Ultravist

6 ADVERSE REACTIONS The most important adverse drug reactions in patients receiving ULTRAVIST are anaphylactoid shock, contrast induced acute kidney injury, coma, cerebral infarction, stroke, brain edema, convulsion, arrhythmia, cardiac arrest, myocardial ischemia, myocardial infarction, cardiac failure, bradycardia, cyanosis, hypotension, shock, dyspnea, pulmonary edema, respiratory insufficiency and aspiration. Most common adverse reactions (>1%) are headache, nausea, injection site and infusion site reactions, vasodilatation, vomiting, back pain, urinary urgency, chest pain, pain, dysgeusia, and abnormal vision. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 or predict the rates observed in practice. The following table of incidence of reactions is based upon controlled clinical trials in which ULTRAVIST Injection was administered to 1142 patients. This listing includes all reported adverse reactions regardless of attribution. Adverse reactions are listed by System Organ Class and in decreasing order of occurrence for rates greater than 1% in the ULTRAVIST group: see Table 3 . Table 3: ADVERSE REACTIONS REPORTED IN > 1% OF PATIENTS WHO RECEIVED ULTRAVIST INJECTION IN CLINICAL TRIALS System Organ Class Adverse Reaction ULTRAVIST Injection N=1142 (%) Nervous system disorders Headache 46 (4) Dysgeusia 15 (1.3) Eye disorders Abnormal Vision 12 (1.1) Cardiac disorders Chest pain 18 (1.6) Vascular disorders Vasodilatation 30 (2.6) Gastrointestinal disorders Nausea 42 (3.7) Vomiting 22 (1.9) Musculoskeletal and connective tissue disorders Back pain 22 (1.9) Renal and urinary disorders Urinary urgency 21 (1.8) General disorders and administration site conditions Injection site and infusion site reactions (hemorrhage, hematoma, pain, edema, erythema, rash) 41 (3.7) Pain 13 (1.4) One or more adverse reactions were recorded in 273 of 1142 (24%) patients during the clinical trials, coincident with the administration of ULTRAVIST Injection or within the defined duration of the study follow-up period (24–72 hours). ULTRAVIST Injection is often associated with sensations of warmth and/or pain. Serious, life-threatening and fatal reactions have been associated with the administration of iodine-containing contrast media, including ULTRAVIST Injection. In clinical trials 7/1142 patients given ULTRAVIST Injection died 5 days or later after drug administration. Also, 10/1142 patients given ULTRAVIST Injection had serious adverse events. The following adverse reactions were observed in ≤ 1% of the subjects receiving ULTRAVIST Injection: Cardiac disorders: atrioventricular block (complete), bradycardia, ventricular extrasystole Gastrointestinal disorders: abdominal discomfort, abdominal pain, abdominal pain upper, constipation, diarrhea, dry mouth, dyspepsia, gastrointestinal disorder, gastrointestinal pain, salivation increased, stomach discomfort, rectal tenesmus General disorders and administration site conditions: asthenia, chest discomfort, chills, excessive thirst, extravasation, feeling hot, hyperhidrosis, malaise, edema peripheral, pyrexia Immune system disorders: asthma, face edema Investigations: blood lactate dehydrogenase increased, blood urea increased, hemoglobin increased, white blood cell count increased Musculoskeletal and connective tissue disorders: arthralgia, musculoskeletal pain, myasthenia, neck pain, pain in extremity Nervous system disorders: agitation, confusion, convulsion, dizziness, hypertonia, hypesthesia, incoordination, neuropathy, somnolence, speech disorder, tremor, paresthesia, visual field defect Psychiatric disorders: anxiety Renal and urinary disorders: dysuria, renal pain, urinary retention Respiratory, thoracic and mediastinal disorders: apnea, cough increased, dyspnea, hypoxia, pharyngeal edema, pharyngitis, pleural effusion, pulmonary hypertension, respiratory disorder, sore throat Skin and subcutaneous tissue disorders: erythema, pruritus, rash, urticaria Vascular disorders: coronary artery thrombosis, flushing, hypertension, hypotension, peripheral vascular disorder, syncope, vascular anomaly 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ULTRAVIST 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. Adverse reactions reported in foreign postmarketing surveillance and other trials with the use of ULTRAVIST Injection include: Cardiac disorders: cardiac arrest, ventricular fibrillation, atrial fibrillation, tachycardia, palpitations, congestive heart failure, myocardial infarction, angina pectoris Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hyperthyroidism, thyrotoxic crisis, hypothyroidism Eye disorders: mydriasis, lacrimation disorder Gastrointestinal disorders: dysphagia, swelling of salivary glands Immune system disorders: anaphylactoid reaction (including fatal cases), respiratory arrest, anaphylactoid shock, angioedema, laryngeal edema, laryngospasm, bronchospasm, hypersensitivity Musculoskeletal and connective tissue disorders: compartment syndrome in case of extravasation Nervous system disorders: cerebral ischemia/infarction, paralysis, paresis, transient cortical blindness, aphasia, coma, unconsciousness, amnesia, hypotonia, aggravation of myasthenia gravis symptoms Renal and urinary disorders: renal failure, hematuria Respiratory, thoracic and mediastinal disorders: pulmonary edema, acute respiratory distress syndrome, asthma Skin and subcutaneous tissue disorders: Reactions range from mild (e.g. rash, erythema, pruritus, urticaria and skin discoloration) to severe [e.g. Stevens-Johnson Syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS)]. Vascular disorders: vasospasm 6.3 Pediatrics The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported in adult patients. Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other information are: epistaxis, angioedema, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder (mucosal swelling), conjunctivitis, hypoxia, fixed eruptions, vertigo, diabetes insipidus, and brain edema [see Use in Specific Populations ( 8.4 )] .

