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    MRI Agents

    BOXED WARNING

    Diabetes mellitus, dialysis, geriatric, hypertension, nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), renal disease, renal failure, renal impairment

    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 gadobenate dimeglumine. 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 (glomerular filtration rate [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. Gadobenate dimeglumine 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 800-257-5181.

    DEA CLASS

    Rx

    DESCRIPTION

    Paramagnetic gadolinium-based contrast agent
    For use during MRI of the central nervous system or MRA of the renal and aorto-ilio-femoral vasculature
    Few, if any, associated cases of nephrogenic systemic fibrosis

    COMMON BRAND NAMES

    Multihance

    HOW SUPPLIED

    Multihance Intravenous Inj Sol: 1mL, 529mg

    DOSAGE & INDICATIONS

    For use as a contrast enhancement in magnetic resonance imaging (MRI) to visualize areas of the brain, spine, and associated tissues with disruption of the blood brain barrier or abnormal vascularity.
    Intravenous dosage
    Adults

    0.2 mL/kg (0.1 mmol/kg) administered as a single rapid IV bolus injection. Imaging may begin immediately after 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. Doses up to 0.4 mmol/kg were administered to adults in clinical trials. The manufacturer provides weight-adjusted dose volumes as follows: 40 kg: 8 mL; 45 kg: 9 mL; 50 kg: 10 mL; 55 kg: 11 mL; 60 kg: 12 mL; 65 kg: 13 mL; 70 kg: 14 mL; 75 kg: 15 mL; 80 kg: 16 mL; 85 kg: 17 mL; 90 kg: 18 mL; 95 kg: 19 mL; 100 kg: 20 mL; 105 kg: 21 mL; 110 kg: 22 mL; 115 kg: 23 mL; 120 kg: 24 mL; 125 kg: 25 mL; 130 kg: 26 mL; 135 kg: 27 mL; 140 kg: 28 mL; 145 kg: 29 mL; 150 kg: 30 mL.

    Children 2 years and older and Adolescents

    0.2 mL/kg (0.1 mmol/kg) administered as a single rapid IV bolus injection. Imaging may begin immediately after 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. Doses up to 0.4 mmol/kg were administered to adults in clinical trials. The manufacturer provides weight-adjusted dose volumes as follows: 2.5 kg: 0.5 mL; 5 kg: 1 mL; 10 kg: 2 mL; 15 kg: 3 mL; 20 kg: 4 mL; 25 kg: 5 mL; 30 kg: 6 mL; 35 kg: 7 mL; 40 kg: 8 mL; 45 kg: 9 mL; 50 kg: 10 mL; 55 kg: 11 mL; 60 kg: 12 mL; 65 kg: 13 mL; 70 kg: 14 mL; 75 kg: 15 mL; 80 kg: 16 mL.

    Neonates and Children younger than 2 years

    0.1 to 0.2 mL/kg (0.05 to 0.1 mmol/kg) administered as a single rapid IV bolus injection. Imaging may begin immediately after 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. Doses up to 0.4 mmol/kg were administered to adults in clinical trials. The manufacturer provides weight-adjusted dose volumes as follows: 2.5 kg: 0.25 to 0.5 mL; 5 kg: 0.5 to 1 mL; 10 kg: 1 to 2 mL; 15 kg: 1.5 to 3 mL; 20 kg: 2 to 4 mL.

    For use as a contrast enhancement in magnetic resonance angiography (MRA) to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease.
    Intravenous dosage
    Adults

