IOMERVU

1 INDICATIONS AND USAGE IOMERVU is a radiographic contrast agent indicated for: Intra-arterial Procedures † ( 1.1 ) Cerebral arteriography, includingintra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients Coronary arteriography and cardiac ventriculography in adults Radiographic evaluation of cardiac chambers and related arteries in pediatric patients Intravenous Procedures † ( 1.2 ) Computed tomography (CT) of the head and body in adults and pediatric patients CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients Coronary CT angiography in adults and pediatric patients CT urography in adults and pediatric patients † Specific concentrations are recommended for each type of imaging procedure. ( 2.2 , 2.3 , 2.4 , 2.5 ) 1.1 Intra-arterial Procedures † IOMERVU is indicated for: Cerebral arteriography, including intra-arterial digital subtraction angiography (IA-DSA), in adults and pediatric patients Visceral and peripheral arteriography and aortography, including IA-DSA, in adults and pediatric patients Coronary arteriography and cardiac ventriculography in adults Radiographic evaluation of cardiac chambers and related arteries in pediatric patients 1.2 Intravenous Procedures † IOMERVU is indicated for: Computed tomography (CT) of the head and body in adults and pediatric patients CT angiography of intracranial, visceral, and lower extremity arteries in adults and pediatric patients Coronary CT angiography in adults and pediatric patients CT urography in adults and pediatric patients † Specific concentrations of IOMERVU are recommended for each type of imaging procedure [see Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )] .

2 DOSAGE AND ADMINISTRATION Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, vessel size, rate of blood flow within the vessel, and structures or areas to be examined. ( 2.2 , 2.3 , 2.4 , 2.5 ) See full prescribing information for complete dosage and administration information. ( 2 ) 2.1 Important Dosing and Administration Information IOMERVU is for intra-arterial or intravenous use only and must not be administered intrathecally [see Warnings and Precautions ( 5.1 )] . Specific concentrations of IOMERVU are recommended for each type of imaging procedure [see Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )]. Individualize the volume, concentration, and injection rate of IOMERVU within the specified ranges [see Dosage and Administration ( 2.2 , 2.3 , 2.4 , 2.5 )]. Consider factors such as age, body weight, vessel size, rate of blood flow 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 IOMERVU administration [see Warnings and Precautions ( 5.3 )] . Use aseptic technique for all handling and administration of IOMERVU. IOMERVU may be administered at either body temperature (37°C, 98.6°F) or room temperature (20°C to 25°C, 68°F to 77°F). Visually inspect IOMERVU for particulate matter or discoloration before administration, whenever the solution and container permit. Do not administer IOMERVU if particulate matter or discoloration is observed. Do not mix IOMERVU with, or inject in intravenous lines containing, other drugs or total nutritional admixtures. Each single-dose container of IOMERVU injection is intended for one procedure only. Discard any unused portion. 2.2 Recommended Dosage for Intra-arterial Procedures in Adults Recommended doses of IOMERVU in adults for intra-arterial procedures are shown in Table 1. Inject at rates approximately equal to the flow rate in the vessel being injected. Table 1. Recommended Concentrations and Volumes of IOMERVU to Administer per Single Injection into Selected Arteries for Intra-arterial Procedures in Adults Imaging Procedure Concentration (mg Iodine/mL) Volume (mL) Maximum Total Dose (mL) Cerebral arteriography 300 Carotid, subclavian, and vertebral arteries: 6 mL to 12 mL Aortic arch: 30 mL to 50 mL 200 mL Visceral and peripheral arteriography; aortography 300 Aortography: 30 mL to 70 mL Renal arteries: 10 mL to 12 mL Other major branches of aorta: 20 mL to 60 mL 200 mL Intra-arterial digital subtraction angiography 300 Carotid, subclavian, and vertebral arteries: 4 mL to 12 mL Aortic arch: 20 mL to 25 mL Aortography: 15 mL to 40 mL Renal arteries: 6 mL to 16 mL Other major branches of aorta: 10 mL to 40 mL Ilio-femoral runoff: 8 mL to 40 mL 200 mL Coronary arteriography and cardiac ventriculography 300 Coronary arteries: 3 mL to 7 mL Cardiac ventriculography: 30 mL to 45 mL 286 mL 350 245 mL 400 215 mL 2.3 Recommended Dosage for Intra-arterial Procedures in Pediatric Patients Recommended doses of IOMERVU in pediatric patients for intra-arterial procedures are shown in Table 2. Inject at rates approximately equal to the flow rate in the vessel being injected. Table 2. Recommended Concentrations and Volumes per Body Weight of IOMERVU to Administer per Single Injection for Intra-arterial Procedures in Pediatric Patients Imaging Procedure Concentration (mg Iodine/mL) Volume (mL/kg body weight) Maximum Total Dose (mL/kg) Cerebral arteriography 300 0.5 mL/kg to 2 mL/kg 5 mL/kg Do not exceed adult maximum dose (see Table 1) Visceral and peripheral arteriography; aortography 300 0.5 mL/kg to 2 mL/kg Intra-arterial digital subtraction angiography 300 0.3 mL/kg to 1 mL/kg Radiographic evaluation of cardiac chambers and related arteries 300, 350, or 400 0.5 mL/kg to 2 mL/kg 2.4 Recommended Dosage for Intravenous Procedures …

