Iopromide

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 )].

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 )

None None

• Hypersensitivity Reactions: Life-threatening or fatal reactions can occur. Always have emergency equipment and trained personnel available. ( 5.2 )
• Acute Kidney Injury : Acute injury including renal failure can occur. Dose minimization and hydration may decrease risk. ( 5.3 )
• Cardiovascular Reactions : Hemodynamic disturbances including shock and cardiac arrest may occur during or after administration. ( 5.4 )
• Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age : Individualize thyroid function monitoring based on risk factors such as prematurity ( 5.8 )

5.1 Risks Associated with Intrathecal Use Intrathecal administration, even if inadvertent, can cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. ULTRAVIST is for intra-arterial or intravenous use only [see Dosage and Administration ( 2.2 , 2.3 , 2.4 )]. ULTRAVIST is not approved for intrathecal use.

5.2 Hypersensitivity Reactions ULTRAVIST can cause life-threatening or fatal hypersensitivity reactions including anaphylaxis. Manifestations include respiratory arrest, laryngospasm, bronchospasm, angioedema, and shock [see Adverse Reactions ( 6.2 )] . Most severe reactions develop shortly after the start of injection (e.g., within 1 to 3 minutes), but delayed reactions can also occur. There is increased risk of hypersensitivity reactions in patients with a history of previous reaction to a contrast agent and known allergic disorders (that is, bronchial asthma, allergic rhinitis, and food allergies), or other hypersensitivities . Premedication with antihistamines or corticosteroids does not prevent serious life-threatening reactions but may reduce both their incidence and severity. Obtain a history of allergy, hypersensitivity, or hypersensitivity reactions to iodinated contrast agents and have emergency resuscitation equipment and trained personnel available prior to ULTRAVIST administration. Monitor all patients for hypersensitivity reactions.

5.3 Acute Kidney Injury Acute kidney injury, including renal failure, may occur after administration of ULTRAVIST. Risk factors include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma or other paraproteinemia, and repetitive and/or large doses of ULTRAVIST. Use the lowest necessary dose of ULTRAVIST in patients with renal impairment. Hydrate patients prior to and following ULTRAVIST administration. Do not use laxatives, diuretics, or preparatory dehydration prior to ULTRAVIST administration.

5.4 Cardiovascular Adverse Reactions ULTRAVIST increases the circulatory osmotic load and may induce acute or delayed hemodynamic disturbances in patients with congestive heart failure, severely impaired renal function, combined renal and hepatic disease, or combined renal and cardiac disease, particularly when repetitive and/or large doses are administered . Fatal cardiovascular reactions have occurred mostly within 10 minutes of ULTRAVIST injection; the main feature was cardiac arrest with cardiovascular disease as the main underlying factor. Hypotensive collapse and shock have occurred. Cardiac decompensation, serious arrhythmias, and myocardial ischemia or infarction can occur during coronary arteriography and ventriculography. The administration of ULTRAVIST may cause pulmonary edema in patients with heart failure. Based upon published reports, deaths from the administration of iodinated contrast agents range from 6.6 per 1 million (0.00066 percent) to 1 in 10,000 patients (0.01 percent). Use the lowest necessary dose of ULTRAVIST in patients with congestive heart failure and always have emergency resuscitation equipment and trained personnel available. Monitor all patients for severe cardiovascular reactions.

5.5 Thromboembolic Events angiography procedures. During these procedures, increased thrombosis and activation of the complement system can occur. Risk of thromboembolic events can be influenced by: length of procedure, catheter and syringe material, underlying disease state, and concomitant medications. To decrease thromboembolic events, use meticulous angiographic techniques and minimize the length of the procedure. Avoid blood remaining in contact with syringes containing iodinated contrast agents, which increases the risk of clotting. Avoid angiography in patients with homocystinura because of the risk of inducing thrombosis and embolism.

5.6 Extravasation and Injection Site Reactions Extravasation can occur with ULTRAVIST, particularly in patients with severe arterial or venous disease. Inflammation, blistering, skin necrosis, and compartment syndrome have been reported following extravasation. In addition, injection site reactions such as pain and swelling at the injection site can also occur [see Adverse Reactions ( 6.1 )] . Ensure intravascular placement of catheters prior to injection. Monitor patients for extravasation and advise patients to seek medical care for progression of symptoms.