    0.2 mL/kg (0.1 mmol/kg) administered as a single rapid IV bolus injection. Begin imaging immediately after administration, with scan delay calculated by automatic bolus detection technique or a 1 to 2 mL test bolus. 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. Doses up to 0.4 mmol/kg were administered during clinical trials. The manufacturer provides weight-adjusted dose volumes as follows: 5 kg: 1 mL; 10 kg: 2 mL; 15 kg: 3 mL; 20 kg: 4 mL; 25 kg: 5 mL; 30 kg: 6 mL; 35 kg: 7 mL; 40 kg: 8 mL; 45 kg: 9 mL; 50 kg: 10 mL; 55 kg: 11 mL; 60 kg: 12 mL; 65 kg: 13 mL; 70 kg: 14 mL; 75 kg: 15 mL; 80 kg: 16 mL; 85 kg: 17 mL; 90 kg: 18 mL; 95 kg: 19 mL; 100 kg: 20 mL; 105 kg: 21 mL; 110 kg: 22 mL; 115 kg: 23 mL; 120 kg: 24 mL; 125 kg: 25 mL; 130 kg: 26 mL; 135 kg: 27 mL; 140 kg: 28 mL; 145 kg: 29 mL; 150 kg: 30 mL.

    MAXIMUM DOSAGE

    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

    0.2 mL/kg (0.1 mmol/kg) IV single dose.

    Infants

    0.2 mL/kg (0.1 mmol/kg) IV single dose.

    Neonates

    Term neonates: 0.2 mL/kg (0.1 mmol/kg) IV single dose.
    Preterm Neonates: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    No dosage adjustments are recommended; do not exceed the recommended dose and allow sufficient time for elimination prior to any repeat administration. The manufacturer recommends avoiding use in patients with chronic, severe renal disease (GFR < 30 mL/min/1.73 m2) and in patients with acute kidney injury; these patients are at highest risk for nephrogenic systemic fibrosis. Avoid use in these patients unless the diagnostic information is essential and not available with non-contrast imaging or other modalities.
     
    Intermittent hemodialysis
    Gadobenate dimeglumine is removed from the body by hemodialysis. For patients receiving hemodialysis, consider initiating a hemodialysis session after drug administration in order to enhance clearance of the contrast agent.

    ADMINISTRATION

     
    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 up to 2 hours after administration.

    Injectable Administration

    Visually inspect for particulate matter and discoloration prior to administration. Solution is clear/colorless to slightly yellow. Do not use if discolored or if particulate matter is present.
    Do not mix with other drugs. Do not administer other medications in the same intravenous line.

    Intravenous Administration

    For single dose vials: Using aseptic technique, draw solution into a sterile syringe. Administer immediately after opening.
    For pharmacy bulk packages: In a suitable environment, such as a laminar flow hood, penetrate the container closure of the pharmacy bulk package with an appropriate transfer device. Once the container closure is punctured, it should not be removed from the aseptic work area, and the temperature of the container should not exceed 25 degrees C (77 degrees F). Using aseptic technique, transfer the contents of the pharmacy bulk package into syringes without delay. When a plastic disposable syringe is used for administration, the contrast medium should be drawn into the syringe and used immediately. A maximum duration of 8 hours from initial closure entry is allowed to complete the transfer process; discard any unused solution 8 hours after initial puncture.
    Ensure catheter and venous patency prior to the injection. Extravasation may result in tissue irritation.
    Administer as a single, rapid intravenous bolus injection.
    To ensure administration of the total dose, follow the bolus injection with >= 5 mL (for MRI) or >= 20 mL (for MRA) normal saline flush.
    Preform the imaging immediately following the bolus injection. For MRA of renal and aorto-ilio-femoral vasculature, a scan delay is required. An appropriate scan delay is calculated by using an automatic bolus detection technique or a 1—2 mL test bolus.
    Usual safety rules customary for magnetic resonance procedures (e.g., exclusion of cardiac pacemakers and ferromagnetic implants) must be observed.
    The product contains no antimicrobial preservatives. Discard any unused product.

    STORAGE

    Multihance :
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Conditions that decrease the activity of MOAT, such as Dubin Johnson syndrome, may prolong exposure to gadobenate dimeglumine.

    Magnetic resonance imaging (MRI)

    Diagnostic procedures that involve use of contrast agents, such as gadobenate dimeglumine, 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 gadobenate dimeglumine during contrast enhanced magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) could impair visualization of lesions seen on non-contrast MRI/MRA. 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.

