Gadavist® (gadobutrol) injection 1 mmol/mL

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Gadavist® (gadobutrol) injection

Gadavist® (gadobutrol) injection is a gadolinium-based contrast agent indicated for use with 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)
  • To assess the presence and extent of malignant breast disease

The Gadavist® macrocyclic chelate binds the Gd3+ ion in a cage, which imparts added strength compared with a linear structure.¹

To view MRI case studies using Gadavist® click here to go to the CNS Image Library.

* Relaxivity of Gadavist® is 5.2 L•mmol–1• s–1 at 1.5 Tesla (r1 in plasma at 37°C)

High Relaxivity*, Macrocyclic Bond

Strong Signal Enhancement

Factors involved in signal enhancement

Signal enhancement is based on multiple factors, including relaxivity, magnet field strength, and concentration in tissue.¹

What is relaxivity?

Relaxivity is a measure of the ability of magnetic compounds—like MR-contrast agents—to increase the relaxation rates of surrounding water protons. A high-relaxivity contrast agent may improve signal enhancement in contrast-enhanced images.

*Relaxivity of Gadavist is 5.2 L•mmol–1• s–1 at 1.5 Tesla (r1 in plasma at 37°C)

Macrocyclic Structure

Gadolinium-chelate complexes

The most widely used MRI-contrast agents are gadolinium-based, due to the high paramagnetism of the gadolinium ion, and are manufactured with a ligand bound to the central gadolinium (Gd3+) ion. The ligand forms a stable chelated complex around the gadolinium ion and reduces the chance of toxicity that could result from exposure to free gadolinium in the body.2

Structural classes of GBCA

There are 2 structural classes of GBCA chelates—macrocyclic and linear.3 Macrocyclic ligands bind gadolinium ions in a cage structure, while linear ligands bind gadolinium ions with a chain structure.4 Gadavist® is 1 of 3 macrocyclic contrast agents approved for use in CNS imaging in the US. Molecular structures of representative agents from each class are shown below.

Structures of GBCA approved for CNS imaging:

References: 1. Gadavist [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2014. 2. Marie-France Bellin, Aart J. Van Der Molen. Extracellular gadolinium-based contrast media: An overview. European Journal of Radiology. 2008;66:160-167. 3. Frenzel T, Lengsfeld P, Schirmer H, et al. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol. 2008;43(12):817-828. 4. Morcos SK. Extracellular gadolinium contrast agents: Differences in stability. European Journal of Radiology. 2008;66:175-179.

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The First and Only Contrast Agent Indicated for Breast MRI (BMR)

Breast MRI is a Radiation-free Imaging Modality with High Sensitivity

According to the American College of Radiology (ACR), some key uses of breast MRI include:

  • Detection and characterization of disease1
  • Assessment of local extent of disease1
  • Guidance for biopsy and localization1

For women with greater than 20% lifetime risk for development of breast cancer, both the Society of Breast Imaging and the American College of Radiology recommend annual screening breast MRI be performed in addition to annual mammography.2

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

Who is At Risk for Breast Cancer

1 in 8 mothers, sisters, daughters, and friends in the United States will be diagnosed with Breast Cancer

*Both invasive and in situ breast cancer

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.

References: 1. American College of Radiology. ACR Practice Guideline for the Performance of Contrast-enhanced Magnetic Resonance Imaging (MRI) of the Breast. http://www.acr.org/~/media/2a0eb28eb59041e28 25179afb72ef624.pdf. Accessed May 27, 2014. 2. Lee CH, Dershaw DD, Kopans D, et al. Breast cancer screening with imaging: recommendations from the Society of Breast Imaging and the ACR on the use of mammography, breast MRI, breast ultrasound, and other technologies for the detection of clinically occult breast cancer. J Am Coll Radiol. 2010;7(1):18-27. 3. American Cancer Society. Breast Cancer Overview. http://www.cancer.org/acs/groups/cid/documents/webcontent/003037-pdf.pdf. Accessed May 27, 2014.

