Gadodiamide is a nonionic, gadolinium-based paramagnetic contrast agent (GBCA) used during magnetic resonance imaging (MRI) to enhance visualization of abnormal vascularity within the central nervous system (CNS), thoracic, abdominal, or pelvic cavities, or the retroperitoneal space. Like all GBCAs, gadodiamide carries a black box warning for nephrogenic systemic fibrosis (NSF). NSF is a serious condition that may result in fatal or debilitating fibrosis of the skin, muscle, and internal organs. The propensity to cause NSF differs among available GBCAs; most unconfounded cases have been reported with gadodiamide, gadopentetate dimeglumine, and gadoversetamide.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Hypersensitivity reactions may occur. Prior to administration, assess all patients for previous reactions to contrast media. Trained personnel and therapies used to treat hypersensitivity reactions (epinephrine, antihistamines, and corticosteroids) should be readily available. Observe patient for signs and symptoms of hypersensitivity reactions during and for several hours after administration.
Route-Specific Administration
Injectable Administration
-Visually inspect for particulate matter and discoloration prior to administration. Solution is clear, colorless to slightly yellow. Do not use the solution if discolored or if particulate matter is present.
Intravenous Administration
Single Dose Vials
-Draw gadodiamide into the syringe and use immediately.
-Storage: The product contains no antimicrobial preservatives. Discard any unused product.
Pharmacy Bulk Package
-In a suitable environment, such as a laminar flow hood, penetrate the container closure of the pharmacy bulk package only once with an appropriate transfer device.
-Immediately withdraw the container contents and label the dose with the supplied peel-off label that identifies the contents and indicates the dose is NOT for intrathecal use.
-If delay is unavoidable, complete the fluid transfer as soon as possible.
-Use each individual dose immediately after withdrawal from the pharmacy bulk package.
-Storage: Once a bulk package container closure is punctured, keep the container in the aseptic area and at room temperature; do not exceed 30 degrees C or 86 degrees F. Discard any unused doses remaining in a pharmacy bulk package 8 hours after initial closure penetration. Discard any unused portion of any dose that is not used immediately. The product contains no antimicrobial preservatives.
IV Push
-Immediately administer as an IV bolus injection.
-To ensure complete delivery of the desired volume of contrast medium, follow the gadodiamide injection with a 5 mL flush of 0.9% Sodium Chloride Injection.
-Complete imaging procedure within 1 hour of the gadodiamide injection.
-Usual safety rules customary for magnetic resonance procedures must be observed.
Cases of nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD) have been reported after administration of gadolinium-based contrast agents (GBCAs), including gadodiamide, in patients with moderate to severe renal impairment. Most reports of NSF/NFD have involved the use of gadodiamide, gadopentetate dimeglumine, and gadoversetamide. In a retrospective study of 370 patients with severe renal insufficiency, the estimated risk for NSF/NFD was 4%. In a report by the CDC, a case-control study from a single hospital found that the risk of NSF/NFD is higher in patients undergoing peritoneal dialysis compared to hemodialysis (estimated 4.6 cases/100 peritoneal dialysis patients vs. 0.61 cases/100 hemodialysis patients). The mechanism of NSF/NFD in patients receiving GBCAs is unknown; however, dissociation of gadolinium from its chelating agent after intravenous injection is hypothesized. The free gadolinium ion then binds to anions such as phosphate, resulting in an insoluble precipitate that deposits in various tissues, and a fibrotic reaction ensues. NFD is characterized by burning, itching, swelling, scaling, tightening, and hardening of the skin, red or dark patches on the skin, stiffness in joints, resulting in trouble moving, straightening or bending the arms, legs or feet; muscle weakness, pain in hip bones or ribs. NSF involves fibrosis of organs (e.g., heart, liver, lungs) and can lead to death. Diagnosis of NSF/NFD is confirmed by skin biopsy. Patients at risk for NSF due to exposure to GBCAs include certain patients with renal insufficiency and those receiving repeated or higher than recommended doses. Although the efficacy of hemodialysis for the prevention of NSF/NFD is unknown, health care providers may consider prompt initiation of a hemodialysis session after administration of GBCAs to aid in the elimination of the agent from the body for those patients already receiving hemodialysis. Hemodialysis is preferred to peritoneal dialysis as available data indicate that continuous ambulatory peritoneal dialysis may not be as efficient as hemodialysis in eliminating GBCAs. Treatment options for NSF/NFD are minimal; patients should be enrolled in physical therapy programs. Limited data in support of plasmapheresis or photopheresis are promising.
