gadoterate meglumine

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. Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection 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 fibrosis affecting the skin, muscle and internal organs. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m 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 > 60 years, hypertension, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing ( 5.1 ). For patients at highest risk for NSF, do not exceed the recommended Gadoterate Meglumine Injection dose and allow a sufficient period of time for elimination of the drug from the body prior to any 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. Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73 m 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 (for example, age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing ( 5.2 ).

5 WARNINGS AND PRECAUTIONS Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. 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 Gadoterate Meglumine Injection have not been established with intrathecal use. Gadoterate Meglumine Injection 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 Gadoterate Meglumine Injection 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 < 30 mL/min/1.73 m 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/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 - 89 mL/min/1.73 m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadoterate Meglumine Injection administration to Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. 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 Gadoterate Meglumine Injection 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 elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12 )] . 5.3 Hypersensitivity Reactions Anaphylactic and anaphylactoid reactions have been reported with Gadoterate Meglumine Injection, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of Gadoterate Meglumine Injection administration and resolved with prompt emergency treatment [see Adverse Reactions ( 6 )] . Before Gadoterate Meglumine Injection administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadoterate Meglumine Injection. Administer Gadoterate Meglumine Injection only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. During and following Gadoterate Meglumine Injection administration, observe patients for signs and symptoms of hypersensitivity reactions. 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, gadolinium 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. Screen all patients for renal impairment by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction. 5.6 Extravasation and Injection Site Reactions Ensure catheter and venous patency before the injection of Gadoterate Meglumine Injection. Extravasation into tissues during Gadoterate Meglumine Injection administration may result in tissue irritation [see Nonclinical Toxicology ( 13.2 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Nephrogenic systemic fibrosis [see Warnings and Precautions ( 5.2 )] . Hypersensitivity [see Warnings and Precautions ( 5.3 )] . Gadolinium Retention [see Warnings and Precautions ( 5.4 )]. The most frequent (≥ 0.2%) adverse reactions in clinical studies were nausea, headache, injection site pain, injection site coldness, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 clinical practice. The data described below reflect Gadoterate Meglumine Injection exposure in 2867 patients, representing 2682 adults and 185 pediatric patients. Overall, 55% of the patients were men. In clinical trials where ethnicity was recorded, the ethnic distribution was 81% Caucasian, 11% Asian, 4% Black, and 4% others. The average age was 53 years (range from < 1 week to 97 years). Overall, 4% of patients reported at least one adverse reaction, primarily occurring immediately or within 24 hours following Gadoterate Meglumine Injection administration. Most adverse reactions were mild or moderate in severity and transient in nature. Table 2 lists adverse reactions that occurred in ≥ 0.2% patients who received Gadoterate Meglumine Injection. Table 2: Adverse Reactions in Clinical Trials Reaction Rate (%) n=2867 Nausea 0.6% Headache 0.4% Injection Site Pain 0.4% Injection Site Coldness 0.2% Rash 0.2% Adverse reactions that occurred with a frequency < 0.2% in patients who received Gadoterate Meglumine Injection include: feeling cold, feeling hot, burning sensation, somnolence, pain, dizziness, dysgeusia, blood creatinine increased, hypotension, hypertension, asthenia, fatigue, injection site reactions (inflammation, extravasation, pruritus, swelling, warmth), paresthesia, pruritus, laryngeal discomfort, pain in extremity, vomiting, anxiety and palpitations. Adverse Reactions in Pediatric Patients During clinical trials, 185 pediatric patients (52 aged < 24 months, 33 aged 2 - 5 years, 57 aged 6 – 11 years and 43 aged 12 - 17 years) received Gadoterate Meglumine Injection. Overall, 7 pediatric patients (3.8%) reported at least one adverse reaction following Gadoterate Meglumine Injection administration. The most frequently reported adverse reaction was headache (1.1%). Most adverse events were mild in intensity and transient in nature. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during postmarketing use of Gadoterate Meglumine 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. Table 3: Adverse Reactions in the Postmarketing Experience System Organ Class Adverse Reaction Cardiac Disorders bradycardia, tachycardia, arrhythmia Immune System Disorders hypersensitivity/anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria Nervous System Disorders coma, convulsion, syncope, presyncope, parosmia, tremor Musculoskeletal and Connective Tissue Disorders muscle contracture, muscle weakness Gastrointestinal Disorders diarrhea, salivary hypersecretion, acute pancreatitis with onset within 48 hours after GBCA administration General Disorders and Administration Site Conditions malaise, fever Adverse reactions with variable onset and duration have been reported after GBCA administration. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. Respiratory, Thoracic and Mediastinal Disorders Acute respiratory distress syndrome, pulmonary edema Skin and Subcutaneous Tissue Disorders NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out. No unconfounded cases of NSF have been reported with Gadoterate Meglumine Injection. Gadolinium-associated plaques Vascular Disorders superficial phlebitis

<table width="100%" styleCode="Noautorules"><caption>Table 2: Adverse Reactions in Clinical Trials</caption><col width="25%"/><col width="21%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Rate (%) n=2867</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection Site Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection Site Coldness</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Rash</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.2%</paragraph></td></tr></tbody></table>

<table width="100%" styleCode="Noautorules"><caption>Table 3: Adverse Reactions in the Postmarketing Experience</caption><col width="33%"/><col width="67%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">System Organ Class</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cardiac Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>bradycardia, tachycardia, arrhythmia</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Immune System Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>hypersensitivity/anaphylactoid reactions including cardiac arrest, respiratory arrest, cyanosis, pharyngeal edema, laryngospasm, bronchospasm, angioedema, conjunctivitis, ocular hyperemia, eyelid edema, lacrimation increased, hyperhidrosis, urticaria</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nervous System Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>coma, convulsion, syncope, presyncope, parosmia, tremor</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Musculoskeletal and Connective Tissue Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>muscle contracture, muscle weakness</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastrointestinal Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>diarrhea, salivary hypersecretion, acute pancreatitis with onset within 48 hours after GBCA administration</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>General Disorders and Administration Site Conditions</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>malaise, fever</paragraph><paragraph>Adverse reactions with variable onset and duration have been reported after GBCA administration. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Respiratory, Thoracic and Mediastinal Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Acute respiratory distress syndrome, pulmonary edema</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Skin and Subcutaneous Tissue Disorders</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>NSF, in patients whose reports were confounded by the receipt of other GBCAs or in situations where receipt of other GBCAs could not be ruled out.</paragraph><paragraph>No unconfounded cases of NSF have been reported with Gadoterate Meglumine Injection.</paragraph><paragraph>Gadolinium-associated plaques</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Vascular Disorders</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>superficial phlebitis</paragraph></td></tr></tbody></table>