EOVIST^® (gadoxetate disodium) Injection

Important Information about Nephrogenic Systemic Fibrosis (NSF)

Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy (NFD), is a systemic disease typically characterized by fibrosis of the skin and other connective tissues. It was first described in medical literature in 2000 with the first reported case dating back to 1997.

Patients with NSF have tight, rigid skin, making it difficult to bend joints. NSF may also result in systemic fibrosis, or scarring, of body organs resulting in the inability of body organs to work properly, and can lead to death. Symptoms may include thickening of the skin, swelling of the lower extremities, redness, pruritus, and burning sensations. In approximately 5% of patients the course of the disease is rapidly progressive and may potentially lead to a fatal outcome. Definitive diagnosis of NSF requires deep skin biopsy and histopathology.

Based on current information, it appears that males and females are affected in approximately equal numbers, with onset generally during middle age although pediatric cases have also been reported. Currently, there is no known cure for NSF. Improving renal function seems to slow or arrest NSF and may even result in a gradual reversal.²

The precise etiology of NSF is unknown, but the cause of the disease is most likely multifactorial. Although the particular combination and severity of co-factors necessary have not been identified, gadolinium-based contrast agents have reportedly been associated with an increased risk of NSF. After performing a review of post-marketing reports, sponsor-supplied information, and published literature, the FDA found that all patients who had acquired NSF after being administered an MR contrast agent had exhibited renal insufficiency prior to contrast administration, with the vast majority of affected patients receiving hemodialysis.²

The FDA issued its first Public Health Advisory on NSF in June 2006, and updated that information in December 2006. In May 2007, the agency requested that all GBCAs marketed in the US include a boxed warning and additional warnings about NSF in the product labels.³ Bayer HealthCare Pharmaceuticals implemented those changes and worked with other GBCA manufacturers to issue a Dear Healthcare Provider letter in September 2007 about the potential risk of Nephrogenic Systemic Fibrosis (NSF) in association with the use of GBCAs.

In September 2010, the FDA requested labeling revisions and announced the following conclusions:

GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs
- The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30mL/min/1.73m²) as well as patients with AKI
- The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m²)
Health care providers should avoid the use of GBCAs among patients with impaired renal function unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities
- 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
- Do not administer MAGNEVIST, Omniscan, or OptiMARK in patients with AKI or chronic, severe kidney disease.⁴ These three GBCA drugs are contraindicated in these patients.
- Monitor for signs and symptoms of NSF after a GBCA is administered to patients suspected or known to have impaired renal function

The current package insert for Eovist injection and the full text of the boxed warning and warnings and precautions section can be found here: vials.

Bayer HealthCare Pharmaceuticals urges healthcare providers and patients to report any adverse event information to either: the FDA via the MedWatch program by phone (1-800-FDA-1088), by fax (1-800-FDA-0178), or by the Internet (www.fda.gov/medwatch).

Preclinical studies and interdisciplinary discussions with NSF experts are ongoing to investigate the possible association between GBCAs and NSF, as well as to evaluate in more detail the pathogenesis of this disease entity and potential differences in risk among the various Gd-based MR contrast agents.

INDICATIONS and IMPORTANT SAFETY INFORMATION

EOVIST (gadoxetate disodium) Injection

INDICATIONS AND USAGE

Eovist^® (gadoxetate disodium) Injection is a gadolinium-based contrast agent indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease.

IMPORTANT SAFETY INFORMATION

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.

The risk for NSF appears highest among patients with:
- chronic, severe kidney disease (GFR < 30 mL/min/1.73m²), 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 Eovist dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration (see WARNINGS AND PRECAUTIONS).

The possibility of life-threatening anaphylactoid/hypersensitivity reactions with cardiovascular, respiratory and/or cutaneous manifestations should always be considered.
The most frequent (≥0.5%) adverse reactions associated with the use of Eovist are nausea, headache, feeling hot, dizziness, and back pain.

Please see full prescribing information.

GADAVIST (gadobutrol) Injection

INDICATIONS AND USAGE

Gadavist^® (gadobutrol) injection is a gadolinium-based contrast agent indicated for intravenous use in diagnostic magnetic resonance imaging (MRI) in adults and children (2 years of age and older) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system.

IMPORTANT SAFETY INFORMATION

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

The risk for NSF appears highest among patients with:
- Chronic, severe kidney disease (GFR < 30 mL/min/1.73m²), 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 Gadavist 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].

The possibility of serious or life-threatening hypersensitivity, anaphylactic or anaphylactoid reactions associated with cardiovascular, respiratory, or cutaneous manifestations, including death, should always be considered.
The most frequent adverse reactions associated with Gadavist in clinical studies were headache, nausea, injection site reaction, dysgeusia and feeling hot.

Please see full prescribing information.

MAGNEVIST (gadopentetate dimeglumine) Injection

INDICATIONS AND USAGE

Central Nervous System: Magnevist^® (gadopentetate dimeglumine) Injection is indicated for use with magnetic resonance imaging (MRI) in adults and pediatric patients (2 years of age and older) to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine and associated tissues. Magnevist has been shown to facilitate visualization of intracranial lesions including but not limited to tumors.

Extracranial/Extraspinal Tissues: Magnevist is indicated for use with MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the head and neck.