    Asthma, atopy, radiopaque contrast media hypersensitivity

    Administration of gadobenate dimeglumine to patients with a history of gadolinium-based radiopaque contrast media hypersensitivity is contraindicated. The drug has been associated with serious, and sometimes fatal, anaphylactoid/anaphylactic reactions involving cardiovascular, respiratory, and/or cutaneous manifestations. In most cases, these reactions developed within minutes of drug administration and resolved with emergency treatment. Prior to administration, assess hypersensitivity risk factors in all potential drug recipients. 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 asthma, atopy (including hay fever, food allergies, and drug allergies) or other allergic disorders. 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 up to 2 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., in adults, prednisone 50 mg PO or equivalent 13, 7, and 1 hour prior to the exam) and antihistamines (e.g., adult dose diphenhydramine 50 mg IM/PO 1 hour prior to the exam) along with the use of a different or low-osmolar contrast agent is recommended.

    Diabetes mellitus, dialysis, geriatric, hypertension, nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy), renal disease, renal failure, renal impairment

    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 gadobenate dimeglumine. 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 (glomerular filtration rate [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. Gadobenate dimeglumine 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 800-257-5181.

    Extravasation

    Ensure the patency and integrity of the intravenous line prior to administering gadobenate dimeglumine. Furthermore, appropriate surveillance of the dosing limb for development of local injection site reactions is recommended. Take care to avoid extravasation as tissue irritation (pain, burning, swelling, blistering, and necrosis) may occur. According to the American College of Radiology (ACR), the risk of significant injury from gadolinium-based contrast agents (GBCA) is extremely low, with GBCAs being much less toxic to the skin/subcutaneous tissue than equal volumes of iodinated contrast media.

    Sickle cell disease

    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 gadobenate dimeglumine, may possibly potentiate sickle erythrocyte alignment. Although the use of gadobenate dimeglumine 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.

    Cardiac arrhythmias, QT prolongation

    Caution is advised when administering gadobenate dimeglumine to patients predisposed to QT prolongation or cardiac arrhythmias. Assess patients for underlying conditions or medications that may increase the risk for arrhythmias. In a crossover study, supratherapeutic doses of 0.2 mmol/kg were associated with a 30—60 msec prolongation of the QT interval in 20 of 47 study subjects. In 6 subjects, prolongations reached > 60 msec. These results were compared against placebo, where 11 subjects had prolongations of 30—60 msec and 3 had prolongations > 60 msec. No malignant arrhythmias were associated with any QT prolongation. The average changes in QTc interval for gadobenate dimeglumine when compared against placebo were minimal at < 5 msec. No malignant arrhythmias were associated with any QT prolongation.

    Children, infants, neonates

    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.

    Pregnancy

    Use gadobenate dimeglumine 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, the drug was found to be teratogenic when administered to pregnant rabbits during organogenesis. When administered intravenously at 6-times the recommended human dose, gadobenate dimeglumine induced microphthalmia and/or focal retinal folds in 3 rabbit fetuses from 3 separate litters. At doses of 10-times the recommended human dose, the drug was associated with increased intrauterine deaths in rabbits. 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.

    Breast-feeding

    Limited data demonstrates that breast-feeding after gadobenate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001% to 0.04% of the maternal dose. There is no information on the effects of gadobenate on the breast-fed infant or on milk production. Gastrointestinal absorption of a gadolinium-based contrast agent (GBCA) is limited. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for gadobenate dimeglumine and any potential adverse effects on the breast-fed infant from gadobenate dimeglumine or 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.