3 DOSAGE FORMS AND STRENGTHS Injection: clear, colorless to pale yellow solution available in the following iodine concentrations and configurations: Concentration (mg Iodine/mL) Package Size Package Type 250 100 mL Single-dose bottles 300 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 350 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles 400 50 mL Single-dose vials 100 mL, 150 mL, and 200 mL Single-dose bottles Injection: 250 mg Iodine/mL, 300 mg Iodine/mL, 350 mg Iodine/mL, and 400 mg Iodine/mL in single-dose vials or bottles ( 3 )

4 CONTRAINDICATIONS None. None ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks Associated with Intrathecal Administration [see Warnings and Precautions ( 5.1 )] Hypersensitivity Reactions [see Warnings and Precautions ( 5.2 )] 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 )] Extravasation and Injection Site Reactions [see Warnings and Precautions ( 5.6 )] Thyroid Dysfunction in Pediatric Patients 0 Years 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 ≥0.5%) are feeling hot, headache, nausea, chest pain, back pain, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bracco Diagnostics Inc. at 1-800-257-5181 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. Adverse Reactions in Adult Patients The safety of IOMERVU was evaluated in 4,621 adult patients who received 1,500 mg to 86,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 60 years (range 18 years to 99 years), and 34% were female. The racial and ethnic distribution was 83% White, 10% Asian, 1% Black, 1% Hispanic, and 5% patients of other or unspecified groups. Table 5 provides a summary of the adverse reactions reported in ≥0.5% of adult patients. Table 5: Adverse Reactions Reported in ≥0.5% of 4,621 Adult Patients Receiving Intra-arterial or Intravenous Administration of IOMERVU in Clinical Trials Adverse Reaction Incidence (%) Feeling hot 2 Headache 1.2 Nausea 1 Chest pain 0.6 Back pain 0.5 Vomiting 0.5 The following adverse reactions were observed in <0.5% of the adult patients receiving IOMERVU: Blood and lymphatic system disorders: activated partial thromboplastin time prolonged, prothrombin time prolonged Cardiovascular disorders: ventricular fibrillation, hypertensive crisis, coronary arteriospasm, congestive cardiac failure, cardiac flutter, atrioventricular block, right bundle branch block, hypotension, arrhythmia, bradycardia, supraventricular extrasystoles, ventricular extrasystoles, increased blood pressure, flushing Ear and labyrinth disorders : vertigo, ear discomfort Eye disorder: vision blurred, periorbital edema, photopsia Gastrointestinal : esophageal varices hemorrhage, abdominal pain, abdominal distension, alanine aminotransferase (ALT) increased, constipation, diarrhea, dry mouth, salivary hypersecretion, oral paresthesia General disorders: pain, injection site reactions (pain, discomfort, or warmth), peripheral edema, chills, asthenia, malaise Musculoskeletal and connective tissue disorders: arthralgia, pain in jaw Nervous system disorders: cerebrovascular disorder, dysarthria, visual field defect, burning sensation, presyncope, dizziness, dysgeusia, paresthesia Psychiatric disorders : delirium, anxiety, insomnia Renal and urinary disorders: acute kidney injury, increased blood creatinine, urinary urgency Respiratory, thoracic, and mediastinal disorders: respiratory arrest, pulmonary edema, bronchospasm, dyspnea, cough, rhinitis, throat irritation or tightness, sneezing Skin and subcutaneous tissue disorders: urticaria, blister, purpura, ecchymosis, rash, pruritus, erythema Adverse Reactions in Pediatric Patients The safety of IOMERVU was evaluated in 184 pediatric patients who received 1,800 mg to 76,000 mg iodine doses of IOMERVU intra-arterially or intravenously in clinical trials. The average age was 6 years (range 11 days to 17 years), and 47% were female. The racial distribution …