Administration of gadodiamide to patients with preexisting renal insufficiency has resulted in worsening renal function and acute renal failure (unspecified) (less than 1%) requiring dialysis. Most cases developed within 48 hours of gadodiamide administration. In patients with preexisting renal insufficiency, acute renal failure, renal impairment, and increased serum creatinine have also been reported in postmarketing experience. The risk of renal failure may increase with increasing doses of gadolinium contrast; therefore, use of the lowest dose necessary for adequate imaging and evaluate renal function in patients with renal insufficiency.
During clinical trials, headache and dizziness were reported in 3% or less of gadodiamide recipients. The majority of these reactions were mild to moderate intensity. Other more serious neurologic adverse events reported in 1% or less of gadodiamide-treated patients included seizures (including grand mal), ataxia, abnormal coordination, paresthesias, tremor, multiple sclerosis exacerbation (characterized by sensory and motor disturbances), and aggravated migraine. During postmarketing experience, inadvertent intrathecal administration has resulted in convulsions, coma, paresthesia, and paresis. Convulsions were also reported with intravenous use in patients with and without a history of convulsions or brain lesions.
During clinical trials, nausea was reported in 3% or less of gadodiamide recipients. The majority of these reactions were mild to moderate intensity. Other gastrointestinal adverse events reported in 1% or less of gadodiamide-treated patients included abdominal pain, diarrhea, eructation, melena, vomiting, and xerostomia. Abnormal hepatic function was also reported in 1% or less of gadodiamide recipients.
Anaphylactic and anaphylactoid reactions (less than 1%), with cardiovascular, respiratory, and cutaneous manifestations, resulting in death have occurred with gadodiamide. Ensure personnel trained in resuscitation and resuscitation equipment are readily available before administering gadodiamide. If a hypersensitivity reaction occurs, stop the gadodiamide injection and begin appropriate therapy. Observe patients closely and up to several hours after gadodiamide administration. Other general adverse reactions reported in 1% or less of gadodiamide-treated patients included fever, hot flashes, rigors, fatigue, malaise, pain, and syncope. Fatigue, asthenia, and pain syndromes with variable onsets and durations have also been reported after gadolinium-based contrast agent administration.
An injection site reaction was reported in 1% or less of gadodiamide recipients during clinical trials. Other dermatologic adverse events reported in 1% or less of gadodiamide-treated patients included rash, erythematous rash, urticaria, pruritus, and diaphoresis. Gadolinium-associated skin plaques have been reported during postmarketing use.
Cardiovascular adverse events reported in 1% or less of gadodiamide recipients during clinical trials included heart failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, peripheral vasodilation, chest pain (unspecified), and deep thrombo-phlebitis.
Adverse sensory reactions reported in 1% or less of gadodiamide recipients during clinical trials included tinnitus, ageusia, dysgeusia, and visual impairment.
Dyspnea and rhinitis were reported in 1% or less of gadodiamide recipients during clinical trials.
Arthralgia and myalgia were reported in 1% or less of gadodiamide recipients during clinical trials.
Diagnostic procedures that involve use of contrast agents, such as gadodiamide, should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. As with any paramagnetic contrast agent, use of gadodiamide during contrast enhanced magnetic resonance imaging (MRI) could impair visualization of lesions seen on non-contrast MRI. Caution must be used when contrast-enhanced imaging is interpreted without a companion non-contrast image. In addition, gadolinium deposits may remain in patients' bodies for months to years after gadolinium-based contrast agent (GBCA) receipt. Bone has been identified as the main reservoir, retaining the highest concentration of gadolinium (nanomoles per gram of tissue) for the longest duration of time. Other organs which retain lesser amounts of gadolinium include the brain, skin, kidney, liver, and spleen. The consequences of gadolinium retention in the brain have not been established; however, retention in the skin and kidney has been associated with pathologic clinical consequences in patients with impaired renal function. There are rare reports of pathologic skin changes in patients with normal renal function. Other patients who may be at higher risk for gadolinium retention include patients requiring multiple lifetime doses, pregnant women, pediatric patients, and patients with inflammatory conditions. Limit repeated GBCA imaging studies, particularly closely spaced MRI studies, but do not defer or avoid necessary GBCA MRI scans. When choosing a GBCA, consider the retention characteristics of each agent. In general, linear GBCAs result in more retention and retention for longer periods of time than do macrocyclic GBCAs. More specifically, at equivalent doses, use of gadodiamide or gadoversetamide results in higher gadolinium concentrations remaining in the body than gadoxetate disodium, gadopentetate dimeglumine, or gadobenate dimeglumine. Gadolinium concentrations in the body are lowest after administration of gadoterate meglumine, gadobutrol, and gadoteridol. Instruct patients to inform their health care professional about all medical conditions, including if pregnant or thinking about becoming pregnant, dates and numbers of any previous gadolinium-enhanced MRIs, and history of kidney problems.
