Gadavist

Bayer HealthCare Pharmaceuticals Inc.
Bayer HealthCare Pharmaceuticals Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Gadavist safely and effectively. See full prescribing information for Gadavist Gadavist (gadobutrol) injection, for intravenous usePHARMACY BULK PACKAGENOT FOR DIRECT INFUSION Initial U.S. Approval: 2011RECENT MAJOR CHANGESIndications and Usage, MRI of the Breast (1.2) 6/2014Contraindications, Hypersensitivity (4) 10/2013Warnings and Precautions, Acute Kidney Injury (5.3) 10/2013 Overestimation of Extent of Malignant Disease in Breast MRI (5.5) 6/2014BOXED WARNINGWARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning 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. • 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. (5.1) INDICATIONS AND USAGEGadavist 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. (1.1) •For MRI of the breast to assess the presence and extent of malignant breast disease. (1.2) DOSAGE AND ADMINISTRATIONGadavist 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 the table in section 2.1 to determine the volume of Gadavist to be administered.The recommended dose of Gadavist is 0.1 mL/kg body weight (0.1 mmol/kg), administered as an intravenous bolus injection at a flow rate of approximately 2 mL/second. Flush the intravenous cannula with physiological saline solution after the injection. (2)DOSAGE FORMS AND STRENGTHSGadavist injection contains 1 mmol gadobutrol/mL (equivalent to 604.72 mg gadobutrol/mL) and is available in vials and prefilled syringes. (3)CONTRAINDICATIONSGadavist is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist. (4)WARNINGS AND PRECAUTIONS •Nephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk. (5.1) •Hypersensitivity: Anaphylactoid/anaphylactic reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred. Monitor patients closely for need of emergency cardiorespiratory support. (5.2) Side Effects •The most frequent (≥ 0.5%) adverse reactions associated with Gadavist in clinical studies were headache, nausea and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch USE IN SPECIFIC POPULATIONSPregnancy: Based on animal data, may cause fetal harm. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: NEPHROGENIC SYSTEMIC FIBROSIS
• 1 GADAVIST INDICATIONS AND USAGE
  • 1.1 Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS)
  • 1.2 MRI of the Breast
• 2 GADAVIST DOSAGE AND ADMINISTRATION
  • 2.1 Adults and Children (2 years and older)
  • 2.2 Dosing Guidelines
• 3 DOSAGE FORMS AND STRENGTHS
• 4 GADAVIST CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Nephrogenic Systemic Fibrosis (NSF)
  • 5.2 Hypersensitivity Reactions
  • 5.3 Acute Kidney Injury
  • 5.4 Extravasation and Injection Site Reactions
  • 5.5 Overestimation of Extent of Malignant Disease in MRI of the Breast
• 6 GADAVIST ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
• 10 OVERDOSAGE
• 11 GADAVIST DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
  • 14.1 MRI of the CNS
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage and Handling
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS)

Gadavist® 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.

1.2 MRI of the Breast

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

2 DOSAGE AND ADMINISTRATION

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. Closely examine the table below to determine the volume to be administered.

2.1 Adults and Children (2 years and older)

The recommended dose of Gadavist is 0.1 mL/kg body weight (0.1 mmol/kg).

• •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.
• •Administer Gadavist as an intravenous bolus injection, manually or by power injector, at a flow rate of approximately 2 mL/second. Flush the intravenous cannula with physiological saline solution after the injection.

2.2 Dosing Guidelines

• •Sterile technique must always be used when preparing and administering injection of contrast media. Do not mix Gadavist with other drugs.
• •Contrast-enhanced MRI can commence immediately following contrast administration.
• •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, colorless to pale yellow solution for injection containing 1 mmol gadobutrol per milliliter (equivalent to 604.72 mg 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 (NSF)

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 enhanced 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 30–59 mL/min/1.73m²) and little, if any, for patients with chronic, mild kidney disease (GFR 60–89 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, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination. The usefulness of hemodialysis in the prevention of NSF is unknown [see Clinical Pharmacology (12) and Dosage and Administration (2)].