4 CONTRAINDICATIONS • Do not administer ULTRAVIST Injection intrathecally. Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. • Preparatory dehydration (for example, prolonged fasting and the administration of a laxative) before ULTRAVIST Injection is contraindicated in pediatric patients because of risk of acute renal failure. • ULTRAVIST Injection is contraindicated for intrathecal use. ( 4 ) • Preparatory dehydration (for example, prolonged fasting and the administration of a laxative before ULTRAVIST Injection) is contraindicated in pediatric patients because of risk of renal failure. ( 4 )

11 DESCRIPTION ULTRAVIST (iopromide) Injection is a nonionic, water soluble x-ray contrast agent for intravascular administration. The chemical name for iopromide is N,N' -Bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]- N -methyl- 1,3- benzenedicarboxamide. Iopromide has a molecular weight of 791.12 (iodine content 48.12%). Iopromide has the following structural formula: ULTRAVIST Injection is a nonionic sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer. ULTRAVIST Injection is available in two strengths: 300 mg Iodine per mL provides 623.4 mg/mL iopromide 370 mg Iodine per mL provides 768.86 mg/mL iopromide During the manufacture of ULTRAVIST Injection, sodium hydroxide or hydrochloric acid may be added for pH adjustment. ULTRAVIST Injection has a pH of 7.4 (6.5–8) at 25± 2°C, is sterilized by autoclaving and contains no preservatives. The iodine concentrations (mg Iodine per mL) available have the following physicochemical properties: ULTRAVIST INJECTION ULTRAVIST INJECTION Property 300 mg Iodine per mL 370 mg Iodine per mL Osmolality*(mOsmol/kg water) @ 37°C 607 774 Osmolarity*(mOsmol/L) @ 37°C 428 496 Viscosity (cP) @ 20°C @ 37°C 9.2 4.9 22 10 Density (g/mL) @ 20°C @ 37°C 1.330 1.322 1.409 1.399 *Osmolality was measured by vapor-pressure osmometry. Osmolarity was calculated from the measured osmolal concentrations. Solutions of ULTRAVIST Injection 300 mg Iodine per mL and 370 mg Iodine per mL have osmolalities respectivelyely 2.1 to 2.7 times that of plasma (285 mOsmol/kg water). structure

