gadobenate (Rx)

1-10%

Nausea (1.3%)

Headache (1.2%)

Injection site reactions (1.1%)

Feeling hot (1%)

<1%

Dysgeusia (0.7%)

Pyrexia, pediatric patients (0.7%)

Hyperhidrosis, pediatric patients (0.7%)

Paresthesia (0.5%)

Dizziness (0.5%)

Postmarketing Reports

Immune system disorders: Anaphylactic, anaphylactoid and hypersensitivity reactions manifested with various degrees of severity up to anaphylactic shock, loss of consciousness and death

General disorders and administration site conditions: Extravasation of the drug may lead to injection site reactions, characterized by local pain or burning sensation, swelling, blistering, and necrosis

Gadolinium retention in patients with normal renal function, adverse events (eg, fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems) with variable onset and duration have been reported

Skin: Gadolinium-associated plaques

Contraindications

Hypersensitivity; known allergy to gadolinium or formulation components

Cautions

Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations; observe patients for signs and symptoms of a hypersensitivity reaction during and for up to 2 hr after administration (see Contraindications)

Risk for nephrogenic systemic fibrosis (NSF) in patients w/ acute or chronic severe renal insufficiency, hepatorenal syndrome or in perioperative liver transplantation period (see Black Box Warnings)

Anemia, hepatic/renal impairment, hemoglobinopathies, thrombotic syndromes

Risk of hypotension/hypertension

Patients with or using medication for metabolic, cardiac, or other abnormalities predisposing to cardiac arrhythmias

Cardiac arrhythmias reported; use caution in patients with predisposing proarrhythmic conditions or that are taking proarrhythmic drug therapy concurrently

May prolong systemic exposure in patients with decreased multispecific organic anion transporters

Local tissue damage may occur in extravasation

Certain lesions seen on non-contrast images may not be seen on contrast- images; exercise caution when interpreting contrast MR images in the absence of companion non-contrast MR images

Gadolinium retention

• Gadolinium is retained for months or years in several organs
• Highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (eg, brain, skin, kidney, liver, and spleen
• Duration of retention also varies by tissue and is longest in bone
• Patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions are at higher risk of gadolinium retention

Brain deposits

• FDA review to date has not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI)
• Restriction of GBCA use is not warranted because there is no evidence associated with gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium
• Recent publications in medical literature have reported that deposits of GBCAs remain in the brains of some patients who undergo ≥4 contrast MRI scans, long after the last administration
• It is unknown whether these gadolinium deposits are harmful or can lead to adverse health effects
• Early data in rat studies show that linear GBCAs are more prone to dissociation into free gadolinium and demonstrate greater brain deposition than macrocyclic GBCAs, which are less prone to dissociation
• Health care professionals should limit GBCA use to circumstances in which additional information provided by the contrast agent is necessary, and assess the necessity of repetitive MRIs with GBCAs

Drug interactions overview

• Gadobenate may prolong systemic exposure of drugs such as cisplatin, anthracyclines (eg, doxorubicin, daunorubicin), vinca alkaloids (eg, vincristine), methotrexate, etoposide, tamoxifen, and paclitaxel
• Consider the potential for prolonged drug exposure in patients with decreased canalicular multispecific organic anion transporter (MOAT also referred to as MRP2 or ABCC2) activity (eg, Dubin Johnson syndrome)

Pregnancy

GBCAs cross the placenta and result in fetal exposure and gadolinium retention

Human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive

In animal reproduction studies, gadobenate has been shown to be teratogenic in rabbits following repeated IV administration during organogenesis at doses up to 6 times the recommended human dose; no adverse developmental effects observed in rats with IV administration of gadobenate dimeglumine during organogenesis at doses up to 3 times the recommended human dose

Estimated background risk of major birth defects and miscarriage for the indicated population is unknown

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes

Lactation

Limited literature reports that breastfeeding after gadobenate administration to the mother would result in the infant receiving an oral dose of 0.001%-0.04% of the maternal dose

Unknown whether the effects of the drug on the breastfed infant or the effects of the drug on milk production

Developmental and health benefits of breastfeeding should be considered together with the mother’s clinical need for gadobenate and any potential adverse effects on the breastfed infant from gadobenate or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Gadobenate dimeglumine is a paramagnetic agent and, as such, develops a magnetic moment when placed in a magnetic field

Large magnetic moment produced by paramagnetic agent results in a large local magnetic field, which can enhance the relaxation rates of water protons in its vicinity leading to an increase of signal intensity (brightness) of tissue

Magnetic resonance imaging (MRI): Visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with differences in proton density; differences of the spin-lattice or longitudinal relaxation times (T1); and differences in spin-spin or transverse relaxation time (T2); when placed in a magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxation time in target tissues

Absorption

Data for plasma concentration and AUC demonstrated linear dependence on administered dose

Distribution

Vd: 0.074-0.158 L/kg (central compartment)

Vd: 0.17-0.282 L/kg (by area)

Metabolism

No detectable biotransformation of gadobenate ion

Dissociation of gadobenate ion in vivo has been shown to be minimal

Elimination

Half-life: 1-2 hr (normal renal function); 6 hr (CrCl 30-60 mL/min); 9.5 hr (10-30 mL/min); 42.4 hr (end-stage renal disease); 1.21 hr (during dialysis)

Clearance: 0.093-0.133 L/hr/kg (plasma); 0.082-0.104 L/hr/kg (renal)

Excretion: Urine 78-96%; feces 0.4-0.6%

IV Incompatibilities

Do not mix IV medications or parenteral nutrition solutions

Do not administer other medications in the same IV line with gadobenate

IV Administration

Visually inspect vials for particulate matter and discoloration prior to administration

Do not use solution if it is discolored or particulate matter is present

Vials are single use only

Administer immediately after opening and discard any unused product

Storage

Vials: Store at 25°C (77°F), excursions permitted to 15-30°C (59-86°F)