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Gadobenate Dimeglumine

Pronunciation

(gad oh BEN ate dye MEG loo meen)

Index Terms

  • Gadolinum-BOPTA
  • Gd-BOPTA

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)

Brand Names: U.S.

  • MultiHance

Pharmacologic Category

  • Diagnostic Agent
  • Gadolinium-Containing Contrast Agent
  • Radiological/Contrast Media, Nonionic (High Osmolality)
  • Radiological/Contrast Media, Paramagnetic Agent

Pharmacology

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.

Distribution

Vd: 0.17-0.282 L/kg; does not cross intact blood-brain barrier; distribution half-life: 0.084-0.605 hours

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

Half-Life Elimination

Normal renal function: ~1-2 hours

CrCl 30-60 mL/minute: ~6 hours

CrCl 10-30 mL/minute: ~9.5 hours

End-stage renal disease (without dialysis): ~42 hours

Special Populations: Renal Function Impairment

Elimination half-life was 6.1 and 9.5 h for the moderate and severe renal impairment groups, respectively, compared with 1-2 hours in healthy patients.

Hemodialysis

The mean elimination half-life on dialysis was 1.21 hours compared with 42.4 hours when off dialysis.

Special Populations: Elderly

Clearance appeared to decrease slightly with increasing age.

Use: Labeled Indications

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

Renal and aorto-ilio-femoral vessel angiography: Magnetic resonance angiography (MRA) agent to evaluate 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

Dosing: Adult

CNS lesions (MRI): IV: 0.1 mmol/kg (0.2 mL/kg); may begin imaging immediately after administration

Renal or aorto-ilio-femoral vasculature imaging (MRA): IV: 0.1 mmol/kg (0.2 mL/kg); may begin imaging immediately after administration (calculate scan delay with test bolus [1-2 mL] or with automatic detection technique)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

CNS lesions: IV: Children ≥2 years and Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

Dose adjustment is not recommended; however, use with caution. Risk for NSF development increases as renal function decreases.

Hemodialysis: If administered to patients already receiving hemodialysis, consider prompt hemodialysis following exposure (eg, within 3 hours) (Kuo, 2007). Data has shown hemodialysis enhances gadolinium elimination with average gadolinium excretory rates of 78%, 96%, and 99% in the first, second, and third hemodialysis sessions, respectively (Kuo, 2007; Okada, 2001).

Peritoneal dialysis: Likely to be less efficient at clearing gadolinium (Joffe, 1998; Kuo, 2007).

Dosing: Hepatic Impairment

Child-Pugh class B or C: Pharmacokinetics were not significantly altered; dose adjustment is not recommended.

Reconstitution

Visually inspect prior to use; do not use if discolored or if particulate matter present. Pharmacy bulk package vial should only be entered once (using a suitable transfer device). Do not mix with other medications, including parenteral nutrition.

Administration

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 angiography). Do not administer other medications in the same IV line.

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

Extravasation management: If extravasation occurs, stop infusion immediately and disconnect (leave cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); remove needle/cannula; initiate hyaluronidase antidote; elevate extremity.

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

Storage

Store at controlled room temperature of 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

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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 (children: 1%)

Local: Injection site reaction (1%)

<1% (Limited to important or life-threatening): Abdominal pain, altered sense of smell, anaphylactoid reaction, anaphylaxis, basophilia, changes in ALT (nonspecific changes), changes in AST (nonspecific changes), chest pain, chills, diarrhea, dizziness, dysgeusia, dyspnea, ECG abnormality (including PR, QRS, QT, and ST-T segment changes), edema (eye edema, facial edema, lip edema, tongue edema), first degree atrioventricular block, hyperhidrosis, hypersensitivity reaction, laryngospasm, loss of consciousness, malaise, myalgia, nasal congestion, necrotizing pancreatitis (acute), nephrogenic systemic fibrosis (NSF/NFD), ocular hyperemia, oral paresthesia, pulmonary edema, pruritus, seizure, shock, skin rash, sneezing, tremor, urticaria, visual disturbance, wheezing, xerostomia

ALERT: U.S. Boxed Warning

Nephrogenic systemic fibrosis:

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) in patients with impaired elimination of the drugs. In these patients, avoid the use of GBCAs unless the diagnostic information is essential and not available with noncontrast-enhanced magnetic resonance imaging (MRI) or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle, and internal organs. The risk of NSF appears highest among patients with chronic, severe kidney disease (glomerular filtration rate [GFR] <30 mL/minute/1.73 m2) or acute kidney injury. Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (eg, >60 years, hypertension, diabetes), estimate the GFR through laboratory testing. For patients at highest risk of NSF, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration.

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 QTc compared to placebo were minimal (<5 msec) and no patients experienced malignant arrhythmias, numerically more patients experienced QTc 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. Avoid extravasation. May cause injection site reactions (local burning/pain, swelling, blistering, and necrosis).

• Hypersensitivity reactions: 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: [U.S. 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, 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 30-59 mL/minute/1.73 m2) and little, if any, in patients with mild, chronic renal disease (GFR 60-89 mL/minute/1.73 m2). NSF can occur days to months after exposure. 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.

• Sickle cell anemia: In in vitro studies, deoxygenated sickle erythrocytes align perpendicular to a magnetic field; the enhancement of magnetic moment by contrast agents may potentiate this alignment possibly resulting in vaso-occlusive complications in vivo. Sickling, possibly leading to vaso-occlusion, has been reported (rare, case reports) with use of hyperosmolar contrast solutions; believed to result from red blood cell dehydration. Use in patients with sickle cell anemia or other hemoglobinopathies has not been studied.

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)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Gadnolinium-based contrast agents cross the placenta; in general, their use in pregnant women is controversial (ACOG 2016). Use should be avoided unless critical for the care of the mother or fetus and it is not prudent to wait until after pregnancy. Agents with a low risk for development of nephrogenic systemic fibrosis should be used at the lowest effective dose (ACR 2015).

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?)

• 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; difficulty moving, bending, or straightening arms, hands, legs, or feet), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), arrhythmia, or severe injection site 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.

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