2 DOSAGE AND ADMINISTRATION • Visually inspect ULTRAVIST for particulate matter and/or discoloration, whenever solution and container permit. Do not administer ULTRAVIST if particulate matter (including crystals) and/or discoloration is observed or if containers are defective. As ULTRAVIST Injection is a highly concentrated solution, crystallization (milky-cloudy appearance and/or sediment at bottom, or floating crystals) may occur. • Use sterile technique for all handling and administration of ULTRAVIST. • Determine the volume and concentration of ULTRAVIST Injection to be used considering factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel; consider also extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed. Specific dose adjustments for age, gender, weight and renal function have not been studied for ULTRAVIST Injection. As with all iodinated contrast agents, lower doses may have less risk. The efficacy of ULTRAVIST Injection below doses recommended has not been established. • Administer ULTRAVIST at or close to body temperature. • Do not mix or inject ULTRAVIST Injection in intravenous administration lines containing other drugs or total nutritional admixtures. ULTRAVIST can be mixed with saline when used in a power injector suitable for simultaneous injection of contrast and saline [see Dosage and Administration ( 2.2 )]. • The maximum recommended total dose of iodine in adults is 86 grams; a maximum recommended total dose of iodine has not been established for pediatric patients. • Hydrate patients, as appropriate, prior to and following the administration of ULTRAVIST [see Warnings and Precautions ( 5.2 )] . Carefully individualize the volume and concentration of ULTRAVIST Injection to be used for a vascular procedure, according to the specific dosing tables. Adjust the dose accounting for factors such as age, body weight, size of the vessel and the rate of blood flow within the vessel. ( 2 ) 2.1 Intra-Arterial Procedures The volume and rate of injection of the contrast agent will vary depending on the injection site and the area being examined. Inject contrast at rates approximately equal to the flow rate in the vessel being injected. • Cerebral Arteriography (300 mg Iodine per mL), Coronary Arteriography and Left Ventriculography (370 mg Iodine per mL), Peripheral Arteriography (300 mg Iodine per mL),: see Table 1 . • Aortography and Visceral Angiography (370 mg Iodine per mL): Use a volume and rate of contrast injection proportional to the blood flow and related to the vascular and pathological characteristics of the specific vessels being studied. Do not exceed 225 mL as total dose for the procedure. Table 1: Suggested Single Injection Doses for Adult Intra-Arterial Procedures Cerebral Arteriography (300 mg Iodine per mL) Peripheral Arteriography (300 mg Iodine per mL) Coronary Arteriography and Left Ventriculography (370 mg Iodine per mL) Intra-Arterial Injection Sites Carotid Arteries Vertebral Arteries Aortic Arch Injection (4 vessel study) 3 ml to 12 mL 4 ml to 12 mL 20 ml to 50 mL - - - - - - Right Coronary Artery Left Coronary Artery Left Ventricle - - - - - - 3 ml to 14 mL 3 ml to 14 mL 30 ml to 60 mL Aorta Major Branches of the Abdominal Aorta - - - - - - Subclavian or Femoral Artery Aortic Bifurcation (distal runoff) - - 5 ml to 40 mL 25 ml to 50 mL - - Maximum Total Dose 150 mL 250 mL 225 mL 2.2 Intravenous Procedures • Contrast Computed Tomography (CT) (300 mg Iodine per mL and 370 mg Iodine per mL) and Excretory Urography (300 mg Iodine per mL): see Table 2. Table 2: Suggested ULTRAVIST Injection Dosing for Adult Intravenous Contrast Administration Excretory Urography (300 mg Iodine per mL) Contrast Computed Tomography (300 mg Iodine per mL) Contrast Computed Tomography (370 mg Iodine per mL) Excretory Urography Approximately 300 mg Iodine per kg body wt. (Adults with normal renal function) - - Head - 50 ml to 200 mL 41 ml to 162 mL Body Single Phase Contrast Bolus Injection - 50 ml to 200 mL 41 ml to 162 mL Rapid Infusion - 100 ml to 200 mL 81 ml to 162 mL Body Multiple Phase Contrast 50 ml to 200 mL total volume Phase 1: 100% contrast Phase 2: 20-60% contrast using a power injector suitable for simultaneous injection 41 ml to 162 mL total volume Phase 1: 100% contrast Phase 2: 20-60% contrast using a power injector suitable for simultaneous injection Maximum Total Dose 100 mL (30 g iodine) 200 mL (60 g iodine) 162 mL (60 g iodine) 2.3 Pediatric Dosing The recommended dose in children over 2 years of age for the following evaluations is: • Intra-arterial: Cardiac chambers and related arteries ( 370 mg Iodine per mL) : Contrast Computerized Tomography or Excretory Urography (300 mg Iodine per mL): Inject 1 to 2 mL/kg. Do not exceed 3 mL/kg as total dose. The safety and efficacy relationships of other doses, concentrations or procedures have not been established [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )] .

1 INDICATIONS AND USAGE ULTRAVIST ® Injection is an iodinated contrast agent indicated for: ULTRAVIST (iopromide) Injection is a radiographic contrast agent indicated for: • Cerebral arteriography and peripheral arteriography (300 mg Iodine per mL) ( 1.1 ) • Coronary arteriography and left ventriculography, visceral angiography and aortography (370 mg Iodine per mL) ( 1.1 ) • Excretory urography (300 mg Iodine per mL) ( 1.2 ) • Contrast computed tomography (CT) imaging of head and body (300 mg Iodine per mL and 370 mg Iodine per mL) ( 1.2 ) 1.1 Intra-Arterial Procedures* • 300 mg Iodine per mL for cerebral arteriography and peripheral arteriography • 370 mg Iodine per mL for coronary arteriography and left ventriculography, visceral angiography, and aortography 1.2 Intravenous Procedures* • 300 mg Iodine per mL for excretory urography • 300 mg Iodine per mL and 370 mg Iodine per mL for contrast Computed Tomography (CT) of the head and body (intrathoracic, intra-abdominal and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions. The usefulness of contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not been demonstrated. *For information on the concentrations and doses for the Pediatric Population [see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.4 )].

