FDA label e0705ae1-d3f0-4fd2-b209-0d48a986554f

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs 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. • Do not administer Magnevist to patients with: • chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ), or • acute kidney injury [see Contraindications ( 4 )] . • 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. Do not exceed the recommended Magnevist 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 ( 5.1 )] . WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning. Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. • Do not administer Magnevist to patients with: • chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ), or • acute kidney injury. ( 4 ) • 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. Do not exceed the recommended Magnevist dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration. ( 5.1 )

5 WARNINGS AND PRECAUTIONS • Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeat dosing appears to increase the risk. ( 5.1 ) • Hypersensitivity: Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. Monitor patients closely for need of emergency cardiorespiratory support. ( 5.2 ) • Renal Failure: In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of Magnevist injection. ( 5.4 ) • Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.3 ) 5.1 Nephrogenic Systemic Fibrosis (NSF) Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs 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/1.73m 2 ) as well as patients with acute kidney injury. Do not administer Magnevist to these patients. 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 Magnevist 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 administered to a patient. When administering Gadopentetate dimeglumine, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to re-administration [see Clinical Pharmacology ( 12.3 ) and Dosage and Administration ( 2 )] . 5.2 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, and/or cutaneous manifestations rarely resulting in death have occurred. The risk of hypersensitivity reactions is higher in patients with a history of reaction to contrast media, bronchial asthma, or allergic disorders. Hypersensitivity reactions can occur with or without prior exposure to GBCAs. Have appropriately trained personnel administer Magnevist in a facility that has immediate availability of resuscitative equipment. If a hypersensitivity reaction occurs, stop Magnevist injection and immediately begin appropriate therapy. Observe closely patients with a history of drug reactions, allergy, or other hypersensitivity disorders, during and up to several hours after Magnevist injection. 5.4 Renal Failure In patients with renal impairment, acute renal failure (acute kidney injury) requiring dialysis or worsening renal function has occurred, mostly within 48 hours of Magnevist injection. The risk of acute renal failure is higher with increasing dose of contrast. Use the lowest possible dose, evaluate renal function in patients with renal impairment, and allow sufficient time for contrast elimination before re-administration. Elimination half-life in patients with mild or moderate renal impairment is 3 to 4 hours. Elimination half-life in patients with severe renal impairment is about 11 hours. Magnevist is cleared by glomerular filtration and is dialyzable. After 3 dialysis sessions of 3 hours each, about 97% of the administered dose is eliminated from the body; each dialysis session removes about 70% of the circulating drug [see Clinical Pharmacology ( 12.3 )] . 5.5 Injection Site Reactions Skin and soft tissue necrosis, thrombosis, fasciitis, and compartment syndrome requiring surgical intervention (e.g. compartment release or amputation) have occurred very rarely at the site of contrast injection or the dosed limb. Total volume and rate of Magnevist injection, extravasation of contrast agent, and patient susceptibility might contribute to these reactions. Phlebitis and thrombophlebitis may be observed generally within 24 hours after Magnevist injection and resolve with supportive treatment. Determine the patency and integrity of the intravenous line before administration of Magnevist injection. Assessment of the dosed limb for the development of injection site reactions is recommended. 5.6 Interference with Visualization of Lesions Visible with Non-Contrast MRI As with any paramagnetic contrast agent, Magnevist injection might impair the visualization of lesions seen on non-contrast MRI. Therefore, caution should be exercised when Magnevist MRI scans are interpreted without a companion non-contrast MRI scan.

6 ADVERSE REACTIONS The most common adverse reactions (≥1%) are headache, nausea, injection site coldness/localized coldness, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 mean age of the 1272 patients who received Magnevist injection in pre-market clinical trials was 46.4 years (range 2 to 93 years). Of these patients, 55% (700) were male and 45% (572) were female. Of the 1271 patients who received Magnevist injection and for whom race was reported, 82.1% (1043) were Caucasian, 9.7% (123) were Black, 5.3% (67) were Hispanic, 2.1% (27) were Oriental/Asian, and 0.9% (11) were other. The most common adverse reaction was headache (4.8%). The majority of headaches were transient and of mild to moderate severity. Other adverse reactions that occurred in ≥ 1% of patients included: nausea (2.7%), injection site coldness/localized coldness (2.3%) and dizziness (1%). The following additional adverse reactions occurred in less than 1% of the patients: General Disorders: Injection site reactions, including phlebitis, pain, localized warmth, localized edema, and burning sensation [see Warnings and Precautions ( 5.5 )] . Substernal chest pain, back pain, pyrexia, asthenia, feeling cold, generalized warmth, fatigue, and chest tightness, and anaphylactoid reactions characterized by cardiovascular, respiratory and/or cutaneous symptoms, such as dyspnea, bronchospasm, and cough. Cardiovascular: Hypotension, hypertension, tachycardia, migraine, syncope, vasodilatation, pallor. Gastrointestinal: Abdominal discomfort, teeth pain, increased salivation, abdominal pain, vomiting, diarrhea. Nervous System: Agitation, anxiety, thirst, somnolence, diplopia, loss of consciousness, convulsions (including grand mal), paresthesia. Respiratory System: Throat irritation, rhinitis, sneezing. Skin: Rash, sweating (hyperhidrosis), pruritus, urticaria (hives), facial edema. Special Senses: Conjunctivitis, taste abnormality, dry mouth, lacrimation, eye irritation, eye pain, ear pain. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of Gadopentetate dimeglumine. 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. • Anaphylactic shock, respiratory distress, and laryngeal edema [see Warnings and Precautions ( 5.2 )] • Cardiac/respiratory arrest, shock • Nephrogenic systemic fibrosis [see Warnings and Precautions ( 5.1 )] • General Disorders and Administrations Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [ see Warnings and Precautions ( 5.3 )] . These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems . • Skin: Gadolinium associated plaques The most frequently reported adverse reactions in the postmarketing experience were nausea, vomiting, urticaria, and rash. General Disorders and Administration Site Conditions: Nephrogenic systemic fibrosis [see Warnings and Precautions ( 5.1 )] , body temperature decreased, tremor, shivering (chills), injection site reactions including skin and soft tissue necrosis. Hypersensitivity Reactions: Anaphylactic/anaphylactoid reactions that may be fatal and include cardiac or respiratory arrest, respiratory distress, cyanosis, laryngeal edema, laryngospasm, pharyngeal edema, and angioedema [see Warnings and Precautions ( 5.2 )] . Delayed hypersensitivity reactions have been reported up to several hours after administration of Gadopentetate dimeglumine. Renal and Urinary: Acute renal failure, worsening renal impairment [see Warnings and Precautions ( 5.4 )] urinary incontinence, urinary urgency. Vascular: Thrombophlebitis, deep vein thrombophlebitis, compartment syndrome requiring surgical intervention. Cardiac: Cardiac arrest, heart rate decreased, arrhythmia. Ear and Labyrinth Disorders: Hearing impairment. Eye Disorders: Visual disturbance. Musculoskeletal and Connective Tissue Disorder: Arthralgia. Nervous System Disorders: Coma, parosmia, speech disorder. Respiratory System: Respiratory arrest, pulmonary edema. Skin: Erythema multiforme, pustules