Iohexol

1 INDICATIONS AND USAGE 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) ].

2 DOSAGE AND ADMINISTRATION 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 Arteriograp …

3 DOSAGE FORMS AND STRENGTHS Injection: Clear, colorless to pale yellow solution available in the following presentations: Dosage Form Concentration (mg of iodine/mL) Package Size Package Type Injection 300 50 mL, 75 mL and 100 mL Single-Dose Bottle 350 50 mL, 75 mL and 100 mL Injection: 300 mg iodine/mL and 350 mg iodine/mL in single-dose bottles. ( 3 )

4 CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS 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 subcuta …

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, 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.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating woman may pump and discard breast milk for 10 hours after iohexol injection administration. ( 8.2 ) 8.1 Pregnancy Risk Summary Hysterosalpingography is contraindicated in pregnant women due to the potential risk to the fetus from an intrauterine procedure [see Contraindications (4) ]. There are no data with iohexol use in pregnant women to inform any drug-associated risks. Iohexol crosses the placenta and reaches fetal tissues in small amounts (see Data) . In animal reproduction studies, no developmental toxicity occurred with intravenous iohexol administration to rats and rabbits at doses up to 0.4 (rat) and 0.5 (rabbit) times the maximum recommended human intravenous dose (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Human Data Literature reports show that intravenously administered iohexol crosses the placenta and is visualized in the digestive tract of exposed infants after birth. Animal Data Iohexol was neither embryotoxic nor teratogenic in either rats or rabbits at the following dose levels tested: 1 g iodine/kg, 2 g iodine/kg, 4 g iodine/kg in rats, administered intravenously to 3 groups of 25 dams once daily during days 6 through 15 of pregnancy; 0.3 g iodine/kg, 1 g iodine/kg, 2.5 g iodine/kg in rabbits, administered intravenously to 3 groups of 18 rabbits dosed once a day during days 6 through 18 of pregnancy. 8.2 Lactation Risk Summary Published literature reports that breast feeding after intravenous iohexol administration to the mother would result in the infant receiving an oral dose of approximately 0.7% of the maternal intravenous dose; however, lactation studies have not been conducted with oral, intrathecal, or intracavity administration of iohexol. There is no information on the effects of the drug on the breastfed infant or on milk production. Iodinated contrast agents are excreted unchanged in human milk in very low amounts with poor absorption from the gastrointestinal tract of a breastfed infant. Exposure to iohexol to a breastfed infant can be minimized by temporary discontinuation of breastfeeding (see Clinical Considerations). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for iohexol and any potential adverse effects on the breastfed infant from iohexol 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 iohexol injection administration to minimize drug exposure to a breastfed infant. 8.4 Pediatric Use Intrathecal Use The safety and effectiveness of iohexol have been established in pediatric patients aged 2 weeks and older for myelography and CT myelography (lumbar, thoracic, cervical, total columnar) and for CT cisternography. Use of iohexol is supported by controlled clinical studies in adults for myelography, in addition to clinical studies in pediatric patients undergoing myelography. The safety and effectiveness of iohexol have not been established for intrathecal use in pediatric patients less than 2 weeks of age. The safety and effectiveness of iohexol for CT cerebral ventriculography have not been established in pediatric patients. Intra-arterial or Intravenous Use Cardiac Ventriculography, Aortography and Pulmonary Angiography The safety and effectiveness of iohexol have been established i …

12.1 Mechanism of Action The iodine atoms in iohexol provide attenuation of X-rays in direct proportion to the concentration of iohexol. Since concentration changes over time, iohexol provides time-dependent image contrast which may assist in visualizing body structures.

11 DESCRIPTION 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

10 OVERDOSAGE The adverse effects of overdosage in intra-arterial or intravenous administration are life-threatening and affect mainly the pulmonary and cardiovascular systems. The symptoms include: cyanosis, bradycardia, acidosis, pulmonary hemorrhage, convulsions, coma and cardiac arrest. Treatment of an overdosage is directed toward the support of all vital functions and prompt institution of symptomatic therapy. Iohexol can be dialyzed.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Iohexol Injection, USP is clear, colorless to pale yellow solution available in the following presentations: Dosage Form Concentration (mg iodine/mL) Package Size Package Type & Material Sale Unit NDC Injection 300 50 mL Single-Dose Polymer Bottles Carton of 10 80830-2466-2 75 mL Single-Dose Polymer Bottles Carton of 10 80830-2467-2 100 mL Single-Dose Polymer Bottles Carton of 10 80830-2468-2 350 50 mL Single-Dose Polymer Bottles Carton of 10 80830-2471-2 75 mL Single-Dose Polymer Bottles Carton of 10 80830-2472-2 100 mL Single-Dose Polymer Bottles Carton of 10 80830-2473-2 The container closure system components (bottle, stopper and cap) of iohexol injection are not made with natural rubber latex. Storage and Handling Iohexol Injection: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. May be stored in a contrast media warmer for up to one month, not to exceed 37°C (98.6°F). Protect from light. Do not freeze. Discard any product that is inadvertently frozen, as freezing may compromise the closure integrity of the immediate container.