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. ULTRAVIST Injection binds negligibly to plasma or serum protein and can, therefore, be dialyzed.

7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions In patients with renal impairment, biguanides can cause lactic acidosis. ULTRAVIST appears to increase the risk of biguanide induced lactic acidosis, possibly as a result of worsening renal function [see Warnings and Precautions ( 5.2 )] . Patients on beta-blockers may be unresponsive to the usual doses of epinephrine used to treat allergic reactions. Because of the risk of hypersensitivity reactions, use caution when administering iodinated contrast agents to patients taking beta-blockers. Interleukins are associated with an increased prevalence of delayed hypersensitivity reactions after iodinated contrast agent administration. These reactions include fever, chills, nausea, vomiting, pruritus, rash, diarrhea, hypotension, edema, and oliguria. Renal toxicity has been reported in a few patients with liver dysfunction who were given an oral cholecystographic agent followed by intravascular contrast agents. Administration of any intravascular contrast agent should therefore be postponed in patients who have recently received a cholecystographic contrast agent. Do not mix other drugs with ULTRAVIST Injection except saline [see Dosage and Administration ( 2.2 )] . 7.2 Drug-Laboratory Test Interactions Thyroid Function Tests: The results of protein bound iodine and radioactive iodine uptake studies, which depend on iodine estimation, will not accurately reflect thyroid function for at least 16 days following administration of iodinated contrast agents. However, thyroid function tests which do not depend on iodine estimations, for example, T 3 resin uptake and total or free thyroxine (T 4 ) assays are not affected. Laboratory Assay of Coagulation Parameters, Fibrinolysis and Complement System: The effect of iopromide on coagulation factors in in vitro assays increased with the administered dose. Coagulation, fibrinolysis and complement activation were evaluated with standard citrated human plasma in the following assays: thrombin time, thrombin coagulase time, calcium thromboplastin time, partial thromboplastin time, plasminogen, thrombin, alpha-2 antiplasmin and factor XIIa activity. Thrombin inhibition was almost complete. Data on reversibility are not available. The thrombin time increased from approximately 20 seconds at an iopromide concentration of 10 mg Iodine per mL, up to 100 seconds at an iopromide concentration of 70 mg Iodine per mL. The PTT increased from approximately 50 seconds at an iopromide concentration of 10 mg Iodine per mL, up to approximately 100 seconds at an iopromide concentration of 70 mg Iodine per mL. A similar increase was noted in the thrombin coagulase time. Lesser effects were noted in the calcium thromboplastin time. Coagulation time increased from 13.5 to 23 seconds at the highest iopromide concentration of 70 mg Iodine per mL. The Hageman factor split products decreased by about 20% over the range of 10 to 70 mg Iodine per mL of iopromide. Plasminogen was relatively stable. There was no evidence of activation of fibrinolysis. The complement alternate pathway was activated. Factor B conversion increased in a dose dependent manner. The duration of these effects was not studied. In vitro studies with human blood showed that iopromide had a slight effect on coagulation and fibrinolysis. No Factor XIIa formation could be demonstrated. The complement alternate pathway also can be activated.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration. Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant hemodilution occurs. 12.2 Pharmacodynamics Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments. Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging). ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3 minutes, with optimum contrast occurring within 5–15 minutes. In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative differences in extravascular diffusion between adjacent tissues. In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool. In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear. For information on coagulation parameters, fibrinolysis and complement system [see Drug Interactions ( 7.2 )]. 12.3 Pharmacokinetics Distribution After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting distribution into extracellular space. Plasma protein binding of iopromide is 1%. Iodinated contrast agents may cross the blood-brain barrier [see Warnings and Precautions ( 5.8 )] . Metabolism Iopromide is not metabolized. Elimination The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and first order. The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively. Specific Populations A pharmacokinetic study was conducted in 11 patients with renal impairment [see Use in Specific Populations ( 8.6 )] .

12.1 Mechanism of Action Iopromide is a nonionic, water soluble, tri-iodinated x-ray contrast agent for intravascular administration. Intravascular injection of iopromide opacifies those vessels in the path of flow of the contrast agent, permitting radiographic visualization of the internal structures until significant hemodilution occurs.

