Gadobutrol

Dosage Forms

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

Solution, Intravenous [preservative free]:

Gadavist: 1 mmol/mL (2 mL, 7.5 mL, 10 mL, 15 mL, 30 mL, 65 mL)

Pharmacology

Mechanism of Action

Gadobutrol is a gadolinium-containing, nonionic 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

Rapid into extracellular space

Metabolism

Not metabolized

Excretion

Urine (>90% as unchanged drug); feces (negligible)

Half-Life Elimination

Normal renal function: ~1.5 to 2 hours; severe renal dysfunction (CrCl <30 mL/minute): 17.6 hours (mean)

Use in Specific Populations

Special Populations: Renal Function Impairment

The elimination half-life was 5.8 hours in mild-to-moderately impaired patients (CrCl 30 to 80 mL/minute) and 17.6 hours in severely impaired patients not on dialysis (CrCl <30 mL/minute). The mean AUC in patients with healthy renal function was 1.1 mmol•h/L compared with 4 mmol•h/L in patients with mild-to-moderate renal impairment, and 11.5 mmol•h/L in patients with severe renal impairment.

Special Populations: Elderly

AUC was slightly higher and clearance slightly lower in elderly patients.

Use: Labeled Indications

US labeling:

Breast malignancy imaging: Contrast medium for use with MRI to assess the presence and extent of malignant breast disease.

Cardiac imaging: MRI (CMRI) to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease.

CNS imaging: MRI in adults, adolescents, and pediatric patients (including term neonates) to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the CNS.

Supra-aortic or renal artery angiography: Magnetic resonance angiography (MRA) in adult and pediatric patients (including term neonates) to evaluate known or suspected supra-aortic or renal artery disease.

Canadian labeling:

Breast malignancy imaging: Contrast medium for use with MRI to assess the presence and extent of malignant breast disease.

CNS imaging: Contrast medium for MRI of CNS lesions (brain, spine, and associated tissues) and for perfusion studies to diagnose stroke, or to detect focal cerebral ischemia or tumor perfusion.

Contrast-enhanced magnetic resonance angiography: Contrast medium for contrast-enhanced magnetic resonance angiography (CE-MRA).

Renal imaging: Contrast medium for MRI of the kidney.

Contraindications

Severe hypersensitivity reactions to gadobutrol or any component of the formulation.

Dosage and Administration

Dosing: Adult

Diagnostic imaging: IV:

US labeling:

Breast malignancy imaging, CNS imaging, and supra-aortic or renal artery angiography: 0.1 mmol/kg (0.1 mL/kg); may begin imaging immediately after administration

Cardiac imaging: 0.05 mmol/kg (0.05 mL/kg) at peak pharmacological stress, followed by 0.05 mmol/kg (0.05 mL/kg) at rest

Canadian labeling:

Breast malignancy imaging: Usual dose: 0.1 mmol/kg (0.1 mL/kg); maximum: 0.3 mmol/kg (0.3 mL/kg)

CNS imaging:

General imaging: 0.1 mmol/kg (0.1 mL/kg); if needed, a second dose of 0.1 to 0.2 mmol/kg (0.1 to 0.2 mL/kg) may be repeated once within 30 minutes of the first dose

Exclusion of metastatic or recurrent tumors: 0.3 mmol/kg (0.3 mL/kg)

Perfusion studies: 0.1 to 0.3 mmol/kg (0.1 to 0.3 mL/kg)

CE-MRA:

Imaging of a single field of view (FOV):

Patient weight <75 kg: 7.5 mL

Patient weight ≥75 kg: 10 mL

Imaging >1 FOV:

Patient weight <75 kg: 15 mL

Patient weight ≥75 kg: 20 mL

Renal imaging: Usual dose: 0.1 mmol/kg (0.1 mL/kg); maximum: 0.3 mmol/kg (0.3 mL/kg)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Diagnostic imaging: IV:

US labeling: CNS imaging, supra-aortic or renal artery angiography: Neonates, Children, and Adolescents: Refer to adult dosing

Canadian labeling: CNS imaging/CE-MRA or renal imaging: Newborns, Infants, Children, and Adolescents: 0.1 mmol/kg (0.1 mL/kg); do not exceed recommended dose. Sequential or repeat dosing has not been studied; allow ≥7 days before considering repeat administration.

Administration

IV: Do not administer other medications in the same IV line simultaneously.

Breast malignancy imaging: Administer as an IV bolus by power injector, followed by NS flush. Post contrast MRI can commence immediately following contrast administration.

