Ambelvist

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. AMBELVIST 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 AMBELVIST 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 (for example, age > 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 AMBELVIST 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. AMBELVIST 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 AMBELVIST 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 Reactions: Serious hypersensitivity reactions have occurred with GBCAs. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.3 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 ) 5.1 Risks Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of AMBELVIST have not been established with intrathecal use. AMBELVIST 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 AMBELVIST among these patients unless the diagnostic information is essential and not available with non-contrast enhanced 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 to 59 mL/min/1.73 m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 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 AMBELVIST administration to Bayer HealthCare (1- 888-842-2937) 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 > 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 degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended AMBELVIST 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . The usefulness of hemodialysis in the prevention of NSF is unknown. 5.3 Hypersensitivity Reactions With GBCAs, serious hypersensitivity reactions have occurred. In most cases, initial symptoms occurred within half an hour of GBCA administration and resolved with prompt emergency treatment. Before AMBELVIST 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 AMBELVIST. AMBELVIST is contraindicated in patients with history of severe hypersensitivity reactions to AMBELVIST [see Contraindications (4) ] . Administer AMBELVIST 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 AMBELVIST 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 gadodiamide causing greater retention than other linear agents such as gadoxetate disodium and gadobenate dimeglumine. Retention is lowest and similar among the macrocyclic GBCAs such as gadoterate meglumine, gadobutrol, gadoteridol, gadopiclenol, and gadoquatrane. 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. 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 chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses. 5.6 Interference with Lesion Visualization As with other GBCAs, AMBELVIST may obscure certain lesions that are visible on non-contrast MRI. When available, non-contrast MRI images should be reviewed during the interpretation of AMBELVIST MRI scans.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Nephrogenic Systemic Fibrosis [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions [see Contraindications (4) and Warnings and Precautions (5.3) ] Most frequently observed adverse reactions (incidence ≥ 0.2%) were dizziness, headache, injection site reactions, nausea, vomiting, feeling hot, paresthesia, and pruritus. ( 6.1 ) 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 the rates observed in clinical practice. The safety of AMBELVIST was evaluated in four clinical studies in a total of 842 patients who received a single 0.01 mmol/kg dose. This safety population included 697 adult patients from two active comparator, cross-over studies [see Clinical Studies (14.1) ], 52 adult patients from a dose-finding study, and 93 pediatric patients [see Use in Specific Populations (8.4) ] . Adult Patients Among the 749 adult patients (who were exposed to gadoquatrane), the mean age was 56 years (range: 18 years to 89 years). Of these patients, 67% were White, 29% Asian, 1% Black or African American, and 3% of other or unspecified race, and 10% were Hispanic or Latino, 76% not Hispanic or Latino, and 14% of unspecified ethnicity. Table 1 lists adverse reactions that occurred in ≥ 0.2% of adult patients who received 0.01 mmol/kg AMBELVIST. Table 1: Adverse Reactions Reported in ≥ 0.2% of Adult Patients Who Received AMBELVIST Adverse Reaction AMBELVIST 0.01 mmol/kg N=749 (%) Dizziness 0.9 Headache 0.9 Injection site reactions Injection site reactions include injection site pain, catheter site pain, injection site coldness, and injection site erythema. 0.7 Nausea 0.5 Vomiting 0.4 Feeling hot 0.4 Paresthesia 0.3 Pruritus 0.3 Adverse reactions that occurred in < 0.2% of adult patients who received 0.01 mmol/kg AMBELVIST included erythema, abdominal discomfort, toothache, feeling cold, decreased glomerular filtration rate, urinary sediment, urinary white blood cells, urticaria, dyspnea, rhinalgia, arthralgia, limb discomfort, hematuria, vertigo, and hyperbilirubinemia. Pediatric Patients Among the 93 pediatric patients, the mean age was 7 years (range: 28 days to less than 18 years). Of these patients, 57% were White, 38% Asian, 1% Black or African American, and 4% of unspecified race, and 14% were Hispanic or Latino, 80% not Hispanic or Latino, and 6% of unspecified ethnicity. Adverse reactions in pediatric patients who received 0.01 mmol/kg AMBELVIST included (each occurring in 1% of patients): apnea, pyrexia, decreased platelet count, erythema, and rash [see Use in Specific Populations (8.4) ] . 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of GBCAs. 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. Gastrointestinal Disorders : Acute pancreatitis with onset within 48 hours after GBCA administration. General Disorders and Administration Site Conditions : Fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems with variable onset and duration after GBCA administration [see Warnings and Precautions (5.4) ] Respiratory, Thoracic, and Mediastinal Disorders : Acute respiratory distress syndrome, pulmonary edema. Skin Disorders : Gadolinium-associated plaques

<table width="60%"><caption>Table 1: Adverse Reactions Reported in &#x2265; 0.2% of Adult Patients Who Received AMBELVIST</caption><col width="50%" align="center" valign="middle"/><col width="50%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="center">Adverse Reaction</th><th styleCode="Rrule">AMBELVIST 0.01 mmol/kg N=749 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Injection site reactions<footnote>Injection site reactions include injection site pain, catheter site pain, injection site coldness, and injection site erythema.</footnote></td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Feeling hot</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paresthesia</td><td styleCode="Rrule">0.3</td></tr><tr><td styleCode="Lrule Rrule">Pruritus</td><td styleCode="Rrule">0.3</td></tr></tbody></table>