12.2 Pharmacodynamics Following ULTRAVIST administration, the degree of contrast enhancement is directly related to the iodine content in the administered dose; peak iodine plasma levels occur immediately following rapid intravenous injection. Iodine plasma levels fall rapidly within 5 to 10 minutes. This can be accounted for by the dilution in the vascular and extravascular fluid compartments. Intravascular Contrast: Contrast enhancement appears to be greatest immediately after bolus injections (15 seconds to 120 seconds). Thus, greatest enhancement may be detected by a series of consecutive two-to-three second scans performed within 30 to 90 seconds after injection (that is, dynamic computed tomographic imaging). ULTRAVIST Injection may be visualized in the renal parenchyma within 30–60 seconds following rapid intravenous injection. Opacification of the calyces and pelves in patients with normal renal function becomes apparent within 1–3 minutes, with optimum contrast occurring within 5–15 minutes. In contrast CT, some performance characteristics are different in the brain and body. In contrast CT of the body, iodinated contrast agents diffuse rapidly from the vascular into the extravascular space. Following the administration of iodinated contrast agents, the increase in tissue density to x-rays is related to blood flow, the concentration of the contrast agent, and the extraction of the contrast agent by various interstitial tissues. Contrast enhancement is thus due to any relative differences in extravascular diffusion between adjacent tissues. In the normal brain with an intact blood-brain barrier, contrast is generally due to the presence of iodinated contrast agent within the intravascular space. The radiographic enhancement of vascular lesions, such as arteriovenous malformations and aneurysms, depends on the iodine content of the circulating blood pool. In tissues with a break in the blood-brain barrier, contrast agent accumulates within interstitial brain tissue. The time to maximum contrast enhancement can vary from the time that peak blood iodine levels are reached to 1 hour after intravenous bolus administration. This delay suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine containing medium within the lesion and outside the blood pool. The mechanism by which this occurs is not clear. For information on coagulation parameters, fibrinolysis and complement system [see Drug Interactions ( 7.2 )].

12.3 Pharmacokinetics Distribution After intravenous administration to healthy young volunteers, plasma iopromide concentration time profile shows an initial distribution phase with a half-life of 0.24 hour; a main elimination phase with a half-life of 2 hours; and a terminal elimination phase with a half-life of 6.2 hours. The total volume of distribution at steady state is about 16 L suggesting distribution into extracellular space. Plasma protein binding of iopromide is 1%. Iodinated contrast agents may cross the blood-brain barrier [see Warnings and Precautions ( 5.8 )] . Metabolism Iopromide is not metabolized. Elimination The amounts excreted unchanged in urine represent 97% of the dose in young healthy subjects. Only 2% of the dose is recovered in the feces. Similar recoveries in urine and feces are observed in middle-aged and elderly patients. This finding suggests that, compared to the renal route, biliary and/or gastrointestinal excretion is not important for iopromide. During the slower terminal phase only 3% of the dose is eliminated; 97% of the dose is disposed of during the earlier phases, the largest part of which occurs during the main elimination phase. The ratio of the renal clearance of iopromide to the creatinine clearance is 0.82 suggesting that iopromide is mainly excreted by glomerular filtration. Additional tubular reabsorption is possible. Pharmacokinetics of iopromide at intravenous doses up to 80 g iodine, are dose proportionate and first order. The mean total and renal clearances are 107 mL/min and 104 mL/min, respectively. Specific Populations A pharmacokinetic study was conducted in 11 patients with renal impairment [see Use in Specific Populations ( 8.6 )] .

20230425

20

3 DOSAGE FORMS AND STRENGTHS ULTRAVIST Injection is a nonionic, sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution of iopromide, containing 2.42 mg/mL tromethamine buffer and 0.1 mg/mL edetate calcium disodium stabilizer. ULTRAVIST Injection is available in two strengths: 300 mg Iodine per mL provides 623.4 mg/mL iopromide 370 mg Iodine per mL provides 768.86 mg/mL iopromide ULTRAVIST Injection is available in two strengths: 300 mg Iodine per mL; 370 mg Iodine per mL. ( 3 )

Ultravist iopromide IOPROMIDE IOPROMIDE IODINE EDETATE CALCIUM DISODIUM TROMETHAMINE SODIUM HYDROXIDE HYDROCHLORIC ACID Ultravist iopromide IOPROMIDE IOPROMIDE IODINE EDETATE CALCIUM DISODIUM TROMETHAMINE SODIUM HYDROXIDE HYDROCHLORIC ACID Ultravist iopromide IOPROMIDE IOPROMIDE IODINE EDETATE CALCIUM DISODIUM TROMETHAMINE SODIUM HYDROXIDE HYDROCHLORIC ACID Ultravist iopromide IOPROMIDE IOPROMIDE IODINE EDETATE CALCIUM DISODIUM TROMETHAMINE SODIUM HYDROXIDE HYDROCHLORIC ACID Ultravist iopromide IOPROMIDE IOPROMIDE IODINE EDETATE CALCIUM DISODIUM TROMETHAMINE SODIUM HYDROXIDE HYDROCHLORIC ACID

