ProHance

WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS Risk Associated with Intrathecal Use Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. ProHance is not approved for intrathecal use [see Warnings and Precautions ( 5.1 )] . Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of ProHance in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: chronic, severe kidney disease (GFR less than 30 mL/min/1.73m 2 ), or acute kidney injury Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age greater than 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration [see Warnings and Precautions ( 5.2 )] . WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS See full prescribing information for complete boxed warning Intrathecal administration of gadolinium based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. ProHance is not approved for intrathecal use. ( 5.1 ) GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of ProHance in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: chronic, severe kidney disease (GFR less than 30 mL/min/1.73m 2 ), or acute kidney injury Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age greater than 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing ( 5.2 ).

5 WARNINGS AND PRECAUTIONS Hypersensitivity: anaphylactic/anaphylactoid reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe reactions including shock can occur. Monitor patients closely for need of emergency cardiorespiratory support ( 5.3 ). Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 ) 5.1 Risk Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of ProHance have not been established with intrathecal use. ProHance is not approved for intrathecal use [see Dosage and Administration ( 2.1 )] . 5.2 Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of ProHance among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR less than 30 mL/min/1.73m 2 ) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance Multipack administration to Bracco Diagnostics (1-800-257-5181) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch ). Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age greater than 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s Page 4 elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Clinical Pharmacology ( 12 )] . 5.3 Hypersensitivity Reactions Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of ProHance administration and resolved with prompt emergency treatment. Prior to ProHance administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions. Consider the risk for hypersensitivity reactions, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders. If such a reaction occurs, stop ProHance and immediately begin appropriate therapy. Observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hours after ProHance administration. 5.4 Gadolinium Retention Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (e.g. brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalent doses, retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)]. Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions ( 5.2 )] . There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions ( 6.2 )] . While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies, particularly closely spaced studies when possible. 5.5 Acute Kidney Injury In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the prescribing information: Nephrogenic systemic fibrosis [see Boxed Warning and Warnings and Precautions ( 5.2 )] Hypersensitivity reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] The most commonly reported adverse reactions are nausea and taste perversion with an incidence ≥ 0.9% ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, Contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse events described in this section were observed in clinical trials involving 3174 subjects (including 2896 adults and 278 pediatric subjects ages 0 to 17 years) exposed to ProHance. Approximately 48% of the subjects were men and ethnic distribution was 78% Caucasian, 6% Black, 3% Hispanic, 6% Asian, and 2% other. In 5% of the subjects, race was not reported. Average age was 47 years (range from 1 day to 91 years) and the exposure ranged from 0.03 to 0.3 mmol/kg. Overall, approximately 5.8% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after ProHance administration. Table 2 lists adverse reactions that occurred in ≥ 0.4% subjects who received ProHance. Table 2: More frequent adverse reactions in clinical trials Reaction Rate (%) N = 3174 Nausea 1.4% Dysgeusia 0.9% Headache 0.7% Dizziness 0.4% Urticaria 0.4% The following additional adverse events occurred in fewer than 0.4% of the subjects: General disorders and administration site conditions: Asthenia; chest discomfort, facial edema, feeling hot, injection site coldness, injection site erythema, injection site pain, injection site warmth, pain, pyrexia Cardiac: Angina pectoris, palpitations, atrio-ventricular block first degree Ear and labyrinth disorders: Ear discomfort, tinnitus Eye disorders: Eye pruritis, lacrimation increased Gastrointestinal disorders: Abdominal discomfort, abdominal pain, diarrhea, dry mouth, gingival pain, oral pruritis, swollen tongue, vomiting Infections and infestations: Gingivitis, rhinitis Investigations: Alanine aminotransferase increased, aspartate aminotransferase increased, blood chloride increased, blood pressure immeasurable, blood urea decreased, hemoglobin decreased, heart rate increased Metabolism and nutrition disorders: Decreased appetite, hypoglycemia Musculoskeletal and connective tissue disorders: Back pain, musculoskeletal stiffness Nervous system disorders: Formication, hypoesthesia, hypokinesia, lethargy, loss of consciousness, migraine, paresthesia, presyncope, seizure, syncope, taste disorder Psychiatric disorders: Anxiety, mental status changes Respiratory, thoracic and mediastinal disorders: Cough, dry throat, dyspnea, nasal discomfort, throat irritation Skin and subcutaneous tissue disorders: Hyperhidrosis, pruritis, rash, rash morbilliform Vascular disorders: Flushing, hypotension, peripheral coldness, vascular rupture, vasodilatation, vasospasm 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of ProHance or other GBCAs that were not observed in the clinical trials. 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. * Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment. The following adverse drug reactions have also been reported: General Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions ( 5.4 )]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. Cardiac disorders: Cardiac arrest, bradycardia, hypertension Gastrointestinal disorders: Acute pancreatitis with onset within 48 hours after GBCA administration Immune system disorders: Hypersensitivity/anaphylactoid reactions including cardiac arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria [see Warnings and Precautions ( 5.3 )] . Nervous system disorders: Coma, loss of consciousness, vasovagal reaction, tremor Respiratory, thoracic and mediastinal disorders: Respiratory arrest, acute respiratory distress syndrome, pulmonary edema Renal and urinary system disorders: Acute renal failure *

