Gadavist

Dosing Form & Strengths

Injectable solution

• 1mmol/mL (ie, 604.72mg/mL)

MRI Contrast

0.1 mmol/kg (0.1 mL/kg) IV bolus

CNS and BBB

• Indicated to detect and visualize areas with disrupted blood brain barrier (BBB) and/or abnormal vascularity of the central nervous system
• Infuse at rate 2 mL/second
• Flush IV cannula with 0.9% NaCl after injection

Breast

• Indicated for use with MRI to assess the presence and extent of malignant breast disease
• Flush IV cannula with 0.9% NaCl after injection

Magnetic resonance angiography

• Indicated for use in magnetic resonance angiography (MRA) to evaluate known or suspected supra-aortic or renal artery disease
• Infuse at rate 1.5 mL/second
• Flush IV cannula with 30 mL of 0.9% NaCl after injection

Renal Impairment

Prior to administration, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests (see Black Box Warnings)

No dosage adjustment is recommended for patients with renal impairment

Removed by hemodialysis

Dosing Form & Strengths

Injectable solution

• 1mmol/mL (ie, 604.72mg/mL)

MRI Contrast

0.1 mmol/kg (0.1 mL/kg) IV bolus

Flush IV cannula with 0.9% NaCl after injection

CNS and BBB

• Indicated 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)
• Infuse at rate 2 mL/second

Magnetic resonance angiography

• Indicated for use in magnetic resonance angiography (MRA) in adult and pediatric patients (including term neonates) to evaluate known or suspected supra-aortic or renal artery disease
• Infuse at rate 1.5 mL/second

Renal Impairment

Prior to administration, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests (see Black Box Warnings)

No dosage adjustment is recommended for patients with renal impairment

Removed by hemodialysis

In clinical studies, 1377 patients were 65 years of age or older, while 104 patients were 80 years of age or older

No overall differences in safety or effectiveness were observed between elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients

In general, use in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy

Gadobutrol is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting during your MRI.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when the medicine is injected.

Your doctor or other healthcare provider may want to watch you for a short time after your test is over. This is to make sure you do not have any unwanted side effects or delayed reactions.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Since gadobutrol is used only during your MRI, you will not be on a dosing schedule.

Included as part of the PRECAUTIONS section.

Gadobutrol can cause a life-threatening condition in people with advanced kidney disease. Before receiving this medicine, tell your doctor if you have kidney disease or if you are on dialysis. You may not be able to receive gadobutrol. Also tell your doctor if you have recently received any contrast agents similar to gadobutrol.

Gadobutrol can cause a life-threatening condition in people with advanced kidney disease. The symptoms of this condition include:

• burning, itching, swelling, scaling, and tightening or hardening of your skin;

• muscle weakness;

• joint stiffness in your arms, hands, legs, or feet;

• deep bone pain in your ribs or your hips;

• trouble moving; or

• skin redness or discoloration.

Before receiving this medicine, tell your doctor if you have kidney disease or if you are on dialysis. You may not be able to receive gadobutrol. Also tell your doctor if you have recently received any contrast agents similar to gadobutrol.

To make sure gadobutrol is safe for you, tell your doctor if you have:

• diabetes;

• high blood pressure;

• liver disease;

• asthma, hay fever, or a history of food or drug allergies;

• a history of seizures;

• if you are over 60 years old;

• if you have ever had any type of reaction to a contrast agent; or

• if you have recently had an injury, surgery, or severe infection.

It is not known whether this medicine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Do not breast-feed within 18 hours after using gadobutrol. If you use a breast pump during this time, throw out any milk you collect. Do not feed it to your baby.

Other drugs may interact with gadobutrol, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

A doctor or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins just before you have an MRI or MRA scan.

It is very important that your doctor check the progress of you or your child while you are receiving this medicine and during the MRI scan. This will allow your doctor to see if the medicine is working properly and to check for unwanted effects.

Check with your doctor or nurse right away if you or your child have burning or itching of the skin, deep bone pain in the hips or ribs, joint stiffness, a limited range of motion in the arms and legs, muscle weakness, red or dark patches on the skin of the arms or legs, or skin swelling, hardening, or tightening within the first few days or weeks after you receive this medicine. These may be symptoms of a very serious disease called nephrogenic systemic fibrosis (NSF).

This medicine may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Check with your doctor or nurse right away if you or your child have chest pain, cold, clammy skin, confusion, dizziness, lightheadedness, a skin rash, itching, sweating, swelling of the face, tongue, and throat, or trouble with breathing after you receive the medicine.

This medicine may increase your risk of having acute kidney injury (AKI). This has occurred in patients with severe kidney problems, and the risk is increased with high doses of gadobutrol.