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal assay.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed with iopromide to evaluate carcinogenic potential or effects on fertility. Iopromide was not genotoxic in a series of studies including the Ames test, an in vitro human lymphocytes analysis of chromosomal aberrations, an in vivo mouse micro-nucleus assay, and in an in vivo mouse dominant lethal assay.

NDA020220

Ultravist

iopromide

50419-346

HUMAN PRESCRIPTION DRUG

INTRA-ARTERIAL,INTRAVENOUS

Package/Label Display Panel 240mg Iodine per 50mL NDC 50419-342-05 50 mL sterile solution Ultravist® (brand of iopromide) 240 mgI/mL injection Rx only Single-dose container Discard unused portion. NOT FOR INTRATHECAL USE Dose: See package insert. For intravascular use only. Each mL contains 498.72 mg iopromide with 2.42 mg tromethamine as a buffer and 0.1 mg edetate calcium disodium as a stabilizer. Contains no antimicrobial preservative. Protect from light. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Mfd. for: Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470 Mfd in Germany 50 mL 240 240mgI/50mL

Warnings and Precautions, Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age ( 5.6 ) 4/2023

17 PATIENT COUNSELING INFORMATION Instruct patients receiving ULTRAVIST Injection to inform their physician or healthcare provider of the following: • Advise patients to inform their physician if they develop a rash after receiving ULTRAVIST [see Warnings and Precautions ( 5.9 )] • Lactation: Advise lactating women that interruption of breast feeding is not necessary, however, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 12 to 24 hours after ULTRAVIST Injection administration to minimize exposure to the breastfed infant ( 8.2 ) • Thyroid Dysfunction – Advise parents/caregivers about the risk of developing thyroid dysfunction after ULTRAVIST administration. Advise parents/caregivers about when to seek medical care for their child to monitor for thyroid function [see Warnings and Precautions ( 5.6 )]. Manufactured for: ©1995, Bayer HealthCare Pharmaceuticals Inc. All rights reserved. The following are representative examples of ULTRAVIST labeling. See the "How Supplied" section for a complete listing of all components.

14 CLINICAL STUDIES ULTRAVIST Injection was administered to 708 patients; 1 patient was less than 18 years of age, 347 patients were between 18 and 59 years of age, and 360 patients were equal to or greater than 60 years of age; the mean age was 56.6 years (range 17–88). Of the 708 patients, 446 (63%) were male and 262 (37%) were female. The racial distribution was: Caucasian 463 (65.4%), Black 95 (13.4%), Hispanic 36 (5.1%), Asian 11 (1.6 %), and other or unknown 103 (14.5%). Efficacy assessment was based on the global evaluation of the quality of the radiographs by rating visualization as either excellent, good, poor, or no image, and on the ability to make a diagnosis. Five (5) intra-arterial and three (3) intravenous procedures were studied with 1 of 2 concentrations (370 mg Iodine per mL and 300 mg Iodine per mL). These procedures were: aortography/visceral angiography, coronary arteriography and left ventriculography, cerebral arteriography, peripheral arteriography, contrast computed tomography (CT) of head and body, and excretory urography. Cerebral arteriography was evaluated in two randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg Iodine per mL in 80 patients with conditions such as altered cerebrovascular perfusion and/or permeability occurring in central nervous system diseases due to various CNS disorders. Visualization ratings were good or excellent in 99% of the patients with ULTRAVIST Injection; a radiologic diagnosis was made in the majority of the patients. Confirmation of the radiologic findings by other diagnostic methods was not obtained. Coronary arteriography/left ventriculography was evaluated in two randomized, double-blind clinical trials and one unblinded, unrandomized clinical trial of ULTRAVIST Injection 370 mg Iodine per mL in 106 patients with conditions such as altered coronary artery perfusion due to metabolic causes and in patients with conditions such as altered ventricular function. Visualization ratings were good or excellent in 99% or more of the patients a radiologic diagnosis was made in the majority of the patients. A confirmation of the radiologic findings by other diagnostic methods was not obtained. Aortography/visceral angiography was evaluated in two randomized, double-blind clinical trials in 78 patients with conditions such as altered aortic blood flow and/or visceral vascular disorders. Visualization ratings were good or excellent in the majority of the patients; a radiologic diagnosis was made in 99% of the patients with ULTRAVIST Injection. A confirmation of radiologic findings by other diagnostic methods was not obtained. The risks of renal arteriography could not be analyzed. Contrast CT of head and body was evaluated in three randomized, double-blind clinical trials of ULTRAVIST Injection 300 mg Iodine per mL in 95 patients with vascular disorders. Visualization ratings were good or excellent in 99% of the patients; a radiologic diagnosis was made in the majority of the patients. A confirmation of contrast CT findings by other diagnostic methods was not obtained. ULTRAVIST Injection was evaluated in a blinded reader trial for CT of the head and body. Among the 382 patients who were evaluated with ULTRAVIST Injection 370 mg Iodine per mL, visualization ratings were good or excellent in approximately 97% of patients. Similar studies were completed with comparable findings noted in intra-arterial digital subtraction angiography, peripheral arteriography and excretory urography.