Cardiac imaging: Administer as 2 separate IV bolus injections by power injector, at a rate of ~4 mL/second; follow each injection by a 20 mL NS flush at the same rate. If concomitantly administering a continuous infusion of pharmacologic stress agent, administer gadobutrol through a separate IV line in the contralateral arm.

CNS imaging: Administer as an IV injection, manually or by power injector, at a rate of ~2 mL/second, followed by a NS flush. Post contrast MRI can commence immediately following contrast administration.

Supra-aortic or renal artery angiography: Image acquisition should coincide with peak arterial concentration, which varies among patients.

Adult: Administer by power injector, at a rate of ~1.5 mL/second, followed by a 30 mL NS flush at the same rate.

Canadian labeling: For perfusion studies, automatic injector is recommended at an infusion rate of 3 to 5 mL/second

May be a 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 five 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 five separate 1 mL injections around the extravasation site has been also used successfully (Rowlett 2012).

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). If freezing occurs; bring to room temperature before use; do not use unless solution is clear, colorless to pale yellow. Discard any unused drug. Pharmacy bulk package must be discarded within 24 hours after opening in a sterile environment.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

1% to 10%:

Central nervous system: Headache (2%)

Gastrointestinal: Nausea (1%)

<1%, postmarketing, and/or case reports: Altered sense of smell, anaphylactic shock, anaphylaxis, angioedema, dizziness, dysgeusia, dyspnea, erythema of skin, feeling hot, hypersensitivity reaction, injection site reaction, loss of consciousness, maculopapular rash, malaise, nephrogenic systemic fibrosis, palpitations, paresthesia, parosmia, pruritus, seizure, sensation of cold, skin rash, tachycardia, urticaria, vomiting, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• Extravasation: May be a vesicant (higher osmolar contrast agents and/or higher volumes are associated with a higher risk). Ensure proper needle or catheter placement prior to and during administration. Monitor infusion site. Avoid extravasation; local tissue irritation may occur.
• 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 other hypersensitivity reactions (some fatal) have occurred (with mild to severe cardiovascular, respiratory or dermatologic involvement). Reactions typically occur within 30 minutes of administration; however, delayed reactions may also occur (up to several days following administration). Appropriate equipment (eg, ventilator) and emergency medications (eg, epinephrine) should be available during use. Use with caution in patients with a history of allergic reactions and/or bronchial asthma may be at an increased risk for developing hypersensitivity reactions.
• Nephrogenic systemic fibrosis (NSF): [US Boxed Warning]: Gadolinium-based contrast agent (GBCA) exposure increases the risk for 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 (GFR <30 mL/minute/1.73 m²). 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).

All patients should be screened for renal dysfunction prior to administration; estimate GFR in patients at risk for chronic renal disease (diabetes, chronic hypertension, age >60 years). In patients at risk of NSF, do not exceed the recommended dosage and allow sufficient time (ie, several half-lives) for elimination prior to readministration (avoidance of readministration preferred). In patients receiving hemodialysis, consider prompt initiation of hemodialysis following administration.

Disease-related concerns:

• 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 gadolinium agents, generally within 48 hours following administration. In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred. Evaluate renal function in patients with renal impairment prior to use; consider follow-up monitoring.
• Seizure disorder: Use with caution in patients with a history of seizure disorder; may lower seizure threshold. Injectable anticonvulsant agents should be readily available.

Other warnings/precautions:

• Scan interpretation: Certain lesions may not appear with contrast-enhanced scan that do appear with noncontrast imaging; use caution when interpreting. Overestimation of extent of malignant disease in MRI of the breast has occurred in up to 50% of patients. A negative MRA study alone should not be used to rule out significant stenosis; performance of MRA for detecting arterial segments with significant stenosis (>50% renal, >70% supra-aortic) has not been shown to exceed 55%.

Monitoring Parameters

Renal function; signs of hypersensitivity (during and for several hours after procedure); short- and long-term monitoring of signs and symptoms of NSF/NFD (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 for signs/symptoms of extravasation.

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

What is this drug used for?

• It is used during an MRI (magnetic resonance imaging) or MRA (magnetic resonance angiography) test.

Frequently reported side effects of this drug

• Headache
• Nausea
• Change in taste
• Cold or warm sensation at injection site
• Sensation of warmth
• Dizziness

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Nephrogenic systemic fibrosis like 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
• Kidney problems like unable to pass urine, blood in urine, change in amount of urine passed, weight gain
• Severe injection site redness, swelling, pain or irritation
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.