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Efficacy in Clinical Trials - Breast

Clinical Trial Design Overview

Gadavist® is Indicated for Intravenous Use in MRI of the Breast to Assess the Presence and Extent of Malignant Breast Disease.

Bayer demonstrated the benefit of Gadavist® in breast MRI in two identical Phase III clinical trials.1

Clinical Trial Design Overview
  • Standard of Truth was determined through a two-physician panel:
  • All available reports from biopsies, surgery, pathology, X-Ray mammography (XRM), and ultrasound (excluding MRI)
  • Histology for all malignant lesions
  • Ultrasound plus XRM for disease-free breast regions

Sensitivity of BMR with Gadavist® for Detection of Malignant Breast Disease

The within-patient sensitivity of BMR with Gadavist® was superior to that of unenhanced MRI. The lower bound of the 95% confidence interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for study 1 and from 12% to 27% for Study 2.2

BMR with Gadavist® demonstrated superior within-patient sensitivity (presence and extent) of malignant disease to that of unenhanced MRI for all six readers. Within-patient sensitivity for Gadavist® ranged from 80-89%.2

Readers reported statistically significant improvement in diagnostic confidence with Gadavist®-enhanced BMR (versus unenhanced).1

Assessment of malignant disease was performed using region-based within-subject sensitivity. Sensitivity for each reading modality was defined as the mean of the percentage of malignant breast regions correctly interpreted for each subject. The false positive detection rates for Gadavist® BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%).2

Sensitivity Charts 1 and 2

Three additional readers in each study read XRM alone. Based on this patient population, within-patient sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94% for these readers over both studies.2

Specificity of Gadavist® BMR in Non-malignant Breasts

BMR with Gadavist® demonstrated breast-level specificity surpassing a performance threshold of 80% in non-malignant breasts for five out of six readers.2

In breasts with malignancy, a false positive detection rate was calculated as the percentage of subjects for which the readers assessed a region as malignant which could not be verified by SoT. The false positive detection rates for Gadavist® BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%).2 Three additional readers in each study read XRM alone. Based on this patient population, specificity in non-malignant breasts ranged from 86% to 94% for these readers over both studies.2

Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant.2

References: 1. Data on File. Bayer HealthCare. 2. Gadavist [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2014.

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Gadavist® Breast Case Study

Patients with recently diagnosed breast cancer were enrolled in two identical clinical trials to evaluate the ability of Gadavist® to assess the presence and extent of malignant breast disease prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to Gadavist® (0.1 mmol/kg) breast MRI. BMR images and Gadavist® BMR (combined contrast plus non-contrast) images were independently evaluated in each study by three readers blinded to clinical information. In separate reading sessions, the BMR images and Gadavist® BMR images were also interpreted together with X-ray mammography images (XRM).

Below is a case study from the US Phase III clinical trial. Overall study results follow below. Additional information can also be found here.

History

63-year-old African American female underwent routine annual mammography and was diagnosed by X-Ray mammography with a Breast Imaging Reporting and Data System (BI-RADS) 4 lesion which was biopsied. Histology confirmed a malignant lesion.

Dosage and Administration

Patient weight was 64 kg, so 6.4 mL of Gadavist® 1.0 molar was administered by Medrad® Spectris Solaris® EP power injector at a rate of 2cc/sec followed by a 20cc saline flush.

Right and Left X-Ray Mammogram

Right and Left X-Ray Mammogram. The white arrow demonstrates a suspicious region in the left breast with architectural distortion, mass effect, and spiculation in region 2 (upper outer quadrant). BI-RADS 4(C). This mass was biopsied and patient has pathologically proven malignant breast cancer.

Unenhanced Breast MRI

Unenhanced Breast MRI. Two axial slices at different levels. Image C shows the level of the index lesion seen on X-Ray mammography but there is no definite lesion seen on the non-contrast MRI. Only a large central area of increased intensity can be seen. Likewise, Image D shows that there is no lesion seen in the contralateral breast.