<table ID="t6401332" width="60%"><caption>Table 2 lists adverse reactions that occurred in &#x2265; 0.4% subjects who received ProHance.</caption><colgroup><col width="30%"/><col width="70%"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" valign="top"><content styleCode="bold">Table 2: More frequent adverse reactions in clinical trials</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"><content styleCode="bold">Reaction</content></td><td styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Rate (%) N = 3174</content></td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule">Nausea</td><td styleCode="Botrule Lrule Rrule Toprule">1.4%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule">Dysgeusia</td><td styleCode="Botrule Lrule Rrule Toprule">0.9%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top">Headache</td><td styleCode="Botrule Lrule Rrule Toprule">0.7%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule">Dizziness</td><td styleCode="Botrule Lrule Rrule Toprule" valign="top">0.4%</td></tr><tr><td styleCode="Botrule Lrule Rrule Toprule">Urticaria</td><td styleCode="Botrule Lrule Rrule Toprule">0.4%</td></tr></tbody></table>

<table ID="t3118330" width="100%"><colgroup><col width="28*"/><col width="69*"/></colgroup><tbody><tr><td colspan="2">The following additional adverse events occurred in fewer than 0.4% of the subjects:</td></tr><tr><td>General disorders and administration site conditions:</td><td>Asthenia; chest discomfort, facial edema, feeling hot, injection site coldness, injection site erythema, injection site pain, injection site warmth, pain, pyrexia</td></tr><tr><td>Cardiac:</td><td>Angina pectoris, palpitations, atrio-ventricular block first degree</td></tr><tr><td>Ear and labyrinth disorders:</td><td>Ear discomfort, tinnitus</td></tr><tr><td>Eye disorders:</td><td>Eye pruritis, lacrimation increased</td></tr><tr><td>Gastrointestinal disorders:</td><td>Abdominal discomfort, abdominal pain, diarrhea, dry mouth, gingival pain, oral pruritis, swollen tongue, vomiting</td></tr><tr><td>Infections and infestations:</td><td>Gingivitis, rhinitis</td></tr><tr><td>Investigations:</td><td>Alanine aminotransferase increased, aspartate aminotransferase increased, blood chloride increased, blood pressure immeasurable, blood urea decreased, hemoglobin decreased, heart rate increased</td></tr><tr><td>Metabolism and nutrition disorders:</td><td>Decreased appetite, hypoglycemia</td></tr><tr><td>Musculoskeletal and connective tissue disorders:</td><td>Back pain, musculoskeletal stiffness</td></tr><tr><td>Nervous system disorders:</td><td>Formication, hypoesthesia, hypokinesia, lethargy, loss of consciousness, migraine, paresthesia, presyncope, seizure, syncope, taste disorder</td></tr><tr><td>Psychiatric disorders:</td><td>Anxiety, mental status changes</td></tr><tr><td>Respiratory, thoracic and mediastinal disorders:</td><td>Cough, dry throat, dyspnea, nasal discomfort, throat irritation</td></tr><tr><td>Skin and subcutaneous tissue disorders:</td><td>Hyperhidrosis, pruritis, rash, rash morbilliform</td></tr><tr><td styleCode="Botrule">Vascular disorders:</td><td styleCode="Botrule">Flushing, hypotension, peripheral coldness, vascular rupture, vasodilatation, vasospasm</td></tr></tbody></table>

<table ID="t6690032" width="100%"><colgroup><col width="30%"/><col width="70%"/></colgroup><tfoot><tr><td colspan="2" valign="top">* Cases of acute renal failure have been reported in patients with pre-existing severe renal impairment.</td></tr></tfoot><tbody><tr><td colspan="2" valign="top">The following adverse drug reactions have also been reported:</td></tr><tr><td valign="top">General Disorders and Administration Site Conditions:</td><td>Adverse events with variable onset and duration have been reported after GBCA administration <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#Section_5.4">5.4</linkHtml>)].</content> These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.</td></tr><tr><td valign="top">Cardiac disorders:</td><td>Cardiac arrest, bradycardia, hypertension</td></tr><tr><td valign="top">Gastrointestinal disorders:</td><td>Acute pancreatitis with onset within 48 hours after GBCA administration</td></tr><tr><td valign="top">Immune system disorders:</td><td>Hypersensitivity/anaphylactoid reactions including cardiac arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, cough, sneezing, conjunctivitis, eyelid edema, hyperhidrosis, urticaria <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#Section_5.3">5.3</linkHtml>)]</content>.</td></tr><tr><td>Nervous system disorders:</td><td>Coma, loss of consciousness, vasovagal reaction, tremor</td></tr><tr><td>Respiratory, thoracic and mediastinal disorders:</td><td>Respiratory arrest, acute respiratory distress syndrome, pulmonary edema</td></tr><tr><td>Renal and urinary system disorders:</td><td>Acute renal failure *</td></tr></tbody></table>