Ultravist

Indications and Usage ( 1.2 ) 5/2023 Dosage and Administration ( 2.3 , 2.5 ) 5/2023 Warning and Precautions ( 5.8 ) 4/2023

1 INDICATIONS AND USAGE ULTRAVIST ® Injection is an iodinated contrast agent indicated for: ULTRAVIST is a radiographic contrast agent indicated for: Intra-Arterial Procedures † • Cerebral arteriography and peripheral arteriography in adults ( 1.1 ) • Coronary arteriography and left ventriculography, visceral angiography, and aortography in adults ( 1.1 ) • Radiographic evaluation of cardiac chambers and related arteries in pediatric patients aged 2 years and older ( 1.1 ) Intravenous Procedures † • Excretory urography in adults and pediatric patients aged 2 years and older ( 1.2 ) • Contrast computed tomography (CT) of head and body in adults and pediatric patients aged 2 years and older ( 1.2 ) • Contrast mammography in adults as an adjunct following mammography and/or ultrasound ( 1.2 ) † Specific concentrations and presentations are recommended for each type of imaging procedure. ( 2.2 , 2.3 , 2.4 ) 1.1 Intra-Arterial Procedures* ULTRAVIST is indicated for: • Cerebral arteriography and peripheral arteriography in adults • Coronary arteriography and left ventriculography, visceral angiography, and aortography in adults • Radiographic evaluation of cardiac chambers and related arteries in pediatric patients aged 2 years and older 1.2 Intravenous Procedures* ULTRAVIST is indicated for: • Excretory urography in adults and pediatric patients aged 2 years and older • Contrast Computed Tomography (CT) of the head and body (intrathoracic, intra-abdominal, and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions in adults and pediatric patients aged 2 years and older • Contrast mammography to visualize known or suspected lesions of the breast in adults, as an adjunct following mammography and/or ultrasound † Specific concentrations and presentations of ULTRAVIST are recommended for each type of imaging procedure [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )].

2 DOSAGE AND ADMINISTRATION • Individualize the volume and concentration according to the specific dosing tables accounting for factors such as age, body weight, size of the vessel, and the rate of blood flow within the vessel. ( 2.2 , 2.3 , 2.4 ) • For contrast mammography, use ULTRAVIST with a device that is cleared for dual-energy full field digital mammography. ( 2.5 ) • See full prescribing information for important dosage and administration instructions and directions for use of pharmacy bulk packages and imaging bulk packages. ( 2.1 , 2.6 , 2.7 ) 2.1 Important Dosage and Administration Information • ULTRAVIST is for intra-arterial or intravenous use only and must not be administered intrathecally [see Warnings and Precautions ( 5.1 )] . • Specific concentrations and presentations of ULTRAVIST are recommended for each type of imaging procedure [see Dosage and Administrations ( 2.2 , 2.3 , 2.4 )] . • Hydrate patients, as appropriate, prior to and following the administration of ULTRAVIST [see Warnings and Precautions ( 5.3 )] . • Individualize the volume, concentration, and injection rate of ULTRAVIST according to the specific dosing tables [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )] . Consider factors such as age, body weight, size of the vessel, and the rate of blood flow within the vessel; also consider extent of opacification required, structure(s) or area to be examined, disease processes affecting the patient, and equipment and technique to be employed. • 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. • Use aseptic technique for all handling and administration of ULTRAVIST. • Warm ULTRAVIST to body temperature before administration. • ULTRAVIST can be used with 0.9% Sodium Chloride Injection in a power injector suitable for simultaneous injection of contrast [see Dosage and Administration ( 2.3 )] . However, do not mix or inject ULTRAVIST in intravenous administration lines containing other drugs or total nutritional admixtures. • Discard any unused portion remaining in the single-dose container following initial use. 2.2 Recommended Dosage for Intra-Arterial Procedures in Adults • The recommended doses for intra-arterial procedures in adults are shown in Table 1. • Inject at rates approximately equal to the flow rate in the vessel being injected. Table 1: Recommended Concentrations and Volume of ULTRAVIST to Administer per Single Injection for Selected Injection Sites of Intra-Arterial Procedures in Adults Imaging Procedure Cerebral Arteriography Peripheral Arteriography Coronary Arteriography and Left Ventriculography Visceral Angiography and Aortography Concentration (mg Iodine per mL) 300 * 300 * 370 * 370 * Intra-Arterial Injection Sites Carotid Arteries 3 mL to 12 mL - - - Vertebral Arteries 4 mL to 12 mL Aortic Arch Injection (four vessel study) 20 mL to 50 mL Subclavian or Femoral Artery - 5 mL to 40 mL - - Aortic Bifurcation (distal runoff) 25 mL to 50 mL Right Coronary Artery - - 3 mL to 14 mL - Left Coronary Artery 3 mL to 14 mL Left Ventricle 30 mL to 60 mL Aorta and Major Abdominal Branches - - - Individualize a volume approximately equal to the blood flow and related to the vascular and pathological characteristics of the specific vessels being studied. Maximum Total Dose 150 mL 250 mL 225 mL 225 mL *Use single-dose vials or pharmacy bulk package. 2.3 Recommended Dosage for Intravenous Procedures in Adults Recommended doses for intravenous procedures in adults are shown in Table 2. Table 2: Recommended Concentrations and Volume of ULTRAVIST for Intravenous Procedures in Adults Imaging Procedure Excretory Urography Contrast Computed Tomography Contrast Mammography Concentration (mg Iodine per mL) 300 * 300 ‡ 370 ‡ 300 ‡ or 370 ‡ Excretory Urography 1 mL/kg body weight - - - CT of Head - 50 mL to 20 …