Gadavist®-enhanced Breast MRI

Gadavist®-enhanced Breast MRI. The two axial images corresponding to the non-contrast again at different levels. Image E shows the index lesion seen on X-Ray mammography indicated by the white arrow. It has bright enhancement exceeding the surrounding breast tissue consistent with a malignant lesion. However, Image F shows that there is an additional enhancing lesion indicated by a white arrow in the contralateral (right) breast consistent with a malignant lesion in the contralateral breast that was not detected by unenhanced breast MRI with or without X-Ray mammography. This lesion was biopsied and pathologically shown to be a second foci of breast cancer.

Conclusion

The primary malignancy in the upper outer quadrant of the left breast was seen on both X-Ray mammography as well as the Gadavist®-enhanced MRI. The contralateral breast malignancy was not seen with unenhanced breast MRI alone or in combination with X-Ray mammography but was detected with Gadavist®-enhanced breast MRI. Gadavist®-enhanced breast MRI revealed that this subject had a greater extent of malignant disease (bilateral breast cancer) which was important for appropriate surgical planning.

The Within-patient Sensitivity of BMR with Gadavist® was Superior to That of Unenhanced MRI

The lower bound of the 95% Confidence Interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for Study 1 and from 12% to 27% for Study 2.

Sensitivity Charts 1 and 2

Three additional readers in each study read XRM alone. Based on this patient population, within-patient sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94% for these readers over both studies.

The false positive detection rates for Gadavist® BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%).1

References: 1. Gadavist [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2014.

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Efficacy in CNS Clinical Trials

In 2 US Phase III clinical trials of 657 patients (18-85), compared to pre-contrast MRI, Gadavist®-enhanced MRI demonstrated:

Improved lesion visualization (average reader)¹

  • Superior contrast enhancement (P<0.001)
  • Superior border delineation (P<0.001)
  • Superior internal morphology (P<0.001)

Improved assessment of normal and abnormal CNS anatomy¹

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. 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 (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.
  • 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 from the body prior to any re-administration.

Pediatric Patients

Two studies in 44 pediatrics patients age younger than 2 years and 135 pediatric patients age 2 to less than 18 years supported extrapolation of adult CNS efficacy findings. For example, comparing pre vs paired pre- and post-contrast images, investigators selected the best of four descriptors under the heading, "Visualization of lesion-internal morphology (lesion characterization) or homogeneity of vessel enhancement" for 27/44 (62% = pre) vs 43/44 (98% = paired) MR images from patients age 0 to less than 2 years and 106/135 (78% = pre) vs 108/135 (80% = paired) MR images from patients age 2 to less than 18 years.1

References: 1. Gadavist [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2014.

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Safety in Clinical Trials

Safety

In 38 clinical trials of 6,330 patients worldwide, Gadavist® established the following safety profile¹. Adverse reactions associated with the use of Gadavist® are usually mild to moderate in severity and transient in nature. The adverse reactions that occured in ≥0.1% of subjects who received Gadavist® were¹:

*Hypersensitivity/anaphylactoid reaction may occur with one or more of the following adverse reactions: for example, hypotension, urticaria, face edema, eyelid edema, flushing.

Contraindication and Important Information about Hypersensitivity Reactions

Gadavist® is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist®. Anaphylactoid and anaphylactic reactions with cardiovascular, respiratory, or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist® administration. Patients with any history of a reaction to contrast media, bronchial asthma, and/or allergic disorders may have an increased risk for a hypersensitivity reaction to Gadavist®.

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.

Please see Full Prescribing Information.

References: 1. Gadavist [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2014. 2. FDA Drug Safety Communication: New warnings for using gadolinium-based contrast agents in patients with kidney dysfunction. FDA website. http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm. Updated September 9, 2010. Accessed November 13, 2012

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Dosing

Double the Concentration, Half the Volume

Concentration

Gadavist® is formulated at a higher concentration (1 mmol/mL) compared to certain other gadolinium-based contrast agents, resulting in a lower volume of administration and a more compact bolus compared to 0.5 molar agents.

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.

Please see Additional Safety Information.

Dosing

The recommended dose of Gadavist® for adult and pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to the chart below to determine the volume to be administered.

