary disorders: Acute kidney injury Intra-arterial or Intravenous Administration Cardiac disorders: Severe cardiac complications (including cardiac arrest, cardiopulmonary arrest), shock, peripheral vasodilatation, palpitations, vasospasm including spasm of coronary arteries, myocardial infarction, syncope, cyanosis, pallor, flushing, chest pain Vascular disorders: Vasospasm and thrombophlebitis following intravenous injection Blood and lymphatic system disorders: Neutropenia Nervous system disorders: Disorientation, coma, depressed or loss of consciousness, transient contrast-induced toxic encephalopathy (including amnesia, hallucination, paralysis, paresis, speech disorder, aphasia, dysarthria), restlessness, tremors, hypoesthesia Psychiatric disorders: Confusional state, agitation Eye disorders: Eye irritation or itchiness, periorbital edema, ocular or conjunctival hyperemia, lacrimation Renal and urinary disorders: Acute kidney injury, toxic nephropathy (CIN), transient proteinuria, oliguria or anuria, increased serum creatinine Gastrointestinal disorders: Abdominal pain, pancreatitis aggravated, salivary gland enlargement Endocrine disorders: Hyperthyroidism, hypothyroidism Respiratory, thoracic and mediastinal disorders: Respiratory distress, respiratory failure, pulmonary edema, bronchospasm, laryngospasm, throat irritation, throat tightness, laryngeal edema, wheezing, chest discomfort, asthmatic attack Skin and subcutaneous tissue disorders: Contrast media reactions range from mild (e.g., pleomorphic rashes, drug eruption, erythema and skin discoloration, blisters, hyperhidrosis, angioedema, localized areas of edema) to severe (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis [SJS/TEN], bullous or exfoliative dermatitis, acute generalized exanthematous pustulosis [AGEP] and drug reaction with eosinophilia and systemic symptoms [DRESS]) Oral Administration Gastrointestinal disorders: Dysphagia, abdominal pain Body Cavity Administration Gastrointestinal disorders: Pancreatitis Musculoskeletal and connective tissue disorders: Arthritis (arthrography) Hysterosalpingography: Injection of iohexol for hysterosalpingography is associated with immediate, transient pain. Monitor injection pressure and volume instilled to minimize pain and to avoid disruptive distention of the uterus and fallopian tubes. Fluoroscopic monitoring is recommended. Nervous system disorders: Pain (49%), somnolence and fever each with an individual incidence of 3% Gastrointestinal disorders: Nausea (3%)

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, iohexol injection 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 Iohexol may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy. Avoid thyroid therapy or testing for up to 6 weeks post iohexol injection. 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Iodinated contrast agents, including iohexol, will temporarily increase protein-bound iodine in blood. Do not perform protein-bound iodine test for at least 16 days following administration of iohexol injection. However, thyroid function tests that do not depend on iodine estimation, e.g., T3 resin uptake or direct thyroxine assays, are not affected.