Body: Magnevist is indicated for use with MRI in adults and pediatric patients (2 years of age and older) to facilitate the visualization of lesions with abnormal vascularity in the body (excluding the heart).

IMPORTANT SAFETY INFORMATION

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Do not administer Magnevist to patients with:
- chronic, severe kidney disease (GFR < 30 mL/min/1.73m²), or
- acute kidney injury (see CONTRAINDICATIONS)
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).

Magnevist is contraindicated in patients with chronic, severe kidney disease (glomerular filtration rate, GFR < 30 mL/min/1.73m²), or acute kidney injury.
The possibility of serious or life-threatening hypersensitivity, anaphylactic or anaphylactoid reactions associated with cardiovascular, respiratory, or cutaneous manifestations, including death, should always be considered.
Caution should be exercised in patients with renal impairment due to the possibility of further deterioration in renal function.
Cases of phlebitis and thrombophlebitis have been reported; assessment of the dosed limb for the development of injection site reactions is recommended.
In clinical trials, the most frequently reported adverse reactions included headache, nausea, injection site coldness/localized coldness and dizziness.

Please see full prescribing information.

ULTRAVIST^® (iopromide) Injection

INDICATIONS AND USAGE

Ultravist^® (iopromide) Injection is an iodinated contrast agent indicated for:

Intra-arterial Procedures*: 300 mg I/mL for cerebral arteriography and peripheral arteriography; 370 mg I/mL for coronary arteriography and left ventriculography, visceral angiography, and aortography.

Intravenous Procedures*: 240 mg I/mL for peripheral venography; 300 mg I/mL for excretory urography; 300 mg I/mL and 370 mg I/mL for contrast Computed Tomography (CT) of the head and body (intrathoracic, intraabdominal and retroperitoneal regions) for the evaluation of neoplastic and non-neoplastic lesions. The usefulness of contrast enhancement for the investigation of the retrobulbar space and of low grade or infiltrative glioma has not been demonstrated.

* For information on the concentrations and doses for the Pediatric Population [see Dosage and Administration (2.3) and Use in Specific Populations (8.4) in the full prescribing information].

IMPORTANT SAFETY INFORMATION

WARNING: NOT FOR INTRATHECAL USE

Inadvertent intrathecal administration may cause death, convulsions, cerebral hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema.

CONTRAINDICATIONS

Ultravist Injection is contraindicated for intrathecal use.

Preparatory dehydration (e.g. prolonged fasting and the administration of a laxative before Ultravist Injection) is contraindicated in pediatric patients because of risk of renal failure.

SELECTED WARNINGS AND PRECAUTIONS

Life-threatening or fatal anaphylactoid reactions may occur during or after Ultravist administration, particularly in patients with allergic disorders.
Acute kidney injury, including renal failure, may occur after intravascular administration of Ultravist. Risk factors include: pre-existing renal insufficiency, dehydration, diabetes mellitus, congestive heart failure, advanced vascular disease, elderly age, concomitant use of nephrotoxic or diuretic medications, multiple myeloma/paraproteinemia, repetitive and/or large doses of Ultravist. Use the lowest necessary dose of Ultravist in patients with renal impairment. Adequately hydrate patients prior to and following Ultravist administration.
Hemodynamic disturbances including shock and cardiac arrest may occur during or shortly after administration of Ultravist.
Angiography may be associated with local and distal organ damage, ischemia, thromboembolism and organ failure. In angiographic procedures, consider the possibility of dislodging plaques or damaging or perforating the vessel wall. The physicochemical properties of the contrast agent, the dose and the speed of injection can influence the reactions.
Extravasation of Ultravist may cause tissue necrosis and/or compartment syndrome, particularly in patients with severe arterial or venous disease.
Thyroid storm has occurred after the intravascular use of iodinated contrast agents in patients with hyperthyroidism, or with autonomously functioning thyroid nodule. Evaluate the risk in such patients before use of any iodinated contrast agent.
Administer iodinated contrast agents with extreme caution in patients with known or suspected pheochromocytoma. Inject the minimal amount of contrast necessary.
Contrast agents may promote sickling in individuals who are homozygous for sickle cell disease when administered intravascularly.

MOST COMMON ADVERSE REACTIONS
Most common adverse reactions (>1%) are headache, nausea, injection site and infusion site reactions, vasodilatation, vomiting, back pain, urinary urgency, chest pain, pain, dysgeusia, and abnormal vision.

Please see full prescribing information.

References:

1.Runge VM, Schaible TF, Goldstein HA, et al. Gd DTPA. Clinical efficacy. Radiographics. 1988;8(1):147-159.

2.Information for Healthcare Professionals Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). Retrieved 2010, from FDA US Food and Drug Administration: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationf.

3.FDA Requests Boxed Warning for Contrast Agents Used to Improve MRI Images. Retrieved 2010, from FDA US Food and Drug Administration: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108919.htm.

4.FDA Drug Safety Communication: New warnings for using gadolinium-based contrast agents in patients with kidney dysfunction. FDA Website. http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm. Accessed 10/25/2010.

Bayer Links

EOVIST^® (gadoxetate disodium) Injection

Important Information about Nephrogenic Systemic Fibrosis (NSF)