Ultravist

WARNING: NOT FOR INTRATHECAL USE WARNING: NOT FOR INTRATHECAL USE See full prescribing information for complete boxed warning. Intrathecal administration, even if inadvertent, may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema. ULTRAVIST is not approved for intrathecal use. (5.1)

5 WARNINGS AND PRECAUTIONS • 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). Reaction severity may increase and time to onset may decrease with repeat administration of contrast agent; prophylactic medications may not prevent or mitigate severe cutaneous adverse reactions. Avoid administering ULTRAVIST to patients with a history of a severe cutaneous adverse reaction to ULTRAVIST. 5.12 Interference with Laboratory Tests ULTRAVIST can interfere with protein-bound iodine test [see Drug Interactions ( 7.2 )] .

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.

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, 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. 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 )] .

<table cellpadding="5.75pt" width="85%"><col width="49%"/><col width="25%"/><col width="22%"/><tbody><tr><td colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Table 4: Adverse Reactions Reported in &gt;1% of Patients Receiving ULTRAVIST in Clinical Trials</content></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">System Organ Class</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">ULTRAVIST</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">N=1,142 (%)</content></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Nervous system disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Headache</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>46 (4)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Dysgeusia</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>15 (1.3)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Eye disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Abnormal Vision</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>12 (1.1)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Cardiac disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Chest pain</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>18 (1.6)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Vascular disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Vasodilatation</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>30 (2.6)</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Gastrointestinal disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Nausea</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>42 (3.7)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Vomiting</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>22 (1.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Musculoskeletal and connective tissue disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Back pain</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>22 (1.9)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Renal and urinary disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Urinary urgency</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>21 (1.8)</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>General disorders and administration site conditions</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>Injection site and infusion site reactions (hemorrhage, hematoma, pain, edema, erythema, rash)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>41 (3.7)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>Pain</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>13 (1.4)</paragraph></td></tr></tbody></table>