Tell your doctor right away if you or your child have burning pain, feeling of warmth or coldness, redness or swelling at the injection site.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Blue or gray skin color.
• This medicine may cause tissue damage if the drug leaks from the vein. Tell your nurse if you have any redness, burning, pain, swelling, blisters, skin sores, or leaking of fluid where the drug is going into your body.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies of gadobutrol have been conducted.

Gadobutrol was not mutagenic in in vitro reverse mutation tests in bacteria, in the HGPRT (hypoxanthine-guanine phosphoribosyl transferase) test using cultured Chinese hamster V79 cells, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of 0.5 mmol/kg.

Gadobutrol had no effect on fertility and general reproductive performance of male and female rats when given in doses 12.2 times the human equivalent dose (based on body surface area).

Animal Toxicology and/or Pharmacology

Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in a clinical setting [see Warnings and Precautions (5.4)].

MRI of the CNS

Patients referred for MRI of the central nervous system with contrast were enrolled in two clinical trials that evaluated the visualization characteristics of lesions. In both studies, patients underwent a baseline, pre-contrast MRI prior to administration of Gadavist at a dose of 0.1 mmol/kg, followed by a post-contrast MRI. In Study A, patients also underwent an MRI before and after the administration of gadoteridol. The studies were designed to demonstrate superiority of Gadavist MRI to non-contrast MRI for lesion visualization. For both studies, pre-contrast and pre-plus-post contrast images (paired images) were independently evaluated by three readers for contrast enhancement and border delineation using a scale of 1 to 4, and for internal morphology using a scale of 1 to 3 (Table 5). Lesion counting was also performed to demonstrate non-inferiority of paired Gadavist image sets to pre-contrast MRI. Readers were blinded to clinical information.

Efficacy was determined in 657 subjects. The average age was 49 years (range 18 to 85 years) and 42% were male. The ethnic representations were 39% Caucasian, 4% Black, 16% Hispanic, 38% Asian, and 3% of other ethnic groups.

Table 6 shows a comparison of visualization results between paired images and pre-contrast images. Gadavist provided a statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study.

 Performances of Gadavist and gadoteridol for visualization parameters were similar. Regarding the number of lesions detected, Study B met the prespecified noninferiority margin of -0.35 for paired read versus pre-contrast read while in Study A, Gadavist and gadoteridol did not.

For the visualization endpoints contrast enhancement, border delineation, and internal morphology, the percentage of patients scoring higher for paired images compared to pre-contrast images ranged from 93% to 99% for Study A, and 95% to 97% for Study B. For both studies, the mean number of lesions detected on paired images exceeded that of the pre-contrast images; 37% for Study A and 24% for Study B. There were 29% and 11% of subjects in which the pre-contrast images detected more lesions for Study A and Study B, respectively.

The percentage of patients whose average reader mean score changed by ≤ 0, up to 1, up to 2, and ≥ 2 scoring categories presented in Table 5 is shown in Table 7. The categorical improvement of (≤ 0) represents higher (< 0) or identical (= 0) scores for the pre-contrast read, the categories with scores > 0 represent the magnitude of improvement seen for the paired read.

For both studies, the improvement of visualization endpoints in paired Gadavist images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy.

Two studies in 44 pediatric patients age younger than 2 years and 135 pediatric patients age 2 to less than 18 years with CNS and non-CNS lesions 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.

14.2 MRI of the Breast

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).

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 5 regions per breast for the presence of malignancy 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 Table 8.

Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant. The lower limit of the 95% confidence interval for specificity of Gadavist BMR was greater than 80% for 5 of 6 readers. (Table 9)

Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity in non-malignant breasts 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%).

MRA

Patients with known or suspected disease of the supra-aortic arteries (for evaluation up to but excluding the basilar artery) were enrolled in Study C, and patients with known or suspected disease of the renal arteries were enrolled in Study D. In both studies, non-contrast, 2D time-of-flight (ToF) magnetic resonance angiography (MRA) was performed prior to Gadavist MRA using a single intravenous injection of 0.1 mmol/kg. The injection rate of 1.5 mL/second was selected to extend the injection duration to at least half of the imaging duration. Imaging was performed with parallel-channel, 1.5T MRI devices and an automatic bolus tracking technique to trigger the image acquisition following Gadavist administration using elliptically encoded, T1-weighted, 3D gradient-echo image acquisition and single breath hold. Three central readers blinded to clinical information interpreted the ToF and Gadavist MRA images. Three additional central readers interpreted separately acquired computed tomographic angiography (CTA) images, which were used as the standard of reference (SoR) in each study.