7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Metformin Stop metformin at the time of, or prior to, IOMERVU 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 metformin only after renal function is stable. Metformin can cause lactic acidosis in patients with renal impairment. Iodinated contrast agents appear to increase the risk of metformin-induced lactic acidosis, possibly as a result of worsening renal function. Radioactive Iodine Avoid thyroid therapy or testing using radioactive iodine for up to 6 weeks post IOMERVU. Administration of IOMERVU may interfere with thyroid uptake of radioactive iodine (I-131 and I-123) and decrease therapeutic and diagnostic efficacy. 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Do not perform a protein-bound iodine test for at least 16 days following administration of IOMERVU. Iodinated contrast agents, including IOMERVU, will temporarily increase protein-bound iodine in blood. However, thyroid function tests that do not depend on iodine estimations, e.g., triiodothyronine (T 3 ) resin uptake and total or free thyroxine (T 4 ) assays, are not affected.

8 USE IN SPECIFIC POPULATIONS Lactation: A lactating woman may pump and discard breast milk for 10 hours after IOMERVU administration. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data from literature and postmarketing reports on iomeprol use in pregnant women over decades have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental outcomes were observed with intravenous administration of iomeprol to pregnant rats and rabbits at doses up to 0.45-times the maximum recommended human dose of 86,000 mg iodine. Animal studies show that iomeprol crosses the placenta ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, 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 Embryo-fetal developmental toxicity studies were performed with intravenous administration of iomeprol in rats at daily doses of 600 mg, 1,500 mg, or 4,000 mg iodine/kg (0.07-, 0.17- or 0.45-fold the human equivalent dose (HED, mg/m 2 ) using the maximum human dose of 86,000 mg iodine per administration) from gestation days (GD) 6 to 15 and in rabbits at daily doses of 300 mg, 800 mg, or 2,000 mg iodine/kg (0.07-, 0.18- or 0.45-fold the HED using the maximum human dose of 86,000 mg iodine per administration) from GD 6 to 18. Iomeprol did not result in fetal harm at the highest doses evaluated, 0.45-times the maximum recommended human dose of 86,000 mg iodine. A biodistribution study with a single intravenous administration of 1,000 mg iodine/kg (0.11-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to pregnant rats showed that iomeprol crosses the placenta. No accumulation of radioactivity in fetal tissues was observed. 8.2 Lactation Risk Summary There are no data on the presence of iomeprol in human milk, the effects on the breastfed infant, or the effects on milk production. Iomeprol is present in animal milk (see Data) . When a drug is present in animal milk, it is likely that the drug will be present in human milk. Iodinated contrast agents are excreted unchanged in human milk in very low amounts, with poor absorption from 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 IOMERVU and any potential adverse effects on the breastfed infant from IOMERVU 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 IOMERVU administration to minimize any potential drug exposure to a breastfed infant. Data An animal study with a single intravenous administration of 500 mg iodine/kg (0.06-fold the HED using the maximum human dose of 86,000 mg iodine per administration) of radiolabeled iomeprol to lactating rats showed that iomeprol rapidly distributed into the milk. 8.4 Pediatric Use Intra-arterial Use The safety and effectiveness of IOMERVU have been established in pediatric patients for cerebral, visceral, and peripheral arteriography, aortography including intra-arterial digital subtraction angiography, and radiographic evaluation of cardiac chambers and related arteries. Use of IOMERVU is supported by evidence from adequate and well-controlled studies of IOMERVU in adults, pharmacokinetic data in pediatric patients aged 3 years to 17 years, pharmacokinetic …

