OMNISCAN

1 INDICATIONS AND USAGE OMNISCAN is a gadolinium-based contrast agent for diagnostic magnetic resonance imaging (MRI) indicated for intravenous use to: Visualize lesions with abnormal vascularity in the brain, spine, and associated tissues ( 1.1 ) Facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space ( 1.2 ) 1.1 CNS (Central Nervous System) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see Clinical Studies (14.1) ]. 1.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see Clinical Studies (14.2) ].

2 DOSAGE AND ADMINISTRATION CNS – Adults and Pediatrics; 2 to 16 years of age: 0.2 mL/kg (0.1 mmol/kg) ( 2.1 , 2.4 ) Body – Adults and Pediatrics; 2 to 16 years of age: Kidney: 0.1 mL/kg (0.05 mmol/kg) Intrathoracic, intra-abdominal, and pelvic cavities: 0.2 mL/kg (0.1 mmol/kg) ( 2.2 , 2.4 ) 2.1 CNS (Central Nervous System) Adults: The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. Pediatric Patients (2 to 16 years of age): The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection [see Dosage and Administration (2.3) ]. 2.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) Adult and Pediatric Patients (2 to 16 years of age): For imaging the kidney, the recommended dose of OMNISCAN is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) [see Dosage and Administration (2.3) ]. 2.3 Dosage Chart BODY WEIGHT PEDIATRIC ADULTS 0.05 0.1 0.05 0.1 kg lb (mmol/kg) (mmol/kg) VOLUME (mL) VOLUME (mL) 12 26 1.2 2.4 - - 14 31 1.4 2.8 - - 16 35 1.6 3.2 - - 18 40 1.8 3.6 - - 20 44 2 4 - - 22 48 2.2 4.4 - - 24 53 2.4 4.8 - - 26 57 2.6 5.2 - - 28 62 2.8 5.6 - - 30 66 3 6 - - 40 88 4 8 4 8 50 110 5 10 5 10 60 132 6 12 6 12 70 154 7 14 7 14 80 176 8 16 8 16 90 198 - - 9 18 100 220 - - 10 20 110 242 - - 11 22 120 264 - - 12 24 130 The heaviest patient in clinical studies weighed 136 kg. 286 - - 13 26 2.4 Dosing Guidelines Inspect OMNISCAN visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not use the solution if it is discolored or particulate matter is present. Draw OMNISCAN into the syringe and use immediately. Discard any unused portion of OMNISCAN Injection. To ensure complete delivery of the desired volume of contrast medium, follow the injection of OMNISCAN with a 5 mL flush of 0.9% sodium chloride. Complete the imaging procedure within 1 hour of administration of OMNISCAN.

4 CONTRAINDICATIONS OMNISCAN is contraindicated in patients with: Chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m 2 ) or acute kidney injury Prior hypersensitivity to OMNISCAN Patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ) or acute kidney injury ( 4 ).

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Anaphylactoid and other serious hypersensitivity reactions including fatal reactions have occurred particularly in patients with history of allergy or drug reactions. 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 ). Acute Renal Failure: Acute renal failure has occurred in patients with preexisting renal insufficiency. Use the lowest necessary dose of OMNISCAN and evaluate renal function in these patients ( 5.5 ). 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 OMNISCAN have not been established with intrathecal use. OMNISCAN is not approved for intrathecal use [see Dosage and Administration (2.1 , 2.2) ]. 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 OMNISCAN 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 OMNISCAN to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 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 OMNISCAN administration to GE HealthCare (1-800-654-0118) 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. 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. When administering a GBCA, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent prior to any readministration [see Boxed Warning , Contraindications (4) , Clinical Pharmacology (12.2) and Dosage and Administration (2) ]. 5.3 Hypersensitivity Reactions Anaphylactoid and anaphylactic reactions, with cardiovascular, respiratory and/or cutaneous manifestations, resulting in death have occurred. Personnel trained in resuscitation techniques and resuscitation equipment should be present prior to OMNISCAN administration. If a hypersensitivity reaction occurs, stop OMNISCAN Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after OMNISCAN Injection. 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 [see Use in Specific Populations (8.1 , 8.4) ], 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 Renal Failure In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of OMNISCAN Injection. The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insufficiency. Acute renal failure was observed in < 1% of patients in OMNISCAN clinical studies [see Adverse Reactions (6) ]. OMNISCAN is cleared by glomerular filtration. Hemodialysis also enhances OMNISCAN clearance [see Use in Specific Populations (8.5 , 8.6) ]. 5.6 Impaired Visualization of Lesions Detectable with Non-contrast MRI Paramagnetic contrast agents such as OMNISCAN might impair the visualization of lesions which are seen on the non-contrast MRI. This may be due to effects of the paramagnetic contrast agent, or imaging parameters. Exercise caution when OMNISCAN MRI scans are interpreted in the absence of a companion non-contrast MRI. 5.7 Laboratory Test Findings Asymptomatic, transitory changes in serum iron have been observed. The clinical significance is unknown. OMNISCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12 to 24 hours. In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN. After patients receive OMNISCAN, careful attention should be used in selecting the type of method used to measure calcium.

7 DRUG INTERACTIONS Specific drug interaction studies have not been conducted.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the label: Nephrogenic systemic fibrosis [see Warnings and Precautions (5.2) ] Hypersensitivity reactions [see Warnings and Precautions (5.3) ] Acute Renal Failure [see Warnings and Precautions (5.5) ] The most frequent adverse reactions (≤ 3%) observed during OMNISCAN adult clinical studies were nausea, headache, and dizziness ( 6.1 ) Serious or life-threatening reactions include: cardiac failure, arrhythmia and myocardial infarction ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact GE HealthCare at 1-800-654-0118 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 practice. Adverse Reactions in Adult Patients In clinical studies 1,160 patients were exposed to OMNISCAN. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity. The following adverse reactions occurred in 1% or less of patients: Application Site Disorders: Injection site reaction. Autonomic Nervous System Disorders: Vasodilation. Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. Hearing and Vestibular Disorders: Tinnitus. Liver and Biliary System Disorders: Abnormal hepatic function. Musculoskeletal System Disorders: Arthralgia, myalgia. Respiratory System Disorders: Rhinitis, dyspnea. Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. Special Senses, Other Disorders: Taste loss, taste perversion. Urinary System Disorders: Acute reversible renal failure. Vision Disorders: Abnormal vision. Adverse Reactions in Pediatric Patients In the 97 pediatric patients in CNS studies with OMNISCAN [see Clinical Studies (14.1) ] and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of OMNISCAN or other 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 : Nephrogenic Systemic Fibrosis (NSF) 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 . Nervous System Disorders: Convulsions in patients with and without a history of convulsions or brain lesions. Respiratory, Thoracic and Mediastinal Disorders : Acute respiratory distress syndrome, pulmonary edema Renal and Urinary System Disorders: In patients with pre-existing renal insufficiency: acute renal failure, renal impairment, blood creatinine increased . Skin : Gadolinium-associated plaques.

8.1 Pregnancy Risk Summary GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data ) . In animal reproduction studies, no adverse fetal effects were observed with administration of gadodiamide to pregnant rats during organogenesis at doses 1.3 times the maximum human dose based on body surface area (see Data ) . Because of the potential risks of gadolinium to the fetus, use OMNISCAN only if imaging is essential during pregnancy and cannot be delayed. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data Contrast enhancement is visualized in the human placenta and fetal tissues after maternal GBCA administration. Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy. Animal Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one-month postnatal age. Reproductive Toxicology Gadodiamide has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to gadodiamide administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made.