Gadobenate Dimeglumine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

MultiHance: 529 mg/mL (5 mL, 10 mL, 15 mL, 20 mL, 50 mL, 100 mL)

Pharmacology

Mechanism of Action

Gadobenate dimeglumine is a gadolinium-containing paramagnetic agent. Exposure to an external magnetic field induces a large local magnetic field in exposed tissues. This local magnetism disrupts water protons in the vicinity, resulting in a change in proton density and spin characteristics, which can be detected by the imaging device.

Pharmacokinetics/Pharmacodynamics

Distribution

Distributes mainly to extracellular space

V_d (central compartment):

Children 2 to 5 years: 0.2 ± 0.05 L/kg (Pirovano 2015)

Adults: 0.074 ± 0.017 to 0.158 ± 0.038 L/kg (Spinazzi 1999)

V_d (steady state): Children 2 to 5 years: 0.32 ± 0.04 L/kg (Pirovano 2015)

V_d (by area): Adults: 0.17 ± 0.016 to 0.262 ± 0.34 L/kg (Spinazzi 1999)

Metabolism

Gadobenate and dimeglumine dissociate after injection; pharmacokinetics are based on gadobenate; there is no additional biotransformation of gadobenate

Excretion

Urine (78% to 96%); feces (0.6% to 4%)

Half-Life Elimination

Half-life elimination:

Distribution half-life:

Children 2 to 5 years: 0.13 ± 0.08 hours (Pirovano 2015)

Adults: 0.084 ± 0.012 to 0.605 ± 0.072 hours (Spinazzi 1999)

Elimination half-life:

Normal renal function:

Children 2 to 5 years: 1.22 ± 0.24 hours (Pirovano 2015)

Adults: 1.2 ± 0.09 to 1.96 ± 0.16 hours (Spinazzi 1999)

CrCl 30 to <60 mL/minute: 6.1 ± 3 hours

CrCl 10 to <30 mL/minute: 9.5 ± 3.1 hours

End-stage renal disease (without dialysis): 42.4 ± 24.4 hours

Use in Specific Populations

Special Populations: Renal Function Impairment

In patients with end-stage renal disease requiring hemodialysis, approximately 72% of the dose was recovered by hemodialysis over a 4-hour period.

Special Populations: Elderly

Clearance appeared to decrease slightly with increasing age.

Use: Labeled Indications

CNS imaging: Magnetic resonance imaging (MRI) agent to visualize CNS lesions in adults and pediatric patients with abnormal blood brain barrier or abnormal vascularity in the brain, spine, and associated tissues

Renal and aorto-ilio-femoral vasculature imaging: Magnetic resonance angiography (MRA) agent to evaluate adults with known or suspected renal or aorto-ilio-femoral occlusive vascular disease

Contraindications

Hypersensitivity to gadobenate dimeglumine, any gadolinium-based contrast agent, or any component of the formulation

Dosage and Administration

Dosing: Adult

CNS imaging: IV: 0.1 mmol/kg (0.2 mL/kg)

Renal and aorto-ilio-femoral vasculature imaging: IV: 0.1 mmol/kg (0.2 mL/kg); calculate scan delay with test bolus (1 to 2 mL) or with automatic detection technique

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Dosing presented in mL/kg and mmol/kg; use caution.

CNS magnetic resonance imaging:

Infants and Children <2 years of age: IV: 0.1 to 0.2 mL/kg (0.05 to 0.1 mmol/kg); may begin imaging immediately after administration.

Children ≥2 years and Adolescents: IV: 0.2 mL/kg (0.1 mmol/kg); may begin imaging immediately after administration.

Reconstitution

Pharmacy bulk package vial should only be entered once (using a suitable transfer device). Do not mix with other medications, including parenteral nutrition.

Administration

IV: Administer as rapid IV bolus injection. To ensure complete injection of medium, flush line with NS after administration using at least 5 mL (for CNS imaging) or at least 20 mL (for renal or aorto-ilio-femoral vasculature imaging). Do not administer other medications in the same IV line. May begin imaging immediately after administration.

Vesicant; ensure proper needle or catheter placement prior to and during infusion; avoid extravasation.

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect; remove needle/cannula; elevate extremity. Aspiration of extravasated contrast media is not recommended (ACR 2018). Information conflicts regarding the use of hyaluronidase; the American College of Radiology (ACR) Manual on Contrast Media does not recommend hyaluronidase in the management of contrast media extravasation (ACR 2018); other sources suggest its utility in extravasation management (Belin 2002; Reynolds 2014).

