"The U.S. Food and Drug Administration is requiring that gadolinium-based contrast agents (GBCAs) carry new warnings on their labels about the risk of a rare and potentially fatal condition known as nephrogenic systemic fibrosis (NSF), if the drug"...
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 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. Do not administer OptiMARK to these patients. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 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 OptiMARK administration to Mallinckrodt Inc. (1-800-778-7898) 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 chronic kidney disease (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 OptiMARK, do not exceed the recommended dose and allow a sufficient period of time for elimination of the drug prior to any re-administration [see DOSAGE AND ADMINISTRATION].
Acute Kidney Injury (AKI)
In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.
Severe hypersensitivity reactions including anaphylaxis have been observed with administration of gadolinium products including OptiMARK. Before administering OptiMARK ensure the availability of resuscitation equipment and personnel trained in resuscitation techniques. Patients with a history of allergy, drug reactions or other hypersensitivity-like disorders may be at greater risk and should be closely observed during the procedure and for several hours after drug administration. If a reaction occurs, stop OptiMARK and immediately begin appropriate therapy including resuscitation.
Interference With Laboratory Testing
Interference by OptiMARK in the measurements of serum iron, copper and zinc has been observed. OptiMARK causes interference in the measurement of serum calcium using the ortho-cresophthalin complexone (OCP) colorimetric method. In the presence of OptiMARK, OCP produces an erroneous, low value for serum calcium. The magnitude of this artifact is proportional to the concentration of OptiMARK in the blood, and accurate values can be obtained approximately 90 minutes following injection. In patients with renal insufficiency, clearance of OptiMARK is slowed and the interference with calcium determination by OCP is prolonged. Neither the arsenazo III dye system nor the inductively coupled plasma mass spectroscopy methods for calcium assay are affected by OptiMARK.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies have not been performed to evaluate the carcinogenic potential of gadoversetamide. The results of the following genotoxicity assays were negative: Salmonella/E. Coli reverse mutation (Ames) assay, mouse lymphoma mutagenesis assay, and the in vivo mammalian micronucleus assay. The in vitro CHO chromosome aberration assay without metabolic activation was positive.
Gadoversetamide administered to rats in a fertility study was shown to have irreversible reduction and degeneration of spermatocytes in testes and epididymides, and impaired male fertility following intravenous doses of 2.0 mmol/kg/day (4 times the human dose based on body surface area) for 7 weeks. These effects were not observed at dose of 0.5 mmol/kg/day (1 times the human dose based on body surface area).
In a separate 28-day repeat dose study in rats, gadoversetamide was shown to have irreversible reduction of male reproductive organ weights, degeneration of the germinal epithelium of the testes, presence of germ cells in the epididymides, and reduced sperm count following daily intravenous doses of 3.0 mmol/kg/day (6 times the human dose based on body surface area). These effects were not observed at 0.6 mmol/kg/day (1 times the human dose based on surface area). These effects were not observed in similar studies conducted in dogs.
In a single dose study in rats, gadoversetamide did not produce adverse effects on the male reproductive system 24 hours and 14 days after intravenous administration of 0.5 to 15 mmol/kg (1 to 25 times the human dose based on body surface area).
Use In Specific Populations
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. OptiMARK should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Gadoversetamide administered to rats reduced neonatal weights from birth through weaning at maternal doses of 0.5 mmol/kg/day (1 times the human dose based on body surface area) for 5 weeks (including gestation) and paternal doses of 0.5 mmol/kg/day for 12 weeks. This effect was not observed at 0.1 mmol/kg (0.2 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.
Gadoversetamide injection caused a reduced mean fetal weight, abnormal liver lobation, delayed ossification of sternebrae, and delayed behavioral development (startle reflex and air righting reflex) in fetuses from female rats dosed with 4.9 mmol/kg/day (10 times the human dose based on body surface area) on days 7 through 17 of gestation. These effects were not observed at 0.7 mmol/kg/day (1 times the human dose based on body surface area). Maternal toxicity was observed at 4.9 mmol/kg/day.
Gadoversetamide injection caused forelimb flexures and cardiovascular changes in fetuses from female rabbits dosed with 0.4 and 1.6 mmol/kg/day (respectively, 1 and 4 times the human dose based on body surface area) on gestation days 6 through 18. The cardiovascular changes were malformed thoracic arteries, a septal defect, and abnormal ventricle. These effects were not observed at 0.1 mmol/kg/day (0.3 times the human dose based on body surface area). Maternal toxicity was not observed at any dose.
Radiolabeled gadoversetamide (153Gd) was excreted in the milk of lactating rats receiving a single intravenous dose of 0.1 mmol/kg. Women should discontinue nursing and discard breast milk up to 72 hours after OptiMARK administration [see CLINICAL PHARMACOLOGY].
The safety and effectiveness of OptiMARK in pediatric patients have not been established. Pediatric patients may be particularly vulnerable to adverse GBCA reactions due to renal immaturity or unrecognized renal insufficiency.
Since gadoversetamide is cleared from the body by glomerular filtration, the risk of adverse reactions may be greater in patients with impaired renal function (GFR ≥ 30 and < 90 mL/min/1.73m²). Due to the risk for NSF, estimate the GFR through laboratory testing for patients > 60 years of age [see WARNINGS AND PRECAUTIONS].
A single intravenous dose of 0.1 mmol/kg of OptiMARK was administered to 28 patients (17 men and 11 women) with impaired renal function (mean serum creatinine of 2.4 mg/dL). Sixteen patients had concurrent central nervous system or liver pathology. Renal impairment was shown to delay the elimination of gadoversetamide (see Table 3). The mean cumulative urinary excretion of gadoversetamide at 72 hours was approximately 93.5% for renally impaired patients and 95.8% for subjects with normal renal function. Dose adjustments in renal impairment have not been studied. OptiMARK has been shown to be removed from the body by hemodialysis [see CLINICAL PHARMACOLOGY].
A single intravenous dose of 0.1 mmol/kg of OptiMARK was administered to 4 patients (2 men and 2 women) with impaired hepatic function. Hepatically impaired patients with normal renal function had plasma kinetics similar to normal subjects (see Table 3).
Table 3 : Elimination Profiles of Normal, Renally
Impaired and Hepatically Impaired Men and Women (mean ± SD)
|Population||Elimination t½ (hours)|
(N = 52)
(N = 48)
|Healthy Volunteers||1.73 ± 0.31 (N = 8)||1.73 ± 0.40 (N = 4)|
|Normal Patients||1.90 ± 0.50 (N = 25)||1.94 ± 0.57 (N = 31)|
|Renally Impaired||8.74 ± 5.14 (N = 17)||6.91 ± 2.46 (N = 11)|
|Hepatically Impaired||2.09 ± 0.03 (N = 2)||2.35 ± 1.09 (N = 2)|
Last reviewed on RxList: 12/15/2014
Additional OptiMARK Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.