Administration to patients with a prior hypersensitivity to gadodiamide is contraindicated. The drug has been associated with serious, and sometimes fatal, anaphylactoid/anaphylactic reactions, with cardiovascular, respiratory, and/or cutaneous manifestations. According to the American College of Radiology (ACR), the risk of adverse reactions is approximately 8-times higher in patients with a previous reaction to gadolinium-based contrast media; the subsequent reactions have the potential to be more severe than the first. Other individuals at increased risk include those with a history of iodinated radiopaque contrast media hypersensitivity, asthma, atopy (including hay fever, food allergies, and drug allergies) or other allergic disorders. Prior to administration, assess hypersensitivity risk factors in all potential drug recipients. The manufacturer recommends appropriate facilities (trained personnel and therapies) be available for coping with the emergency treatment of severe reactions, and patients be closely observed for signs and symptoms of a hypersensitivity reaction during and for several hours after drug administration. One group of authors recommends taking similar precautions to those that are taken in patients who have previously reacted to iodinated radiopaque contrast media that require subsequent doses. First, the necessity of contrast enhancement during MRI should be determined. If it is determined that contrast enhancement outweighs any potential risk, the intensity of a previous reaction (to either iodinated or gadolinium-based contrast media) should guide precautionary measures. If the previous reaction to contrast media was mild or nonallergic, use of a different or low-osmolar (i.e., gadoteridol or gadodiamide) agent is recommended. If the previous reaction to contrast media was moderate or severe, premedication with steroids (e.g., prednisone or equivalent given 13, 7, and 1 hour prior to the exam; adult dose, 50 mg PO; pediatric dose, 0.5 to 0.7 mg/kg PO, up to 50 mg) and antihistamines (e.g., diphenhydramine given 1 hour prior to the exam; adult dose 50 mg IV/IM/PO; pediatric dose 1.25 mg/kg PO, up to 50 mg) along with the use of a different or low-osmolar contrast agent is recommended.
Gadodiamide use is contraindicated in chronic, severe kidney disease (glomerular filtration rate [GFR] less than 30 mL/minute/m2) or acute kidney injury. Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadolinium-based contrast agents (GBCAs), such as gadodiamide. NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF are those with chronic, severe renal disease or renal failure (GFR less than 30 mL/minute/1.73 m2) and patients with acute renal injury. Avoid use of GBCAs in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. Use of higher than recommended doses or repeated administration may increase the risk for NSF; therefore, administer the lowest dose necessary for adequate imaging and, if needed, only repeat the dose after a sufficient period of time has passed for elimination of the agent from the body. Gadodiamide is removed by hemodialysis. For patients receiving hemodialysis, it may be prudent to dialyze patients after receiving the contrast agents, although a relationship between dialysis and prevention of NSF has not been determined. Of note, hemodialysis is the preferred method of dialysis as continuous ambulatory peritoneal dialysis does not appear to be as effective in eliminating GBCAs. All patients should be screened for evidence of renal dysfunction by obtaining a medical history and/or laboratory results prior to the administration of GBCAs. Acute renal injury occurs commonly after surgery, severe infection, injury, or drug-induced renal toxicity. In patients with acute renal injury, serum creatinine concentrations and estimated GFR may not reliably assess renal function; therefore, obtaining a medical history in these patients is of utmost importance. For patients at risk of chronic renal disease (e.g., patients with hypertension, diabetes mellitus, or geriatric patients [older than 60 years]), estimate the GFR through laboratory testing. Counsel patients on the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA MedWatch program at 800-FDA-1088 and to the manufacturer at 800-654-0118.
