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/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ProHance administration to Bracco Diagnostics (1-800-257-8151) or FDA (1-800-FDA-1088 or
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. For patients at highest risk for NSF, do not exceed the recommended ProHance 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).
Deoxygenated sickle erythrocytes have been shown in in vitro studies to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by ProHance may possibly potentiate sickle erythrocyte alignment. ProHance in patients with sickle cell anemia and other hemoglobinopathies has not been studied.
Patients with other hemolytic anemias have not been adequately evaluated following administration of ProHance to exclude the possibility of increased hemolysis.
Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders should be closely observed during the procedure and for several hours after drug administration. (See
Gadoteridol is cleared from the body by glomerular filtration. The hepato-biliary enteric pathway of excretion has not been demonstrated with ProHance®. Dose adjustments in renal or hepatic impairment have not been studied. Therefore, caution should be exercised in patients with either renal or hepatic impairment.
In a patient with a history of grand mal seizure, the possibility to induce such a seizure by ProHance® is unknown.
The possibility of a reaction, including serious, life threatening, or fatal, anaphylactic or cardiovascular reactions, or other idiosyncratic reactions (see
ADVERSE REACTIONS), should always be considered, especially in those patients with a history of a known clinical hypersensitivity or a history of asthma or other allergic respiratory disorders.
Diagnostic procedures that involve the use of contrast agents should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed.
When ProHance (Gadoteridol) Injection is to be injected using nondisposable equipment, scrupulous care should be taken to prevent residual contamination with traces of cleansing agents. After ProHance is drawn into a syringe, the solution should be used immediately.
Repeat Procedures: Repeated procedures have not been studied. Sequential use during the same diagnostic session has only been studied in central nervous system use. (See
under CLINICAL PHARMACOLOGY and
under DOSAGE AND ADMINISTRATION).
Information for patients:
Patients scheduled to receive ProHance should be instructed to inform their physician if the patient;
- is pregnant or breast feeding
- has anemia or diseases that affect the red blood cells
- has a history of renal or hepatic disease, seizure, hemoglobinopathies, asthma or allergic respiratory diseases.
has recently received a GBCA.
GBCAs increase the risk for NSF among patients with impaired elimination of the drugs. To counsel patients at risk for NSF:
Describe the clinical manifestations of NSF
Describe procedures to screen for the detection of renal impairment
Instruct the patients to contact their physician if they develop signs or symptoms of NSF following ProHance administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness.
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
No animal studies have been performed to evaluate the carcinogenic potential of
gadoteridol or potential effects on fertility.
ProHance did not demonstrate genotoxic activity in bacterial reverse mutation
assays using Salmonella typhimurium and Escherichia coli, in a mouse lymphoma
forward mutation assay, in an in vitro cytogenetic assay measuring chromosomal
aberration frequencies in Chinese hamster ovary cells, nor in an in vivo mouse
micronucleus assay at intravenous doses up to 5.0 mmol/kg.
Pregnancy Category C
ProHance administered to rats at 10 mmol/kg/day (33 times the maximum recommended human dose of 0.3 mmol/kg or 6 times the human dose based on a mmol/m2 comparison) for 12 days during gestation doubled the incidence of postimplantation loss. When rats were administered 6.0 or 10.0 mmol/ kg/day for 12 days, an increase in spontaneous locomotor activity was observed in the offspring. ProHance increased the incidence of spontaneous abortion and early delivery in rabbits administered 6 mmol/kg/day (20 times the maximum recommended human dose or 7 times the human dose based on a mmol/m2 comparison) for 13 days during gestation.
There are no adequate and well-controlled studies in pregnant women. ProHance (Gadoteridol) Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ProHance is administered to a nursing woman.
Safety and efficacy in children under the age of 2 years have not been established. The safety and efficacy of doses > 0.1 mmol/kg; and sequential and/or repeat procedures has not been studied in children. (See
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION