Gadavist® (gadobutrol) injection 1 mmol/mL


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Gadavist® (gadobutrol) injection

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

* 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 2 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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Efficacy in Breast Clinical Trials

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 noncontrast) 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).

The studies evaluated 787 patients. Study 1 enrolled 390 women with an average age of 56 years: 74% were white; 25% Asian; 0.5% black; and 0.5% other. Study 2 enrolled 396 women and 1 man with an average age of 57 years: 71% were white; 24% Asian; 3% black; and 2% other.

The readers assessed the presence of malignancy in 5 regions per breast, using each reading modality. The readings were compared to an independent standard of truth (SoT) consisting of histopathology for all regions where excisions were made and tissue evaluated. XRM plus ultrasound was used for all other regions.

The assessment of malignant disease was performed using a 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 within-subject sensitivity of Gadavist® BMR was superior to that of BMR. 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. The within-subject sensitivity for Gadavist® BMR and BMR, as well as for Gadavist® BMR plus XRM, and BMR plus XRM, is presented in the table below.

Specificity was defined as the percentage of non-malignant breasts correctly identified as nonmalignant. The lower limit of the 95% confidence interval for specificity of Gadavist® BMR was greater than 80% for 5 of 6 readers. (See table below.)

Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity ranged from 86% to 94%.

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%)

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Efficacy in CNS Clinical Trials

In 2 US Phase III clinical trials of 657 patients, 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

Lesion counting was also performed in both studies to demonstrate non-inferiority of Gadavist®-enhanced to pre-contrast MRI. While this endpoint was met in 1 of the 2 studies, in the study including gadoteridol, neither Gadavist® nor gadoteridol met this endpoint.

In one of the two studies, as a secondary endpoint, the non-inferiority of Gadavist®-enhanced MRI compared to pre-contrast MRI vs gadoteridol MRI compared to pre-contrast MRI was also evaluated.

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.

Non-inferiority of Gadavist®-enhanced MRI to gadoteridol-enhanced MRI

In 1 of the 2 studies, as a secondary endpoint, the non-inferiority of Gadavist®-enhanced MRI compared to pre-contrast MRI vs gadoteridol-enhanced MRI compared to pre-contrast MRI was also evaluated.

Performances of Gadavist® and gadoteridol for visualization parameters were similar.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 5,748 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. Avoid intramuscular administration of Gadavist®.

Please see Additional Safety Information.

Dosing

The recommended dose of Gadavist® in adults and children 2 years of age and older is 0.1 mL/kg body weight (0.1 mmol/kg).

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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. This code will be available to all payers on January 1, 2012.

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.

INDICATIONS and IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE

Gadavist® (gadobutrol) injection is a gadolinium-based contrast agent indicated for intravenous use:

  • In diagnostic magnetic resonance imaging (MRI) in adults and children (2 years of age and older) to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system.
  • For MRI of the breast 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®. 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.

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. Avoid intramuscular administration of Gadavist®.

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 (1.1%), and dizziness (0.5%).

Please see Full Prescribing Information

You are encouraged to report negative side effects or quality complaints of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.