Deoxygenated sickle erythrocytes have been shown in vitro to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadolinium-based contrast agents (GBCAs), such as gadodiamide, may possibly potentiate sickle erythrocyte alignment. Although the use of gadodiamide in patients with sickle cell disease and other hemoglobinopathies has not been studied, the American College of Radiology (ACR) manual on contrast media considers any special risk to sickle cell patients from administration of GBCAs to be extremely low; no restrictions for use of GBCAs are recommended by the ACR.
Gadodiamide is for intravenous use only. Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Safety and effectiveness of gadodiamide have not been established with intrathecal use.
Gadodiamide causes laboratory test interference with serum calcium measurements with some colorimetric methods resulting in falsely low serum calcium concentrations. In patients with normal renal function, this effect lasts for 12 to 24 hours; however, in patients with decreased renal function, interference with serum calcium measurements is expected to persist throughout the prolonged elimination of gadodiamide. After patients receive gadodiamide, use careful attention in selecting the type of method to measure serum calcium. In addition, transitory changes in serum iron concentrations have been observed. The clinical significance of this observation is unknown.
Pediatric patients (i.e., neonates, infants, children, and adolescents) may be at higher risk for gadolinium retention. Limit repeated GBCA imaging studies, particularly closely spaced MRI studies, but do not defer or avoid necessary GBCA MRI scans. The glomerular filtration rate in neonates and infants is much lower than that of adults.
Use gadodiamide during pregnancy only if imaging is essential and cannot be delayed. Gadolinium-based contrast agents (GBCAs) cross the placenta and result in fetal exposure and gadolinium retention. Pregnant women may be at greater risk for gadolinium retention. Data on the association between GBCAs and adverse fetal outcomes in human pregnancy are limited and inconclusive. In animal studies, increased incidences of flexed appendages and skeletal malformations were observed when gadodiamide at doses approximately 0.6 times the human dose based on body surface area comparison was administered to pregnant rabbits for 13 days during gestation. The American College of Radiology (ACR) advises against GBCA routine use in pregnant women; GBCA should only be administered during pregnancy if absolutely necessary and only after informed consent is obtained. The Guidelines for Computed Tomography and Magnetic Resonance Imaging in Pregnancy and Lactation state that because of the potential for fetal toxicity, the drug should only be used during pregnancy if deemed absolutely essential.
There are no data on the presence of gadodiamide in human breast milk, the effects on the breast-fed infant, or the effects on milk production. However, published data with other gadolinium-based contrast agents (GBCAs) indicate that 0.01% to 0.04% of the maternal gadolinium dose is excreted in breast milk. Further, gastrointestinal absorption of GBCA is limited. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for gadodiamide and any potential adverse effects on the breast-fed infant from gadodiamide or from the underlying maternal condition. Previous American Academy of Pediatrics (AAP) recommendations considered GBCAs compatible with breast-feeding. Additionally, the Guidelines for Computed Tomography and Magnetic Resonance Imaging Use During Pregnancy and Lactation and the American College of Radiology (ACR) manual on contrast media state that lactating women receiving GBCAs can continue to breast-feed without interruption. The reasoning for this recommendation is based on estimates of limited systemic exposure in the breast-fed infant and reviews that conclude maternally administered drug poses no risk to the nursing infant.
For use with magnetic resonance imaging (MRI) to enhance visualization of lesions with abnormal vascularity within the central nervous system and body:
-for imaging of the kidney:
Intravenous dosage:
Adults: 0.1 mL/kg (0.05 mmol/kg) administered as a single IV bolus injection. Complete imaging procedure within 1 hour of administration. Data for repeat injections are not available; however, if in the clinical judgment of the physician repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. The manufacturer provides weight-adjusted dose volumes as follows: 40 kg: 4 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL; 90 kg: 9 mL; 100 kg: 10 mL; 110 kg: 11 mL; 120 kg: 12 mL; 130 kg: 13 mL.