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Packaging

Gadavist® is a clear, colorless-to-pale yellow solution containing 1 mmol gadobutrol per milliliter (equivalent to 604.72 mg gadobutrol per mL).

Gadavist® is supplied in the following sizes:

Ordering Information

Gadavist® is available through all suppliers currently providing our other imaging products. To establish an account, call Bayer HealthCare LLC's master distributor, McKesson Specialty Distribution, at 1-877-259-4624 (option #1), or contact your local distributor.

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Reimbursement

Reimbursement Helpline

The Bayer Imaging Reimbursement Helpline is available to all institutions to provide further information. The Helpline can be reached at 1-800-423-7539.

Billing for Gadavist®

HCPCS code A9585 has been established by the Centers for Medicare and Medicaid Services (CMS) for Gadavist®. CMS sought to assign a code which would allow for accurate billing of Gadavist® presentations.

The code descriptor for A9585 is per 0.1mL. When billing it is important to remember to multiply the amount of Gadavist® used by 10 in order to list the correct number of units on the claim form.

  • 2 mL = 20 units
  • 7.5 mL = 75 units
  • 10 mL = 100 units
  • 15 mL = 150 units

Hospital-based outpatient HCPCS code for use with Gadavist®

Freestanding HCPCS code for use with Gadavist

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Purchasing

Reference: 1. Morcos SK. Extracellular gadolinium contrast agents: Differences in stability. European Journal of Radiology. 2008;66:175-179.

Featured Videos

Gadavist® Video Case Study 1 (8:39 mins)

45-year-old female with relapsing, remitting multiple sclerosis demonstrated slight disease progression. A Gadavist®-enhanced MRI was performed to detect the presence of disease activity. Gadavist® is Pregnancy Category C. Patient was screened for pregnancy prior to Gadavist® administration.

Gadavist® Video Case Study 2 (10:44 mins)

29-year-old female with multiple sclerosis presented with unilateral visual decrease. A Gadavist®-enhanced MRI was performed to detect lesions in the central nervous system. Gadavist® is Pregnancy Category C. Patient was screened for pregnancy prior to Gadavist® administration.

Gadavist® Video Case Study 3 (8:43 mins)

A 44-year-old female presented with glioblastoma and a previous history of low-grade astrocytoma that changed into anaplastic high-grade glioma. Follow-up was conducted with a Gadavist®-enhanced MRI. Gadavist® is Pregnancy Category C. Patient was screened for pregnancy prior to Gadavist® administration.

Gadavist® Video Case Study 4 (9:47 mins)

A 45-year-old male presented with altered mental status. Initial CT scan indicated a mass lesion within the CNS. The patient was immediately admitted for follow up with a Gadavist®-enhanced MRI.

Gadavist® Video Case Study 5 (7:37 mins)

A 25-year-old woman presented with sudden onset of parasthesia and weakness on her right side. The patient was evaluated with a Gadavist®-enhanced MRI. Gadavist® is Pregnancy Category C. Patient was screened for pregnancy prior to Gadavist® administration.

Gadavist® Video Case Study 6 (9:52 mins)

Learn about breast imaging and the Gadavist® clinical trial for breast MRI from one of the clinical trial's Principal Investigators (PI), Dr Gillian Newstead, of the University of Chicago.

Gadavist® Video Case Study 7 (10:25 mins)

63-year-old female with an abnormal finding in the left breast, seen on mammography and ultrasound.

Gadavist® Video Case Study 8 (10:00 mins)

76-year-old female with a mass in the left breast.

INDICATIONS and IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE

Gadavist® (gadobutrol) injection is a gadolinium-based contrast agent indicated for use with 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)
  • To assess the presence and extent of malignant breast disease

IMPORTANT SAFETY INFORMATION

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. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.

  • The risk of 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.
  • 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 from the body prior to any re-administration.

Contraindication and Important Information about Hypersensitivity Reactions: Gadavist® is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist®. 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®.

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: The most frequent (≥0.5%) adverse reactions associated with Gadavist® in clinical studies were headache (1.5%), nausea (1.2%) and dizziness (0.5%).

Please see Full Prescribing Information.

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