5.2 Hypersensitivity Reactions

Anaphylactoid and anaphylactic 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 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.

5.4 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 [see Nonclinical Toxicology (13.2)].

5.5 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 [see Clinical Studies (14.2)].

6 ADVERSE REACTIONS

The most serious reactions to Gadavist are nephrogenic systemic fibrosis and hypersensitivity reactions [see Warnings and Precautions (5.1 and 5.2)].

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described below reflect Gadavist exposure in 5748 subjects (including 140 children aged 2–17) with the majority receiving the recommended dose. Overall 49% of the subjects were men and the ethnic distribution was 63% Caucasian, 28% Asian, 4.5% Hispanic, 1.3% Black, and 2.9% patients of other ethnic groups. The average age was 55 years (range from 2 to 93 years).

Overall, 3.5% of subjects reported one or more adverse reactions during a follow-up period that ranged from 24 hours to 7 days after Gadavist administration.

Adverse reactions associated with the use of Gadavist are usually mild to moderate in severity and transient in nature.

Table 1 lists adverse reactions that occurred in ≥0.1% subjects who received Gadavist.

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

Adverse reactions that occurred with a frequency of <0.1% in subjects who received Gadavist include: loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold.

6.2 Postmarketing Experience

The following additional adverse reactions have been reported during postmarketing use of Gadavist. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• •Cardiac arrest
• •Nephrogenic Systemic Fibrosis (NSF)
• •Hypersensitivity/anaphylactoid reaction (anaphylactoid shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) [see Warnings and Precautions (5.2)]

7 DRUG INTERACTIONS

There are no known drug interactions. Gadavist does not interfere with serum and plasma calcium measurements determined by colorimetric assays. Do not mix Gadavist with other drugs.

8 USE IN SPECIFIC POPULATIONS

8.3 Nursing Mothers

It is not known whether gadobutrol is excreted in human milk. Limited case reports on use of GBCAs in nursing mothers indicate that 0.01 to 0.04% of the maternal gadolinium dose is excreted in human breast milk. Studies have shown limited GBCA gastrointestinal absorption. Nonclinical data show that gadobutrol is excreted into breast milk in very small amounts (<0.1% of the dose intravenously administered) and the absorption via the gastrointestinal tract is poor (approximately 5% of the dose orally administered was excreted in the urine) [see Clinical Pharmacology (12.3)]. In lactating rats given 0.5 mmol/kg of intravenous [¹⁵³Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the neonate via maternal milk, mostly within 3 hours after the intravenous administration. Because many drugs are excreted in human milk, exercise caution when gadobutrol is administered to a nursing woman.

8.4 Pediatric Use

The pharmacokinetics, safety and efficacy of Gadavist at a single dose of 0.1 mmol/kg have been established in children 2 to 17 years of age. No dose adjustment according to age is necessary in this population. The safety and effectiveness of Gadavist have not been established in children below two years of age. [See Dosage and Administration (2.1), Clinical Pharmacology (12.3).]

8.5 Geriatric Use

In clinical studies of Gadavist, 1377 patients were 65 years of age and over, while 104 patients  were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of Gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No dose adjustment according to age is necessary in this population.

8.6 Renal Impairment

Prior to administration of Gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests [see Warnings and Precautions (5.1)]. No dosage adjustment is recommended for patients with renal impairment.

Gadavist can be removed from the body by hemodialysis [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

The maximum dose of Gadavist tested in healthy volunteers, 1.5 mL/kg body weight (1.5 mmol/kg) (15 times the recommended dose), was tolerated in a manner similar to lower doses. Gadavist can be removed by hemodialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

11 DESCRIPTION

Gadavist (gadobutrol) injection is a paramagnetic macrocyclic contrast agent administered for magnetic resonance imaging. The chemical name for gadobutrol is 10–[(1SR,2RS)–2,3–dihydroxy–1–hydroxymethylpropyl]–1,4,7,10–tetraazacyclododecane–1,4,7–triacetic acid, gadolinium complex. Gadobutrol has a molecular formula of C₁₈H₃₁GdN₄O₉ and a molecular weight of 604.72.