If using hyaluronidase: Intradermal or SubQ: Inject a total of 1 to 1.7 mL (15 units/mL) as 5 separate 0.2 to 0.3 mL injections (using a 25-gauge needle) into area of extravasation at the leading edge in a clockwise manner (MacCara 1983; Reynolds 2014; Zenk 1981) or injection of a total of 5 mL (150 units/mL) as 5 separate 1 mL injections around the extravasation site has also been used successfully (Rowlett 2012).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F); do not freeze. Pharmacy bulk package must be discarded within 8 hours after opening in a sterile environment; discard unused portion after 8 hours (storage temperature should not exceed 25°C [77°F] during this time frame). If drawn into a plastic disposable syringe for administration, use immediately after preparation.

Drug Interactions

Chloroquine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Chloroquine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Clofazimine: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Clofazimine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Domperidone: QT-prolonging Agents (Moderate Risk) may enhance the QTc-prolonging effect of Domperidone. Management: Consider alternatives to this drug combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

Fexinidazole [INT]: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

Haloperidol: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Haloperidol. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Ondansetron: QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Ondansetron. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Pentamidine (Systemic): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of Pentamidine (Systemic). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Pimozide: May enhance the QTc-prolonging effect of QT-prolonging Agents (Moderate Risk). Avoid combination

QT-prolonging Agents (Highest Risk): May enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Consider alternatives to this combination. If combined, monitor for QTc interval prolongation and ventricular arrhythmias. Patients with additional risk factors for QTc prolongation may be at even higher risk. Consider therapy modification

QT-prolonging Antidepressants (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Antipsychotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Antipsychotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Pimozide. Monitor therapy

QT-prolonging Class IC Antiarrhythmics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Class IC Antiarrhythmics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Kinase Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Miscellaneous Agents (Moderate Risk): May enhance the QTc-prolonging effect of Gadobenate Dimeglumine. Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Exceptions: Chloroquine; Clofazimine; Domperidone. Monitor therapy

QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Moderate CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Quinolone Antibiotics (Moderate Risk): QT-prolonging Miscellaneous Agents (Moderate Risk) may enhance the QTc-prolonging effect of QT-prolonging Quinolone Antibiotics (Moderate Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk): May enhance the QTc-prolonging effect of QT-prolonging Miscellaneous Agents (Moderate Risk). QT-prolonging Strong CYP3A4 Inhibitors (Moderate Risk) may increase the serum concentration of QT-prolonging Miscellaneous Agents (Moderate Risk). Avoid combination

Test Interactions

May cause transient increase in serum ferritin, urine zinc (with renal disease), or bilirubin (with hepatic metabolic disorders)

Adverse Reactions

1% to 10%:

Central nervous system: Feeling hot (1%), headache (1%)

Gastrointestinal: Nausea (1%), vomiting (≤1%)

Local: Injection site reaction (1%)