8.5 Geriatric Use Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1 hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for iopromide.

8.4 Pediatric Use The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age. Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274 pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian 93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99) and 28 other procedures. In these pediatric patients, a concentration of 300 mg Iodine per mL was employed for intravenous contrast CT or excretory urography. A concentration of 370 mg Iodine per mL was employed for intra-arterial and intracardiac administration in the radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2 mL/kg. Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has not been established. In the pediatric population, the pharmacokinetic parameters have not been established. Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL. Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; Some patients were treated for hypothyroidism. After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients 0 to 3 years of age based on underlying risk factors, especially in term and preterm neonates. [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6.2 )] The injection rates in small vascular beds, and the relationship of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting the dose. Safety and effectiveness in pediatric patients below the age of two have not been established.

8.1 Pregnancy Risk Summary There are no data on ULTRAVIST Injection use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Iopromide crosses the placenta and reaches fetal tissues in small amounts (see Data). In animal reproduction studies, intravenous administration of iopromide to pregnant rats and rabbits during organogenesis at doses up to 0.35 and 0.7 times, respectively, the maximum recommended human dose based on body surface area resulted in no relevant adverse developmental effects (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 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 Human Data Limited case reports demonstrate that intravenously administered iodinated contrast agents, including iopromide, cross the placenta and are visualized in the digestive tract of exposed infants after birth. Animal Data Reproduction studies performed with intravenous iopromide in rats (day 6 to 15 of gestation) and rabbits (day 6 to 18 of gestation) at dose levels of 0, 0.37, 1.11 and 3.7 g iodine per kg corresponding to doses up to 0.35 times (rats) and 0.7 times (rabbits) the maximum human recommended dose based on body surface area. Iopromide was not teratogenic at any dose level in rats and rabbits and embryolethality was observed in rabbits that received 3.7 g iodine per kg, but this was considered to have been secondary to maternal toxicity.

