Gadavist: Package Insert and Label Information

GADAVIST- gadobutrol injection
Bayer HealthCare Pharmaceuticals Inc.

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 [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 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 and/or abnormal vascularity of the central nervous system.

1.2 MRI of the Breast

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

1.3 Magnetic Resonance Angiography (MRA)

Gadavist is 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.

1.4 Cardiac MRI

Gadavist is indicated for use in cardiac MRI (CMRI) to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD).

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

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 Table 1 to determine the volume to be administered.

Table 1: Volume of Gadavist Injection by Body Weight*

Body Weight (kg)

Volume to be Administered (mL)

2.5

0.25

5

0.5

10

1

15

1.5

20

2

25

2.5

30

3

35

3.5

40

4

45

4.5

50

5

60

6

70

7

80

8

90

9

100

10

110

11

120

12

130

13

140

14

* For Cardiac MRI, the dose is divided into 2 separate, equal injections

2.2 Administration Guidelines

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. Use Table 1 to determine the volume to be administered.
Use sterile technique when preparing and administering Gadavist.

MRI of the Central Nervous System

Administer Gadavist as an intravenous injection, manually or by power injector, at a flow rate of approximately 2 mL/second.
Follow Gadavist injection with a normal saline flush to ensure complete administration of the contrast.
Post contrast MRI can commence immediately following contrast administration.

MRI of the Breast

Administer Gadavist as an intravenous bolus by power injector, followed by a normal saline flush to ensure complete administration of the contrast.
Start image acquisition following contrast administration and then repeat sequentially to determine peak intensity and wash-out.

MR Angiography

Image acquisition should coincide with peak arterial concentration, which varies among patients.

Adults
Administer Gadavist by power injector, at a flow rate of approximately 1.5 mL/second, followed by a 30 mL normal saline flush at the same rate to ensure complete administration of the contrast.
Pediatric patients
Administer Gadavist by power injector or manually, followed by a normal saline flush to ensure complete administration of the contrast.

Cardiac MRI

Administer Gadavist through a separate intravenous line in the contralateral arm if concomitantly providing a continuous infusion of a pharmacologic stress agent.
Administer Gadavist as two (2) separate bolus injections: 0.05 mL/kg (0.05 mmol/kg) body weight at peak pharmacologic stress followed by 0.05 mL/kg (0.05 mmol/kg) body weight at rest.
Administer Gadavist via a power injector at a flow rate of approximately 4 mL/second and follow each injection with a normal saline flush of 20 mL at the same flow rate.

2.3 Drug Handling

Visually inspect Gadavist for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged.
Do not mix Gadavist with other medications and do not administer Gadavist in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility.
Instructions of the device manufacturer must be followed.

Pharmacy Bulk Package Preparation

Pharmacy Bulk Packages are not for use in direct intravenous infusions.
After the Pharmacy Bulk Package has been opened, Gadavist remains stable for 24 hours at 20–25°C (68–77°F).
The Pharmacy Bulk Package contains many single doses and is used with an appropriate transfer device for filling empty sterile syringes.
The transfer of Gadavist from the Pharmacy Bulk Package must be performed in an aseptic work area, such as a laminar flow hood, using aseptic technique.
Once the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic work area during the entire 24 hour period of use.
IV tubing and syringes used to administer Gadavist must be discarded at the conclusion of the radiological examination.

The contents of the Pharmacy Bulk Package after initial puncture should be used within 24 hours. Discard any unused portion in accordance with regulations dealing with the disposal of such materials.

3 DOSAGE FORMS AND STRENGTHS

Gadavist is a sterile, clear, and colorless to pale yellow solution for injection containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol/ mL).

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The usefulness of hemodialysis in the prevention of NSF is unknown [see Clinical Pharmacology (12.3)].

5.2 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 [see Adverse Reactions (6)].

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.

5.3 Gadlinium Retention

Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (for example, brain, skin, kidney, liver, and spleen). The duration of retention also varies by tissue and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalent doses, gadolinium retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)].

Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions (5.1)]. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions (6.2)].

While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing a GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible.

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