<1%, postmarketing, and/or case reports: Abdominal pain, altered sense of smell, anaphylactic shock, anaphylaxis, asthenia, basophilia, chest pain, chills, diarrhea, dizziness, dysgeusia, dyspnea, ECG abnormality (including PR, QRS, QT, and ST-T segment changes), eye pruritus, facial edema, fatigue, fever, first degree atrioventricular block, hyperhidrosis, hypersensitivity reaction, laboratory test abnormality (including blood chemistry, hematology, hepatic enzymes, urinalysis), laryngospasm, loss of consciousness, malaise, myalgia, nasal congestion, necrotizing pancreatitis (acute), ocular hyperemia, oral paresthesia, pain, paresthesia, pruritus, pulmonary edema, seizure, shock, skin changes (plaques), skin rash, sneezing, swelling of lips, tongue edema, tremor, urticaria, visual disturbance, wheezing, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Cardiac arrhythmias have been observed; use with caution in patients with predisposing proarrhythmic conditions or concurrent proarrhythmic drug therapy. Although average changes in QT_c compared to placebo were minimal (<5 msec) and no patients experienced malignant arrhythmias, numerically more patients experienced QT_c prolongation between 30-60 msecs and ≥61 msecs compared to placebo in one clinical trial.
• Extravasation: Vesicant; ensure proper needle or catheter placement prior to and during administration. Monitor infusion site. Avoid extravasation. May cause injection site reactions (local burning/pain, swelling, blistering, and necrosis).
• Gadolinium retention: Gadolinium is retained for months or years in brain, bone, skin, and other organs (kidney, liver, spleen); the highest concentration and longest duration have been found in the bone. Linear GBCAs (gadodiamide and gadoversetamide > gadoxetate disodium, gadopentetate dimeglumine, and gadobenate dimeglumine) result in more retention than macrocyclic GBCAs (gadoterate meglumine, gadobutrol, and gadoteridol). Pathologic and clinical consequences of gadolinium retention in skin and other organs have been established in patients with impaired renal function; there also have been rare reports of pathologic skin changes in patients with normal renal function. Consequences of gadolinium retention in the brain or in patients with normal renal function have not been established. Patients with normal renal function that may be at higher risk for gadolinium retention include: patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions; take GBCA retention characteristics into consideration for these patients. Minimize repetitive GBCA imaging studies.
• Hypersensitivity: Anaphylactic and anaphylactoid reactions (some fatal) have occurred (with cardiovascular, respiratory or dermatologic involvement); symptoms typically occurred within minutes of administration. Monitor patients closely during and for up to 2 hours after infusion. If hypersensitivity occurs, begin immediate management. Appropriate equipment (eg, ventilator) and emergency medications (eg, epinephrine) should be available during use. Delayed reactions may also occur (within several hours of administration). Patients with a history of allergic reactions and/or bronchial asthma may be at an increased risk for developing hypersensitivity reactions; use caution in these patients.
• Nephrogenic systemic fibrosis: [US Boxed Warning]: Gadolinium-based contrast agents (GBCAs) exposure increases the risk for nephrogenic systemic fibrosis (NSF) in patients with renal impairment; avoid use unless GBCA enhanced imaging is essential for diagnostic purposes. The risk is highest in patients with acute kidney injury or chronic, severe renal disease (glomerular filtration rate [GFR] <30 mL/minute/1.73 m²). NSF may result in debilitating or fatal systemic fibrosis; affects the skin, muscle, and internal organs. Prior to administration, screen all patients for acute kidney injury or other conditions which may reduce renal function; estimate GFR in patients at risk for chronic declines in renal function (eg, age >60, chronic hypertension, diabetes). Do not exceed the recommended dose and allow a sufficient interval between readministration in patients at risk for NSF. The risk for NSF appears lower in patients with moderate, chronic renal disease (GFR 30 to 59 mL/minute/1.73 m²) and little, if any, in patients with mild, chronic renal disease (GFR 60 to 89 mL/minute/1.73 m²). In patients receiving hemodialysis, consider prompt initiation of hemodialysis following administration. If NSF occurs, report to manufacturer or the Food and Drug Administration (FDA).

Disease-related concerns:

• Metabolic disorders: May prolong systemic exposure with some drugs (eg, cisplatin, anthracyclines) due to competition for certain multispecific organic anion transporters (MOAT) especially in patients with decreased MOAT activity (eg, Dubin Johnson syndrome).
• Renal impairment: Use with caution in patients with renal impairment. Dose-dependent worsening of renal function or acute renal failure has occurred in patients with renal insufficiency following use of other gadolinium agents, generally within 48 hours following administration. Evaluate renal function in patients with renal impairment prior to use; consider follow-up monitoring.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Scan interpretation: Certain lesions may not appear with contrast-enhanced scan that do appear with noncontrast imaging; use caution when interpreting.

Monitoring Parameters

Signs of hypersensitivity (during and for several hours after procedure); renal function (prior to administration); short- and long-term monitoring of signs and symptoms of NSF (eg, burning, itching, swelling, hardening and/or tightening of skin, joint stiffness, deep hip or rib bone pain, muscle weakness, limited range of motion, and/or yellowed/raised spots on whites of eye). Monitor infusion site.

Pregnancy

Pregnancy Considerations

Gadolinium-based contrast agents may cross the placenta (ACOG 723 2017; ACR 2018).

Use of gadolinium-based contrast agents in pregnancy is controversial and should be limited. A gadolinium-based contrast agent with MRI may be considered for use in pregnancy if it will significantly improve diagnostic performance and is expected to improve fetal or maternal outcome (ACOG 723 2017). In addition, use should only be considered if information needed from the MRI study cannot be acquired without using a contrast agent and cannot be deferred until after delivery. Agents with a low risk for development of nephrogenic systemic fibrosis should be used at the lowest effective dose (ACR 2018).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, headache, cold or warm sensation at injection site, or sensation of warmth. Have patient report immediately to prescriber signs of nephrogenic systemic fibrosis (skin burning, itching, swelling, or scaling; red or dark spots on the skin; hard or tight skin; stiff joints; muscle weakness; hip or rib pain; or difficulty moving, bending, or straightening arms, hands, legs, or feet), signs of kidney problems (unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain), abnormal heartbeat, or severe injection site redness, edema, pain or irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.