3 DOSAGE FORMS AND STRENGTHS ULTRAVIST injection is a clear, colorless to slightly yellow, odorless solution available in two concentrations: 300 mg Iodine per mL available as • 50 mL, 100 mL, 125 mL, and 150 mL in single-dose vials • 200 mL and 500 mL in pharmacy bulk packages • 200 mL and 500 mL in imaging bulk packages 370 mg Iodine per mL available as • 50 mL, 100 mL, 125 mL, and 150 mL in single-dose vials • 200 mL and 500 mL in pharmacy bulk packages • 200 mL and 500 mL in imaging bulk packages Injection: 300 mg Iodine per mL and 370 mg Iodine per mL in single-dose vials, pharmacy bulk packages, and imaging bulk packages. ( 3 )

4 CONTRAINDICATIONS None None

6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: • Risks Associated with Intrathecal Use [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 to 3 Years of Age [see Warnings and Precautions ( 5.8 )] • Severe Cutaneous Adverse Reactions [see Warnings and Precautions ( 5.11 )] 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 common adverse reactions reported in >1% of patients in clinical studies with ULTRAVIST are shown in Table 4. Table 4: Adverse Reactions Reported in >1% of Patients Receiving ULTRAVIST in Clinical Trials System Organ Class Adverse Reaction ULTRAVIST N=1,142 (%) 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 1,142 (24%) patients during the clinical trials, coincident with the administration of ULTRAVIST or within the defined duration of the study follow-up period (24–72 hours). ULTRAVIST 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. In clinical trials 7 of 1,142 patients given ULTRAVIST died 5 days or later after drug administration. Also, 10 of 1,142 patients given ULTRAVIST had serious adverse events. The following adverse reactions were observed in ≤1% of the patients receiving ULTRAVIST: 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 …

7 DRUG INTERACTIONS 7.1 Drug-Drug Interactions Metformin In patients with renal impairment, biguanides 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, ULTRAVIST administration in patients with an eGFR between 30 and 60 mL/min/1.73 m2; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast agents. Re-evaluate eGFR 48 hours after the imaging procedure and reinstitute only after renal function is stable. Radioactive Iodine ULTRAVIST 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 ULTRAVIST. 7.2 Drug-Laboratory Test Interactions Protein-Bound Iodine Test Iodinated contrast agents, including ULTRAVIST, will temporarily increase protein-bound iodine in blood. Do not perform protein-bound iodine test for at least 16 days following administration of ULTRAVIST. 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data on ULTRAVIST 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 to0.35 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 were 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 and any potential adverse effects on the breastfed infant from ULTRAVIST 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 administration in order to minimize drug exposure to a breast fed infant. 8.4 Pediatric Use The safety and efficacy of ULTRAVIST have been established in pediatric patients aged 2 years and older for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of head and body. Use of ULTRAVIST in these age groups for these indications is supported by evidence from adequate and well-controlled studies in adults and additional safety data in pediatric patients aged 2 years and older, including data from published studies [see Adverse Reactions ( 6.1 , 6.2 ) and Clinical Studies ( 14.1 , 14.2 )]. Pediatric patients at higher risk of experiencing an adverse reaction during and after administration of any contrast agent include those with asthma, sensitivity to medication and/or allergens, cyanotic and acyanotic heart disease, congestive heart failure, or 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 io …

12.1 Mechanism of Action Intravascular injection of iopromide opacifies those vessels where the contrast agent is present, permitting radiographic visualization of the internal structures through attenuation of 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, contrast does not diffuse into the extravascular space. In patients with a disrupted blood-brain barrier, contrast agent accumulates in the extravascular space in the region of disruption.

11 DESCRIPTION ULTRAVIST (iopromide) injection is a nonionic radiographic contrast agent for intra-arterial or intravenous 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: Each mL contains 623.4 mg or 768.86 mg iopromide (300 mg or 370 mg iodine, respectively) and the following inactive ingredients: 0.1 mg edetate calcium disodium as a stabilizer and 2.42 mg tromethamine as a buffer. It may also contain sodium hydroxide or hydrochloric acid to adjust pH to 7.4 (6.5–8) at 25± 2°C and contains no preservatives. ULTRAVIST is a sterile (sterilized by autoclaving), clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution and has the following physicochemical properties: Property Concentration of ULTRAVIST (mg Iodine/mL) 300 370 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. ULTRAVIST 300 mg Iodine per mL and 370 mg Iodine per mL have osmolalities respectively 2.1 and 2.7 times that of plasma (285 mOsmol/kg water). Chemical diagram

10 OVERDOSAGE The manifestations 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. Iopromide can be removed by dialysis.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ULTRAVIST injection is a sterile, clear, colorless to slightly yellow, odorless, pyrogen-free aqueous solution available in the following presentations: ULTRAVIST 300 mg Iodine per mL Package Type Volume Sale Unit NDC Single-Dose Vials 50 mL Carton of 10 50419-344-05 100 mL Carton of 10 50419-344-10 125 mL Carton of 10 50419-344-12 150 mL Carton of 10 50419-344-15 Pharmacy Bulk Package 200 mL Carton of 10 50419-344-21 500 mL Carton of 8 50419-344-58 Imaging Bulk Package 200 mL Carton of 10 50419-344-23 500 mL Carton of 8 50419-344-65 ULTRAVIST 370 mg Iodine per mL Package Type Volume Sale Unit NDC Single-Dose Vials 50 mL Carton of 10 50419-346-05 100 mL Carton of 10 50419-346-10 150 mL Carton of 10 50419-346-15 200 mL Carton of 10 50419-346-20 Pharmacy Bulk Package 200 mL Carton of 10 50419-346-26 500 mL Carton of 8 50419-346-58 Imaging Bulk Package 200 mL Carton of 10 50419-346-28 500 mL Carton of 8 50419-346-65 Storage and Handling Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Protect from light.