12.1 Mechanism of Action Iomeprol is a radiographic iodinated contrast agent that opacifies the vessels and body structures where the contrast agent is present following intravenous or intra-arterial administration, permitting radiographic visualization of the internal structures through attenuation of X-ray photons. In imaging of the body, iodinated contrast agents diffuse from the vessels into the extravascular space. In normal brain with an intact blood-brain barrier, the contrast agent does not diffuse into the extravascular space and contrast enhancement is generally due to the presence of contrast within the vascular space. In patients with a disrupted blood-brain barrier, the contrast agent accumulates in the extravascular space in the region of disruption.

11 DESCRIPTION IOMERVU (iomeprol) injection is a tri-iodinated, non-ionic radiographic contrast agent for intra-arterial or intravenous use. It is provided as a sterile, nonpyrogenic, clear, colorless to pale yellow solution. The chemical name for iomeprol is N,N’-bis(2,3-dihydroxypropyl)-5-[(hydroxyacetyl)-methylamino]-2,4,6-tri-iodo-1,3-benzenedicarboxamide. Iomeprol has a molecular formula of C 17 H 22 I 3 N 3 O 8 , a molecular weight of 777.09 (iodine content of 49%), and the following structural formula: IOMERVU injection is available in four iodine concentrations: IOMERVU 250 mg Iodine/mL: Each mL contains 510 mg iomeprol (providing 250 mg bound iodine) and 1 mg tromethamine. IOMERVU 300 mg Iodine/mL: Each mL contains 612 mg iomeprol (providing 300 mg bound iodine) and 1 mg tromethamine. IOMERVU 350 mg Iodine/mL: Each mL contains 714 mg iomeprol (providing 350 mg bound iodine) and 1 mg tromethamine. IOMERVU 400 mg Iodine/mL: Each mL contains 816 mg iomeprol (providing 400 mg bound iodine) and 1 mg tromethamine. The pH of IOMERVU has been adjusted to 6.5 to 7.2 with hydrochloric acid. Physical characteristics are noted in Table 6. IOMERVU has osmolalities approximately 1.5 to 2.5 times that of plasma (285 mOsm/kg water) as shown in the table below and are hypertonic under conditions of use. Table 6. Physical Characteristics of IOMERVU Concentration (mg Iodine/mL) Density (d 20 4 ± 0.0002) Osmolality (mOsmol/kg) Viscosity (mPa·s) 37°C 20°C 37°C 250 1.278 435 4.9 2.9 300 1.334 521 8.1 4.5 350 1.390 618 14.5 7.5 400 1.446 726 27.5 12.6 Iomeprol-Structural-Formula

10 OVERDOSAGE The adverse effects of overdosage are 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. Iomeprol can be removed by dialysis [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied IOMERVU (iomeprol) injection is a clear, colorless to pale yellow solution supplied in clear glass single-dose vials or bottles in the following configurations: Concentration (mg Iodine/mL) Packages Size Package Type Sale Unit NDC 250 100 mL Single-dose bottles Carton of 10 0270-7013-14 300 50 mL Single-dose vials Carton of 10 0270-7016-15 100 mL Single-dose bottles Carton of 10 0270-7016-17 150 mL Carton of 10 0270-7016-18 200 mL Carton of 10 0270-7016-19 350 50 mL Single-dose vials Carton of 10 0270-7017-20 100 mL Single-dose bottles Carton of 10 0270-7017-21 150 mL Carton of 10 0270-7017-24 200 mL Carton of 10 0270-7017-25 400 50 mL Single-dose vials Carton of 10 0270-7018-26 100 mL Single-dose bottles Carton of 10 0270-7018-27 150 mL Carton of 10 0270-7018-28 200 mL Carton of 10 0270-7018-29 Storage and Handling Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Keep in original carton with the cover closed to protect from light. Do not freeze.