Children 2 years and older and Adolescents: 0.1 mL/kg (0.05 mmol/kg) administered as a single IV bolus injection. Complete imaging procedure within 1 hour of administration. Data for repeat injections are not available; however, if in the clinical judgment of the physician repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. The manufacturer provides weight-adjusted dose volumes as follows: 12 kg: 1.2 mL; 14 kg: 1.4 mL; 16 kg: 1.6 mL; 18 kg: 1.8 mL; 20 kg: 2 mL; 22 kg: 2.2 mL; 24 kg: 2.4 mL; 26 kg: 2.6 mL; 28 kg: 2.8 mL; 30 kg: 3 mL; 40 kg: 4 mL; 50 kg: 5 mL; 60 kg: 6 mL; 70 kg: 7 mL; 80 kg: 8 mL.
-for imaging of the brain, spine, and associated tissues, thoracic (noncardiac), abdominal, and pelvic cavities, and retroperitoneal space:
Intravenous dosage:
Adults: 0.2 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection. Complete imaging procedure within 1 hour of administration. Data for repeat injections are not available; however, if in the clinical judgment of the physician repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. The manufacturer provides weight-adjusted dose volumes as follows: 40 kg: 8 mL; 50 kg: 10 mL; 60 kg: 12 mL; 70 kg: 14 mL; 80 kg: 16 mL; 90 kg: 18 mL; 100 kg: 20 mL; 110 kg: 22 mL; 120 kg: 24 mL; 130 kg: 26 mL.
Children 2 years and older and Adolescents: 0.2 mL/kg (0.1 mmol/kg) administered as a single IV bolus injection. Complete imaging procedure within 1 hour of drug administration. Data for repeat injections are not available; however, if in the clinical judgment of the physician repeat examinations are required, a suitable interval of time between administrations should be observed to allow for normal clearance of the drug from the body. The manufacturer provides weight-adjusted dose volumes as follows: 12 kg: 2.4 mL; 14 kg: 2.8 mL; 16 kg: 3.2 mL; 18 kg: 3.6 mL; 20 kg: 4 mL; 22 kg: 4.4 mL; 24 kg: 4.8 mL; 26 kg: 5.2 mL; 28 kg: 5.6 mL; 30 kg: 6 mL; 40 kg: 8 mL; 50 kg: 10 mL; 60 kg: 12 mL; 70 kg: 14 mL; 80 kg: 16 mL.
Maximum Dosage Limits:
-Adults
0.2 mL/kg (0.1 mmol/kg) IV single dose.
-Geriatric
0.2 mL/kg (0.1 mmol/kg) IV single dose.
-Adolescents
0.2 mL/kg (0.1 mmol/kg) IV single dose.
-Children
2 to 12 years: 0.2 mL/kg (0.1 mmol/kg) IV single dose.
1 year: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
GFR 30 mL/minute/1.73 m2 or more: No dosage adjustments are recommended; do not exceed the recommended dose and allow sufficient time for elimination prior to any repeat administration. Use with caution in patients with renal insufficiency.
GFR less than 30 mL/minute/1.73 m2 or acute kidney injury: Contraindicated.
*non-FDA-approved indication
There are no drug interactions associated with Gadodiamide products.
Gadodiamide, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI). In magnetic resonance, the visualization of normal or pathological tissue depends on changes in the radiofrequency signal intensity that occur with: differences in proton density; differences of the spin-lattice or longitudinal relaxation time (T1); and differences in the spin-spin or transverse relaxation time (T2). Gadodiamide causes increased signal intensity by developing a magnetic moment when placed in a magnetic field. This magnetic moment enhances the relaxation rates of water protons, thereby shortening T1 and T2 in target tissues. When administered at recommended doses, the effects are primarily observed in the T1 relaxation time. Disruption of the blood-brain barrier or abnormal vascularity allows accumulation of the diagnostic agent in lesions such as neoplasms, abscesses, and subacute infarcts.
Gadodiamide is administered intravenously. In normal subjects, gadodiamide conforms to an open, 2-compartment pharmacokinetic model. Gadodiamide does not bind to human serum proteins in vitro. The volume of distribution of gadodiamide (200 +/- 61 mL/kg) is equivalent to extracellular body water. Gadodiamide is primarily eliminated via the kidneys by glomerular filtration, with approximately 95% of the dose excreted in the urine within 24 hours.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
After intravenous administration, the mean distribution and elimination half-lives of gadodiamide are 3.7 +/- 2.7 minutes and 77.8 +/- 16 minutes, respectively.