Gadobutrol (Gadavist) is a gadolinium-based MRI contrast agent that is used in the diagnosis of CNS imaging, cardiac imaging, renal angiography, and detection of breast malignancy.

Gadobutrol Uses:

• US labeling:

  • Breast malignancy imaging: Contrast medium for use with MRI to assess the presence and extent of malignant breast 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 (spine, brain, 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.

Gadobutrol (Gadavist) Dose in Adults

Gadobutrol (Gadavist) Dose in Diagnostic imaging: IV:

• US labeling:

  • Breast malignancy imaging, CNS imaging, and supra-aortic or renal artery angiography:

    • 0.1 mmol per kg (0.1 mL per kg);
    • May begin imaging immediately after administration

• Canadian labeling:

  • Breast malignancy imaging:

    • Usual dose: 0.1 mmol per kg (0.1 mL per kg);
    • The maximum dose: 0.3 mmol per kg (0.3 mL per kg)

  • CNS imaging:

    • General imaging: 0.1 mmol per kg (0.1 mL per kg); if needed, a second dose of 0.1 to 0.2 mmol per kg (0.1 to 0.2 mL per kg) may be repeated once within 30 minutes of the first dose
    • Exclusion of metastatic or recurrent tumors: 0.3 mmol per kg (0.3 mL per kg)
    • Perfusion studies: 0.1 to 0.3 mmol per kg (0.1 to 0.3 mL per 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 per kg (0.1 mL per kg);
    • The maximum: 0.3 mmol per kg (0.3 mL per kg)

Gadobutrol (Gadavist) Dose in Childrens

Gadobutrol (Gadavist) Dose in 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 for a weak or more than a weak before considering repeat administration.

Pregnancy Category: C

• Contrast agents containing gadolinium may cross the placenta.
• If it is expected to significantly improve diagnostic performance, and to improve fetal and maternal outcomes, a gadolinium-based contrast agents with MRI might be considered for pregnancy.
• Contrast agents containing gadolinium-based compounds in pregnancy are controversial and should be avoided.
• Low-risk agents should not be administered at lower doses. Considerations for Breast-Feeding
• Additionally, it is important to only consider using a contrast agent if the information required from an MRI study can't be obtained without using one. This cannot be delayed until after delivery.

Gadobutrol use during breastfeeding:

• Breast milk may contain gadolinium-based, contrast agents.
• Theoretically speaking, milk's taste could be affected if it contains contrast media.
• Women who choose to temporarily stop breastfeeding can express breast milk and then discard it after 12-24 hours.
• Breastfeeding may continue after discontinuation due to the low expected excretion of breast milk and low absorption by infants' GI tract.
• They can store and pump milk before the procedure, then bottle-feed the milk stored during that time.
• According to the manufacturer breastfeeding during therapy is a decision that should be made after considering the risks to infants and the benefits to mothers.

Gadobutrol (Gadavist) Dose in Kidney Disease:

Dose adjustment is not necessary; however, use with caution. The 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 percent, 96 percent, and 99 percent in the first, second, and third hemodialysis sessions, respectively.

• Peritoneal dialysis:

  • Likely to be less efficient at clearing gadolinium.

Dose in Liver disease:

The manufacturer’s labeling doesn't provide any dosage adjustments; however, based on exclusive renal excretion of gadobutrol, dose adjustment in hepatic impairment is likely unnecessary.

Side Effects of Gadobutrol (Gadavist):

• Central nervous system:

  • Headache

• Gastrointestinal:

  • Nausea

Contraindications to Gadobutrol (Gadavist):

Hypersensitivity to gadobutrol and any component of the formulation.

Warnings and precautions

• Extravasation:

  • Monitor infusion site.
  • Could be a vesicant (higher volumes and/or osmolar contrast agents are associated with a greater risk).
  • Before and during administration, ensure proper placement of the needles or catheters.
  • Avoid extravasation. Local tissue irritation could occur.

• Gadolinium retention:

  • Minimize repetitive GBCA imaging studies.
  • Gadolinium can be retained in the brain, bones, skin, liver, and other organs for many months to years. The bone has the highest concentration and longest retention.
  • Gadolinium retention in the brain and in patients with normal renal function has not been shown to have any adverse effects.
  • Linear GBCAs, such as gadodiamide, gadoversetamide, gadoxetate dimeglumine and gadobenate dimeglumine, have a higher retention rate than macrocyclic ones (gadoterate, gadobutrol and gadoteridol).
  • Patients with impaired renal function have had to deal with the clinical and pathologic consequences of gadolinium storage in their skin and other organs.
  • Rarely, however, have they experienced skin problems that were not related to renal impairment.
  • Patients with normal renal function may be more at risk of gadolinium retention.
  • These include patients who require multiple lifetime doses, pregnant or pediatric patients, as well as patients with inflammatory conditions.

