Multihance

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Multihance

Classes

MRI Agents

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.

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

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 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. In contrast, guidelines suggest kidney function screening is optional for American College of Radiology (ACR) group II GBCAs, which includes gadobenate dimeglumine, given risk of NSF is very low comparatively; the risk of NSF is very low for a standard dose (0.1 mmol/kg) of group II GBCA, even in patients with eGFR less than 30 mL/minute/1.73 m2. Do not withhold or delay group II GBCA in patients with kidney disease if harm would result from not proceeding with an indicated contrast-enhanced MRI. If multiple urgent group II GBCA doses are indicated, do not delay subsequent dose(s) for NSF concerns. If not urgent, delaying the subsequent dose(s) for more than 24 hours or performing intercurrent dialysis can promote GBCA clearance. In general, do not initiate or alter dialysis based on group II GBCA administration. These recommendations are not altered by patients receiving concomitant nephrotoxic medications, chemotherapy, or contrast-enhanced CT.

Common Brand Names

Multihance

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

Dosage And 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.

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.

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) Monitor for an increase in cisplatin-related adverse reactions if coadministration with gadobenate dimeglumine is necessary. 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.
Daunorubicin Liposomal: (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.
Daunorubicin Liposomal; Cytarabine Liposomal: (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.
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 Liposomal: (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.
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.

How Supplied

Multihance Intravenous Inj Sol: 1mL, 529mg

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.

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.

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.