Gadobutrol

Gadobutrol
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING See full prescribing information for complete Boxed Warning. NEPHROGENIC SYSTEMIC FIBROSIS (NSF): Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), 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 (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

Overview

Gadobutrol is a gadolinium-based contrast agent that is FDA approved for the {{{indicationType}}} of magnetic resonance imaging (MRI) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system in adult and pediatric patients (including term neonates and to assess the presence and extent of malignant breast disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, and dizziness.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS)

Gadavist is indicated for use with magnetic resonance imaging (MRI) in adult and pediatric patients (including term neonates) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system.

MRI of the Breast

Gadavist is indicated for use with MRI to assess the presence and extent of malignant breast disease.

Recommended Dose

• The recommended dose of Gadavist for adult is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Gadobutrol in adult patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadobutrol in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS)

Gadavist is indicated for use with magnetic resonance imaging (MRI) in adult and pediatric patients (including term neonates) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system.

MRI of the Breast

Gadavist is indicated for use with MRI to assess the presence and extent of malignant breast disease.

Recommended Dose

• The recommended dose of Gadavist for pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table 1 to determine the volume to be administered.

T1

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Gadobutrol in pediatric patients.

Non–Guideline-Supported Use

Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadobutrol in pediatric patients.

Contraindications

• Gadavist is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist.

Warnings

WARNING See full prescribing information for complete Boxed Warning. NEPHROGENIC SYSTEMIC FIBROSIS (NSF): Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. The risk for NSF appears highest among patients with: Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), 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 (for example, age >60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

Precautions

• Nephrogenic Systemic Fibrosis

• Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadavist administration to Bayer Healthcare (1-888-842-2937) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).
• Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
• Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended Gadavist dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown.

• Hypersensitivity Reactions

• Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist administration.

• • Before Gadavist administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to Gadavist.
  • Administer Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.

• Most hypersensitivity reactions to Gadavist have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following Gadavist administration.

• Acute Kidney Injury

• In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses.

• Extravasation and Injection Site Reactions

• Ensure catheter and venous patency before the injection of Gadavist. Extravasation into tissues during Gadavist administration may result in moderate irritation.

• Overestimation of Extent of Malignant Disease in MRI of the Breast

• Gadavist MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients.

Adverse Reactions

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

• The adverse reactions described in this section reflect Gadavist exposure in 6,330 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 50% of the subjects were male and the ethnic distribution was 60% Caucasian, 30% Asian, 6% Hispanic, 2% Black, and 3% patients of other ethnic groups. The average age was 55 years (range from1 week to 93 years).

• Overall, approximately 4% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after Gadavist administration.

• Adverse reactions associated with the use of Gadavist were usually mild to moderate in severity and transient in nature.

• Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received Gadavist.

T2

• Adverse reactions that occurred with a frequency of < 0.1% in subjects who received Gadavist include: loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold.

Postmarketing Experience

• The following additional adverse reactions have been reported during postmarketing use of Gadavist. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Cardiac arrest
• Nephrogenic Systemic Fibrosis (NSF)
• Hypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) [see Warnings and Precautions (5.2)]

Drug Interactions

There is limited information regarding Gadobutrol Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category C

• Risk Summary

• There are no adequate and well-controlled studies of Gadavist in pregnant women. GBCAs cross the human placenta. Limited human data on exposure to GBCAs during pregnancy does not show adverse effects in exposed neonates. Animal reproductive studies were conducted (see Animal Data). Embryolethality but no teratogenic effects were observed in monkeys, rabbits and rats. Use Gadavist during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Animal Data

• Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol (≥ 7.5 mmol/kg body weight; equivalent to12 times the human dose based on body surface area) and in pregnant rabbits (≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses).
• Gadavist was not teratogenic when given intravenously to monkeys during organogenesis at doses up to 8 times the recommended single human dose (based on body surface area) but was embryolethal at that dose. Because pregnant animals received repeated daily doses of Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadobutrol in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Gadobutrol during labor and delivery.

Nursing Mothers

• It is not known whether Gadavist is present in human milk. However, reports on use of other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breast-fed infant. In rat lactation studies, gadobutrol was present in milk in amounts less than 0.1% of the dose intravenously administered and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). In lactating rats receiving 0.5 mmol/kg of intravenous [153Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk, within 3 hours after administration.

• A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk up to18 hours after Gadavist administration in order to minimize exposure to a breastfed infant.