The studies included 749 subjects: 457 were evaluated in Study C, with an average age of 68 (range 25–93); 64% were male; 80% white, 28% black, and 16% Asian. An additional 292 subjects were evaluated in Study D, with an average age of 55 (range 18–88); 54% were male; 68% white, 7% black, and 22% Asian.

Efficacy was evaluated based on anatomical visualization and performance for distinguishing between normal and abnormal anatomy. The visualization metric depended on whether readers selected, “Yes, it can be visualized along its entire length...” when responding to the question, “Is this segment assessable?” Twenty-one segments in Study C and six segments in Study D were presented per subject to each reader. The performance metrics, sensitivity and specificity, depended on digital caliper-based quantitation of arterial narrowing in visualized, non-occluded, abnormal-appearing segments. Significant stenosis was defined as at least 70% in Study C and 50% in Study D. Performance of Gadavist MRA compared to ToF MRA was calculated using an imputation method for non-visualized segments by assigning them as a 50% match with SoR and a 50% mismatch. Performance of Gadavist MRA compared to a pre-specified threshold of 50% was calculated after excluding non-visualized segments. Measurement variability and visualization of accessory renal arteries was also evaluated.

Results were analyzed for each of the three central readers.

Table 10: Visualization, Sensitivity, Specificity

GAD MRA = Post-contrast Gadavist Magnetic Resonance Angiography, ToF = Non-contrast 2D-Time of Flight.

For all three supra-aortic artery readers in Study C, the lower bound of confidence for the sensitivity of Gadavist MRA did not exceed 54%. For all three renal artery readers in Study D, the lower bound of confidence for the sensitivity of Gadavist MRA did not exceed 46%.

Measurement Variability

For both MRA and CTA, readers varied in the quantity of narrowing they assigned to the same arterial segments. Table 11 shows the percentage of patients in whom the measurement range was 30% or greater for the left or right internal carotid and proximal renal artery segments. There were approximately four measurements per patient segment, one from the site and three central readers. Measurement variability was high for both CTA and MRA, but numerically lower for Gadavist compared to non-contrast ToF MRA.

Table 11: Percent of Patients with Range ≥ 30%, ≥ 50%, ≥ 70% for Measurement of Stenoses and Normal Vessel Diameters

Visualization of Accessory Renal Arteries for Surgical Planning and Renal Donor Evaluation (Study D only)

Of 1752 main arteries visualized by the central CTA readers, 266 (15%) were also associated with positive visualization of at least one accessory (duplicate) artery. With the central MRA readers, the comparable rates were 232 of 1752 (13%) for Gadavist MRA compared to 53 of 1752 (3%) for ToF MRA.

Gadavist is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting during your MRI or MRA.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when Gadavist is injected.

Your doctor or other healthcare provider may want to watch you for a short time after your test is over. This is to make sure you do not have any unwanted side effects or delayed reactions to the Gadavist injection.

Since this medicine is given by a healthcare professional in a medical setting, an overdose is unlikely to occur.

Applies to gadobutrol: intravenous solution

Hypersensitivity

Uncommon (0.1% to 1%): Hypersensitivity/anaphylactoid reaction[Ref]

Nervous system

Common (1% to 10%): Headache
Uncommon (0.1% to 1%): Dizziness, paresthesia, dysgeusia
Rare (less than 0.1%): Loss of consciousness, convulsion, parosmia[Ref]

Gastrointestinal

Common (1% to 10%): Nausea
Uncommon (0.1% to 1%): Vomiting
Rare (less than 0.1%): Dry mouth[Ref]

Dermatologic

Common (1% to 10%): Nausea
Uncommon (0.1% to 1%): Vomiting
Rare (less than 0.1%): Dry mouth[Ref]

Cardiovascular

Rare (less than 0.1%): Tachycardia, palpitation, pallor
Postmarketing reports: Cardiac arrest[Ref]

Respiratory

Respiratory side effects have included dyspnea.[Ref]

Local

Uncommon (0.1% to 1%): Injection site reactions[Ref]

Ocular

Very rare (less than 0.01%): Eyelid edema[Ref]

Other

Uncommon (0.1% to 1%): Feeling hot
Rare (less than 0.1%): Malaise, feeling cold[Ref]

General

The most common adverse reactions were headache, nausea, and dizziness.[Ref]

Some side effects of Gadavist may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Animal studies have shown evidence of embryolethality. There are no controlled data in human pregnancy. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

This drug should be used only if clearly needed and the benefit outweighs the risk to the fetus. AU TGA pregnancy category B3 US FDA pregnancy category C

LactMed Record Number

991

Last Revision Date

20170127

Disclaimer

Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.