    ADVERSE REACTIONS

    Severe

    angioedema / Rapid / 0-0.5
    laryngospasm / Rapid / 0-0.5
    visual impairment / Early / 0-0.5
    AV block / Early / 0-0.5
    anaphylactoid reactions / Rapid / 0.1-0.1
    pancreatitis / Delayed / 0.1-0.1
    pulmonary edema / Early / 0.1-0.1
    nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    respiratory arrest / Rapid / Incidence not known
    cardiac arrest / Early / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 0-0.5
    wheezing / Rapid / 0-0.5
    hyperemia / Delayed / 0-0.5
    ocular inflammation / Early / 0-0.5
    QT prolongation / Rapid / 0-0.5

    Mild

    vomiting / Early / 0-1.4
    nausea / Early / 1.3-1.3
    injection site reaction / Rapid / 0-1.2
    headache / Early / 1.2-1.2
    hyperhidrosis / Delayed / 0-0.7
    fever / Early / 0.7-0.7
    dysgeusia / Early / 0.7-0.7
    chills / Rapid / 0-0.5
    malaise / Early / 0-0.5
    urticaria / Rapid / 0-0.5
    pruritus / Rapid / 0-0.5
    rash / Early / 0-0.5
    ocular pruritus / Rapid / 0-0.5
    paresthesias / Delayed / 0.5-0.5
    tremor / Early / 0-0.5
    dizziness / Early / 0.5-0.5
    parosmia / Delayed / 0-0.5
    abdominal pain / Early / 0-0.5
    diarrhea / Early / 0-0.5
    xerostomia / Early / 0-0.5
    nasal congestion / Early / 0-0.5
    sneezing / Early / 0-0.5
    fatigue / Early / Incidence not known
    asthenia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Anthracyclines: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Cisplatin: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as cisplatin, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Daunorubicin: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Doxorubicin: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Epirubicin: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Etoposide, VP-16: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as etoposide, VP-16, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Idarubicin: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as anthracyclines, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Methotrexate: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as methotrexate, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Paclitaxel: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as paclitaxel, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Tamoxifen: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as tamoxifen, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.
    Vinca alkaloids: (Moderate) Gadobenate dimeglumine is a substrate for the canalicular multi-specific organic anion transporter (MOAT). Use with other MOAT substrates, such as vinca alkaloids, may result in prolonged systemic exposure of the coadministered drug. Caution is advised if these drugs are used together.

    PREGNANCY AND LACTATION

    Pregnancy

    Use gadobenate dimeglumine 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, the drug was found to be teratogenic when administered to pregnant rabbits during organogenesis. When administered intravenously at 6-times the recommended human dose, gadobenate dimeglumine induced microphthalmia and/or focal retinal folds in 3 rabbit fetuses from 3 separate litters. At doses of 10-times the recommended human dose, the drug was associated with increased intrauterine deaths in rabbits. 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.

    Limited data demonstrates that breast-feeding after gadobenate dimeglumine administration to the mother would result in the infant receiving an oral dose of 0.001% to 0.04% of the maternal dose. There is no information on the effects of gadobenate on the breast-fed infant or on milk production. Gastrointestinal absorption of a gadolinium-based contrast agent (GBCA) is limited. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for gadobenate dimeglumine and any potential adverse effects on the breast-fed infant from gadobenate dimeglumine or 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.

    MECHANISM OF ACTION

    Gadobenate dimeglumine, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI) and to evaluate occlusive vascular disease during magnetic resonance angiography (MRA). 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). Gadobenate dimeglumine 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 infarcts.

    PHARMACOKINETICS

    Gadobenate dimeglumine is administered intravenously. After administration, the meglumine salt completely dissociates from the gadobenate dimeglumine complex; the resulting gadobenate ion conforms to a 2-compartment pharmacokinetic model. At steady state, the volume of distribution by area approaches that of extracellular body water at 0.17 to 0.282 L/kg. No protein binding has been observed in vitro, and the gadobenate ion is not known to be metabolized. The mean elimination half-life ranges from 1.17 to 2.02 hours. Elimination occurs primarily via the kidneys, with 78% to 96% of the dose excreted in the urine and 0.6% to 4% recovered in the feces.
     
    Affected cytochrome P450 isoenzymes and drug transporters: MOAT
    Gadobenate dimeglumine is a substrate for canalicular multi-specific organic anion transporter (MOAT).

    Intravenous Route

    Within the studied dosage range (0.005 to 0.4 mmol/kg), plasma concentration (Cmax) and exposure (AUC) of gadobenate dimeglumine appear to be linear based on dose.