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Gadobutrol

Pronunciation

(gad oh BYOO trol)

Index Terms

  • Gadovist 1.0

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)

Brand Names: U.S.

  • Gadavist

Pharmacologic Category

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

Pharmacology

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.

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)

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. 68%of gadobutrol is removed from the body after dialysis, 94% after a second dialysis, and 98% after a third dialysis session.

Special Populations: Elderly

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

Use: Labeled Indications

US labeling:

Central nervous system (CNS) imaging: Magnetic resonance 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.

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

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.

Central nervous system (CNS) imaging: Contrast medium for magnetic resonance imaging (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.

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

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.

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. 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 (Okada, 2001).

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

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, based on exclusive renal excretion of gadobutrol, dose adjustment in hepatic impairment is likely unnecessary.

Administration

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.

Central nervous system 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.

Pediatric: Administer manually or by power injector; followed by a NS flush.

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

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 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% (Limited to important or life-threatening): Allergic reaction, anaphylactoid reaction, cardiac arrest, convulsions, dysgeusia, erythema, feeling hot, loss of consciousness, nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy (NSF/NFD), orthostatic hypotension, palpitation, paresthesia, parosmia, pruritus, seizure, tachycardia, urticaria

ALERT: U.S. Boxed Warning

Nephrogenic systemic fibrosis:

Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of gadolinium-based contrast agents in these patients unless the diagnostic information is essential and not available with noncontrasted magnetic resonance imaging (MRI) or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle, and internal organs.

The risk for 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 for NSF, do not exceed the recommended gadobutrol dose and allow a sufficient period of time for elimination of the drug from the body prior to any readministration.

Warnings/Precautions

Concerns related to adverse effects:

• Extravasation: High osmolar contrast agents are vesicants. Ensure proper needle or catheter placement prior to and during administration. Avoid extravasation; local tissue damage/reactions may occur.

• Hypersensitivity reactions: 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). 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).

All patients should be screened for renal dysfunction prior to administration; estimate GFR in patients at risk for chronic renal disease (diabetes, 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 for signs/symptoms of extravasation.

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), severe injection site pain or irritation, burning, or blue or gray skin color (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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