Pediatric Use

• The safety and effectiveness of Gadavist have been established in pediatric patients born at 37 weeks gestation or later based on imaging and pharmacokinetic data in 138 patients ages 2 to 17 years and 44 patients ages 0 to less than 2 years and extrapolation from adult data. The frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults. No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of Gadavist have not been established in premature infants.

• NSF Risk

• No case of NSF associated with Gadavist or any other GBCA has been identified in pediatric patients ages 6 years and younger. Pharmacokinetic studies suggest that clearance of Gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. No increased risk factor for NSF has been identified in juvenile animal studies of gadobutrol. Normal estimated GFR (eGFR) is around 30 mL/min/1.73m2 at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum eGFR: 31 mL/min/1.73m2 (age 2 to 7 days), 38 mL/min/1.73m2 (age 8 to 28 days), 62 mL/min/1.73m2 (age 1 to 6 months), and 83 mL/min/1.73m2 (age 6 to 12 months).

• Juvenile Animal Data

• Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants.

Geriatic Use

• In clinical studies of Gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of Gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No dose adjustment according to age is necessary in this population.

Gender

There is no FDA guidance on the use of Gadobutrol with respect to specific gender populations.

Race

There is no FDA guidance on the use of Gadobutrol with respect to specific racial populations.

Renal Impairment

• Prior to administration of Gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. No dosage adjustment is recommended for patients with renal impairment.

• Gadavist can be removed from the body by hemodialysis.

Hepatic Impairment

There is no FDA guidance on the use of Gadobutrol in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Gadobutrol in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Gadobutrol in patients who are immunocompromised.

Administration and Monitoring

Administration

• Intravenous

Monitoring

There is limited information regarding Monitoring of Gadobutrol in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Gadobutrol in the drug label.

Overdosage

Acute Overdose

• The maximum dose of Gadavist tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg) (15 times the recommended dose), was tolerated in a manner similar to lower doses. Gadavist can be removed by hemodialysis.

Chronic Overdose

There is limited information regarding Chronic Overdose of Gadobutrol in the drug label.

Pharmacology

Template:Px
Gadobutrol
Systematic (IUPAC) name
gadolinium(III) 2,2',2''-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate
Identifiers
CAS number	138071-82-6
ATC code	V08CA09
PubChem	72057
DrugBank	DB06703
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	604.710 g/mol
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Licence data	US
Pregnancy cat.	C(US)
Legal status	POM(UK) [[Prescription drug|Template:Unicode-only]](US)
Routes	IV

Mechanism of Action

• In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with:

• Differences in proton density
• Differences of the spin-lattice or longitudinal relaxation times (T 1)
• Differences in the spin-spin or transverse relaxation time (T 2)

• When placed in a magnetic field, Gadavist shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from Gadavist, is based upon several factors including the concentration of Gadavist in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1-weighted magnetic resonance sequences. In T2*-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to a signal decrease.

Structure

• Gadavist (gadobutrol) injection is a paramagnetic macrocyclic contrast agent administered for magnetic resonance imaging. The chemical name for gadobutrol is 10–[(1SR,2RS)–2,3–dihydroxy–1–hydroxymethylpropyl]–1,4,7,10–tetraazacyclododecane–1,4,7–triacetic acid, gadolinium complex. Gadobutrol has a molecular formula of C18H31GdN4O9 and a molecular weight of 604.72.

This image is provided by the National Library of Medicine.

• Gadavist is a sterile, clear, colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol/mL) as the active ingredient and the excipients calcobutrol sodium, trometamol, hydrochloric acid (for pH adjustment) and water for injection. Gadavist contains no preservatives.

• The main physicochemical properties of Gadavist (1 mmol/mL solution for injection) are listed below:

T

• The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Gadobutrol in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Gadobutrol in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Gadobutrol in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Gadobutrol in the drug label.

How Supplied

Storage

There is limited information regarding Gadobutrol Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Gadobutrol |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Gadobutrol |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Gadobutrol in the drug label.

Precautions with Alcohol

• Alcohol-Gadobutrol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

{{#subobject:

 |Page Name=Gadobutrol
 |Pill Name=No image.jpg
 |Drug Name=
 |Pill Ingred=|+sep=;
 |Pill Imprint=
 |Pill Dosage=
 |Pill Color=|+sep=;
 |Pill Shape=
 |Pill Size (mm)=
 |Pill Scoring=
 |Pill Image=
 |Drug Author=
 |NDC=

}}

{{#subobject:

 |Label Page=Gadobutrol
 |Label Name=Gadobutrol11.png

}}

{{#subobject:

 |Label Page=Gadobutrol
 |Label Name=Gadobutrol11.png

}}