FDA approves Bayer's Gadavist® (gadobutrol) injection as first contrast agent for use with magnetic resonance angiography of supra-aortic arteries

- FDA approves Gadavist® for magnetic resonance angiography to evaluate known or suspected supra-aortic or renal artery disease

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Bayer

Apr 29, 2016, 11:00 ET

WHIPPANY, N.J., April 29, 2016 /PRNewswire/ -- For U.S. media only -- Bayer announced today that the U.S. Food and Drug Administration (FDA) has approved Gadavist^® (gadobutrol) injection for use with magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates).¹ The FDA approval is based on the results of two, multi-center, Phase 3, open-label clinical studies – the GEMSAV study of patients with known, or suspected vascular disease, of the supra-aortic arteries and the GRAMS study of patients with known or suspected renal artery disease.¹

"Until now, no contrast agents were FDA approved for use with MRA of the supra-aortic arteries," said Dr. Elias Melhem, M.D., Chair, Department of Diagnostic Radiology & Nuclear Medicine, University of Maryland, and principal investigator for the GEMSAV study. "With FDA's action, radiologists now have an approved MRA contrast agent to help visualize supra-aortic arteries in patients with known or suspected supra-aortic arterial disease, including conditions such as prior stroke or transient ischemic attack (TIA)."

In the GEMSAV and GRAMS studies, gadobutrol met the primary objective of superior assessability (ability to see more vessel segments) and non-inferior sensitivity and specificity as compared to non-contrast MRA. Gadobutrol-enhanced MRA demonstrated statistically significant higher assessability (visualization) versus non-contrast MRA images.

"Bayer is delighted to obtain FDA approval for the use of Gadavist for MRA to evaluate known or suspected supra-aortic or renal artery disease," said Dennis Durmis, Vice President of Radiology Commercial Operations – Region Americas. "As an industry leader in contrast media, this is the third expansion of the Gadavist label in the past 24 months based on a robust clinical development program."

About the Studies
The GEMSAV (Gadavist-Enhanced MRA of the Supra-Aortic Vessels) study evaluated 457 patients with known or suspected disease of the supra-aortic arteries. Efficacy was evaluated based on visualization and performance for distinguishing between normal and abnormal anatomy. Significant stenosis was defined as at least 70%.

Key findings of this open-label Phase 3 study, in which Gadavist was delivered at 1.5mL/second, include:

Gadavist MRA significantly improved visualization, or assessability, (range across three readers: 88-97%) as compared to unenhanced MRA (range across three readers: 24-82%).
Gadavist MRA specificity for exclusion of clinically significant disease (range across three readers: 92-97%) showed non-inferiority as compared to unenhanced MRA (range across three readers: 62-89%).
Gadavist MRA sensitivity (range across three readers: 58-60%) showed non-inferiority as compared to unenhanced MRA (range across three readers: 54-55%).
- Low sensitivity for significant arterial stenosis. For all three supra-aortic artery readers, the lower bound of confidence for the sensitivity of Gadavist MRA for detecting arterial segments with significant stenosis did not exceed 54%. A negative MRA alone should not rule out significant stenosis.¹

The GRAMS (Gadavist-Enhanced Renal Artery MRA) study evaluated 292 patients with known or suspected disease of the renal arteries. Efficacy was evaluated based on visualization and performance for distinguishing between normal and abnormal anatomy. Significant stenosis was defined as at least 50%.¹

Key findings of this open-label Phase 3 study, in which Gadavist was delivered at 1.5mL/second, include:

Gadavist MRA significantly improved visualization, or assessability, (range across three readers: 96-98%) as compared to unenhanced MRA (range across three readers: 72-82%).
Gadavist MRA specificity for exclusion of clinically significant disease (range across three readers: 94-95%) showed non-inferiority as compared to unenhanced MRA (range across three readers: 81-85%).
Gadavist MRA sensitivity (range across three readers: 52-54%) showed non-inferiority as compared to unenhanced MRA (range across three readers: 39-51%).
- Low sensitivity for significant arterial stenosis. For all three renal artery readers, the lower bound of confidence for the sensitivity of Gadavist MRA for detecting arterial segments with significant stenosis did not exceed 46%. A negative MRA alone should not rule out significant stenosis.
Gadavist MRA improved visualization of accessory renal arteries for surgical planning and renal donor evaluation as compared to unenhanced MRA.¹

Finally, overall the safety results from the two, Phase 3 MRA studies in patients with known or suspected arterial disease are consistent with the safety data observed in clinical trials in more than 6,000 subjects. The results support the benefit-risk profile of Gadavist for appropriate patients.

These studies are planned to be presented at medical meetings later this spring.

About Gadavist
Gadavist (gadobutrol) injection was first approved in the U.S. in March 2011 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 and/or abnormal vascularity of the central nervous system. Gadavist was further approved in the U.S. in June 2014 for MRI of the breast to assess the presence and extent of malignant breast disease and in December 2014 for pediatric patients less than 2 years of age, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system.

Gadavist, also known as Gadovist^® and Gadovist^® 1.0 in other regions, is the U.S. brand name of the aqueous 1.0M solution of gadobutrol, a gadolinium (Gd)-based extracellular contrast agent for MRI with a macrocyclic structure. The safety profile of Gadavist has been established in clinical trials involving 6,809 patients (including 184 pediatric patients ages 0-17). The safety and effectiveness of Gadavist have not been established in premature infants. Please see Important Safety Information, including Boxed Warning below.

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<30mL/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. 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.

Low Sensitivity for Significant Arterial Stenosis: The performance of Gadavist MRA for detecting arterial segments with significant stenosis >50% renal, >70% supra-aortic has not been shown to exceed 55%. Therefore, a negative MRA study alone should not be used to rule out significant stenosis.

Adverse reactions: The most frequent adverse reactions (>0.5%) associated with Gadavist in clinical studies were headache (1.5%), nausea (1.1%), and dizziness (0.5%).

Please see full prescribing information at
http://labeling.bayerhealthcare.com/html/products/pi/gadavist_PI.pdf

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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.

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Forward-Looking Statements
This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at http://www.bayer.com/. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References

1.Gadavist^® (gadobutrol) Prescribing Information. Whippany, New Jersey, USA: Bayer Pharmaceuticals, Inc.

PP-325-US-0366

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