8 USE IN SPECIFIC POPULATIONS • Lactation: Advise lactating women that interruption of breast feeding is not necessary, however, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for 12 to 24 hours after ULTRAVIST Injection administration to minimize exposure to the breastfed infant ( 8.2 ) • The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age. ( 8.4 ) 8.1 Pregnancy Risk Summary There are no data on ULTRAVIST Injection use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Iopromide crosses the placenta and reaches fetal tissues in small amounts (see Data). In animal reproduction studies, intravenous administration of iopromide to pregnant rats and rabbits during organogenesis at doses up to 0.35 and 0.7 times, respectively, the maximum recommended human dose based on body surface area resulted in no relevant adverse developmental effects (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 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 Human Data Limited case reports demonstrate that intravenously administered iodinated contrast agents, including iopromide, cross the placenta and are visualized in the digestive tract of exposed infants after birth. Animal Data Reproduction studies performed with intravenous iopromide in rats (day 6 to 15 of gestation) and rabbits (day 6 to 18 of gestation) at dose levels of 0, 0.37, 1.11 and 3.7 g iodine per kg corresponding to doses up to 0.35 times (rats) and 0.7 times (rabbits) the maximum human recommended dose based on body surface area. Iopromide was not teratogenic at any dose level in rats and rabbits and embryolethality was observed in rabbits that received 3.7 g iodine per kg, but this was considered to have been secondary to maternal toxicity. 8.2 Lactation Risk Summary There are no data on the presence of iopromide in human milk, the effects on the breastfed infant, or the effects on milk production. Iodinated contrast agents are poorly excreted into human milk and are poorly absorbed by the gastrointestinal tract of a breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ULTRAVIST Injection and any potential adverse effects on the breastfed infant from ULTRAVIST Injection or from the underlying maternal condition (see Clinical Considerations). 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 12 to 24 hours (approximately 5 elimination half-lives) after ULTRAVIST Injection administration in order to minimize drug exposure to a breast fed infant. 8.4 Pediatric Use The safety and efficacy of ULTRAVIST Injection have been established in the pediatric population over 2 years of age. Use of ULTRAVIST Injection in these age groups is supported by evidence from adequate and well controlled studies of ULTRAVIST Injection in adults and additional safety data obtained in literature and other reports in a total of 274 pediatric patients. Of these, there were 131 children (2–12 years), 57 adolescents, and 86 children of unreported or other ages. There were 148 females, 94 males and 32 in whom gender was not reported. The racial distribution was: Caucasian 93 (33.9%), Black 1 (0.4%), Asian 6 (2.2%), and unknown 174 (63.5%). These patients were evaluated in intra-arterial coronary angiographic (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99) and 28 other procedures. In these pediatric patients, a concentration of 300 mg Iodine per mL was employed for intravenous contrast CT or excretory urography. A concentration of 370 mg Iodine per mL was employed for intra-arterial and intracardiac administration in the radiographic evaluation of the heart cavities and major arteries. Most pediatric patients received initial volumes of 1–2 mL/kg. Optimal doses of ULTRAVIST Injection have not been established because different injection volumes, concentrations and injection rates were not studied. The relationship of the volume of injection with respect to the size of the target vascular bed has not been established. The potential need for dose adjustment on the basis of immature renal function has not been established. In the pediatric population, the pharmacokinetic parameters have not been established. Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with asthma, a sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or a serum creatinine greater than 1.5 mg/dL. Thyroid function tests indicative of thyroid dysfunction, characterized by hypothyroidism or transient thyroid suppression have been reported following iodinated contrast media administration in pediatric patients, including term and preterm neonates; Some patients were treated for hypothyroidism. After exposure to iodinated contrast media, individualize thyroid function monitoring in pediatric patients 0 to 3 years of age based on underlying risk factors, especially in term and preterm neonates. [see Warnings and Precautions ( 5.6 ) and Adverse Reactions ( 6.2 )] The injection rates in small vascular beds, and the relationship of the dose by volume or concentration in small pediatric patients have not been established. Exercise caution in selecting the dose. Safety and effectiveness in pediatric patients below the age of two have not been established. 8.5 Geriatric Use Middle-aged and elderly patients, without significantly impaired renal function, who received ULTRAVIST Injection in doses corresponding to 9–30 g iodine, had mean steady-state volumes of distribution that ranged between 30–40 L. Mean total and renal clearances were between 81–125 mL/min and 70–115 mL/min respectively in these patients, and were similar to the values found in the young volunteers. The distribution phase half-life in this patient population was 0.1 hour, the main elimination phase half-life was 2.3 hours, and the terminal elimination phase half-life was 40 hours. The urinary excretion (97% of the dose) and fecal excretion (2%) was comparable to that observed in young healthy volunteers, suggesting that, compared to the renal route, biliary and/or gastrointestinal excretion is not significant for iopromide. 8.6 Renal Impairment In patients with renal impairment, opacification of the calyces and pelves by iopromide may be delayed due to slower renal excretion of iopromide. A pharmacokinetic study in patients with mild (n=2), moderate (n=6), and severe (n=3) renal impairment was conducted. The total clearance of iopromide was decreased proportionately to the baseline decrease in creatinine clearance. The plasma AUC increased about 2-fold in patients with moderate renal impairment and 6-fold in patients with severe renal impairment compared to subjects with normal renal function. The terminal half-life increased from 2.2 hrs for subjects with normal renal function to 11.6 hrs in patients with severe renal impairment. The peak plasma concentration of iopromide was not influenced by the extent of renal impairment. Exercise caution and use the lowest necessary dose of ULTRAVIST in patients with renal dysfunction [see Warnings and Precautions ( 5.2 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING ULTRAVIST Injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in four strengths. Glass Vials NDC Number ULTRAVIST Injection 300 mg Iodine per mL (Single-Dose containers) 50 mL vials (carton of 10) 50419-344-05 ULTRAVIST Injection 370 mg Iodine per mL (Single-Dose containers) 50 mL vials (carton of 10) 50419-346-05 Store ULTRAVIST at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) and protected from light [see USP Controlled Room Temperature].

WARNING: NOT FOR INTRATHECAL USE Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema [see Contraindications ( 4 )] . WARNING: NOT FOR INTRATHECAL USE See full prescribing information for complete boxed warning. Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.