5.7 Thyroid Storm in Patients with Hyperthyroidism Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism or with an autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of ULTRAVIST.

5.8 Thyroid Dysfunction in Pediatric Patients 0 to 3 Years of Age Thyroid dysfunction characterized by hypothyroidism or transient thyroid suppression has been reported after both single exposure and multiple exposures to iodinated contrast media (ICM) in pediatric patients 0 to 3 years of age. Younger age, very low birth weight, prematurity, underlying medical conditions affecting thyroid function, admission to neonatal or pediatric intensive care units, and congenital cardiac conditions are associated with an increased risk of hypothyroidism after ICM exposure. Pediatric patients with congenital cardiac conditions may be at the greatest risk given that they often require high doses of contrast during invasive cardiac procedures. An underactive thyroid during early life may be harmful for cognitive and neurological development and may require thyroid hormone replacement therapy. After exposure to ICM, individualize thyroid function monitoring based on underlying risk factors, especially in term and preterm neonates. The safety and effectiveness of ULTRAVIST in pediatric patients younger than 2 years of age have not been established, and ULTRAVIST is not approved for use in pediatric patients younger than 2 years of age [see Use in Specific Populations ( 8.4 )].

5.9 Hypertensive Crisis in Patients with Pheochromocytoma Hypertensive crisis in patients with pheochromocytoma has occurred with iodinated contrast agents. Closely monitor patients when administering ULTRAVIST if pheochromocytoma or catecholamine-secreting paragangliomas are suspected. Inject the minimum amount of ULTRAVIST necessary and have measures for treatment of a hypertensive crisis readily available.

5.10 Sickle Cell Crisis in Patients with Sickle Cell Disease Iodinated contrast agents may promote sickling in individuals who are homozygous for sickle cell disease. Hydrate patients prior to and following ULTRAVIST administration and use only if the necessary imaging information cannot be obtained with alternative imaging modalities.

5.11 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCAR) may develop from 1 hour to several weeks after intravascular contrast agent administration. These reactions include Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). […]

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, 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 Pediatric Patients A total of 274 pediatric patients were evaluated with intra-arterial coronary angiography (n=60), intravenous contrast computerized tomography (CT) (n=87), excretory urography (n=99), and 28 other procedures. These patients received 1 mL/kg to 2 mL/kg body weight of a concentration of 300 mg Iodine per mL for intravenous contrast CT or excretory urography and 370 mg Iodine per mL for intra-arterial and intracardiac administration in the radiographic evaluation of the heart cavities and major arteries [see Dosage and Administration ( 2.4 )]. Among these, 131 were 2 to 12 years old, 57 were adolescents, and 86 were unreported or other ages. There were 148 females, 94 males, and 32 in whom gender was not reported. The racial distribution was: White 33.9%, Black 0.4%, Asian 2.2%, and unknown 63.5%. The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported in adult patients.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ULTRAVIST. 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 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 Pediatric Patients Additional adverse reactions reported in pediatric patients from foreign marketing surveillance or other information include: epistaxis, migraine, joint disorder (effusion), muscle cramps, mucous membrane disorder (mucosal swelling), conjunctivitis, fixed eruptions, diabetes insipidus, and brain edema.

6.3 Pediatrics The overall character, quality, and severity of adverse reactions in pediatric patients are generally similar to those reported in adult patients. […]

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.

8.1 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 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 ( 5.8 ) and Adverse Reactions ( 6.2 )]. Safety and effectiveness of ULTRAVIST have not been established in pediatric patients younger than 2 years for radiographic evaluation of cardiac chambers and related arteries, excretory urography, and contrast computed tomography of head and body. Safety and effectiveness of ULTRAVIST for cerebral arteriography, peripheral arteriography, coronary arteriography and left ventriculography, visceral angiography, aortography, and contrast mammography have not been established in pediatric patients.

8.5 Geriatric Use In a clinical study of ULTRAVIST for CT, 96/434 (22.1%) of patients were 65 and over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. Iopromide is known to be substantially excreted by the kidney, and the risk of adverse reactions to iopromide may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Impairment The clearance of iopromide decreases with increasing degree of renal impairment and results in delayed opacification of the urinary system [see Clinical Pharmacology ( 12.3 )] . In addition, preexisting renal impairment increases the risk for acute kidney injury [see Warnings and Precautions ( 5.3 )] . Iopromide can be removed by dialysis.

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.