• Hypersensitivity

  • Reactions usually occur within 30 minutes after administration. However, delayed reactions can occur (up to several weeks following administration).
  • Appropriate equipment (eg, ventilator) and emergency medications (eg, epinephrine) should be available during use.
  • Anaphylactic reactions and other hypersensitivity reactions (some deadly) have been reported (with mild to severe cardiovascular, respiratory or dermatologic involvement).
  • Patients with a history or bronchial asthma and allergic reactions should be cautious. They may be at greater risk of developing hypersensitivity reactions.

• Nephrogenic systemic Fibrosis (NSF: [US Boxed Warning]

  • Gadolinium-based contrast agents (GBCAs) increase the risk of NSF in patients suffering from renal impairment.
  • Avoid using GBCA-enhanced imagery unless it is absolutely necessary for diagnostic purposes.
  • Patients with severe, acute kidney disease or acute kidney injury are at greatest risk (GFR 30mL/minute/1.73m2).
  • Patients with moderate to severe chronic kidney disease have a lower risk of NSF (GFR 30 to 60 mL/minute per 1.73m2) and patients with milder chronic renal disease have a low GFR (GFR 60 mL/minute per 1.73m2).
  • Consider prompt initiation for patients on hemodialysis.
  • NSF should be reported to the manufacturer or Food and Drug Administration (FDA).
  • Before administering medication, all patients should be tested for kidney dysfunction.
  • Patients at high risk for NSF should not exceed the recommended dose and allow enough time (i.e. several half-lives), for elimination before re-administration. Avoidance of readministration is preferred.
  • Consider prompt hemodialysis for patients on hemodialysis.

• Renal impairment

  • Acute kidney injury has been reported in patients with chronically impaired renal function.
  • Before using, evaluate the renal function of patients with kidney impairment; consider following-up monitoring.
  • Patients with impaired renal function should be cautious.
  • Patients with acute renal impairment have experienced a dose-dependent worsening or severe renal dysfunction after the administration of gadolinium agents. This usually occurs within 48 hours.

• Seizure disorder:

  • Patients with seizure disorders should be cautious as it can lower the seizure threshold.
  • It is important to have injectable anticonvulsant drugs readily available.

Monitoring parameters:

• Renal function;
• signs of hypersensitivity (during and for several hours after the procedure);
• short- and long-term monitoring of signs and symptoms of Nephrogenic systemic fibrosis (NSF/NFD) such as itching, swelling, hardening and/or tightening of skin burning, joint stiffness, deep hip or rib bone pain, muscle weakness, limited range of motion, and/or yellowed/raised spots on whites of eyes.
• monitor infusion site for signs/symptoms of extravasation.

How to administer Gadobutrol?

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.

CNS imaging:

• Administer as an IV injection, manually or by power injector, at a rate of ~2 mL per second, followed by an 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 per second, followed by a 30 mL NS flush at the same rate.

Canadian labeling:

• For perfusion studies, an automatic injector is recommended at an infusion rate of 3 to 5 mL per second.
• It 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, and elevate extremity.
• Aspiration of extravasated contrast media is not recommended. 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, however, other sources suggest its utility in extravasation management.
• If using hyaluronidase: Intradermal or SubQ:
  • Inject a total of 1 to 1.7 mL (15 units per mL) as five separate 0.2 to 0.3 mL injections (using a 25-gauge needle) into the area of extravasation at the leading edge in a clockwise manner or injection of a total of 5 mL (150 units per mL) as five separate 1 mL injections around the extravasation site has been also used successfully.

Mechanism of action of Gadobutrol (Gadavist):

• Gadobutrol is a gadolinium-containing, nonionic paramagnetic agent. 
• The local magnetic field is created when tissues are exposed to an external magnetic force.
• The local magnetism causes water protons to lose their magnetic field, which results in a change of proton density and spin characteristics.
• This can be detected using an imaging device.

Distribution:

• Rapid into extracellular space

Metabolism:

• Not metabolized

Half-life elimination:

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

Excretion:

• Urine (>90 percent  as unchanged drug);
• feces (negligible)

International Brand Names of Gadobutrol:

• Gadavist

Gadobutrol Brand Names in Pakistan:

There is no brand available in Pakistan.