Gadavist

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).

Gadavist is a sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to 1 mmol gadobutrol) per mL. Gadavist is supplied in the following sizes:

30 mL Pharmacy Bulk Package, rubber stoppered in cartons of 5, Boxes of 10 (NDC 50419-325-14)

65 mL Pharmacy Bulk Package, rubber stoppered, Boxes of 10 (NDC 50419-325-15)

Storage And Handling

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Should freezing occur, Gadavist should be brought to room temperature before use. If allowed to stand at room temperature, Gadavist should return to a clear and colorless to pale yellow solution. 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.

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 (BBB) and/or abnormal vascularity of the central nervous system.

MRI Of The Breast

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

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.

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

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.

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.

Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981. Manufactured in Germany

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

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 readministration. 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 . The usefulness of hemodialysis in the prevention of NSF is unknown.

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.

• 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.

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.

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.

Nonclinical Toxicology

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).

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data of Gadavist in pregnant women to inform the drug-associated risk. Gadolinium-based contrast agents (GBCAs) are reported to cross the placenta. Limited human data on exposure to GBCAs during pregnancy does not show adverse effects in exposed neonates. Animal reproductive studies were conducted. Although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and is 15 to 20%, respectively.

Data

Animal Data

Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol ( ≥ 7.5 mmol/kg body weight; equivalent to12 times the human dose based on body surface area) and in pregnant rabbits ( ≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses).

Because pregnant animals received repeated daily doses of Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

Lactation

Risk Summary

There are no data on the presence of gadobutrol in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breast-fed infant. In rat lactation studies, gadobutrol was present in milk in amounts less than 0.1% of the dose intravenously administered and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Gadavist and any potential adverse effects on the breastfed infant from Gadavist or from the underlying maternal condition.

Clinical Considerations

A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk up to18 hours after Gadavist administration in order to minimize exposure to a breastfed infant.

Data

In lactating rats receiving 0.5 mmol/kg of intravenous [153Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk within 3 hours after administration.

Pediatric Use

The safety and effectiveness of Gadavist have been established in pediatric patients born at 37 weeks gestation or later based on imaging and pharmacokinetic data in 138 patients ages 2 to 17 years and 44 patients ages 0 to less than 2 years and extrapolation from adult data. The frequency, type, and severity of adverse reactions in pediatric patients were similar to adverse reactions in adults. No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of Gadavist have not been established in premature infants.

NSF Risk

No case of NSF associated with Gadavist or any other GBCA has been identified in pediatric patients ages 6 years and younger. Pharmacokinetic studies suggest that clearance of Gadavist is similar in pediatric patients and adults, including pediatric patients age younger than 2 years. No increased risk factor for NSF has been identified in juvenile animal studies of gadobutrol. Normal estimated GFR (eGFR) is around 30 mL/min/1.73m² at birth and increases to mature levels around 1 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than 1 year of age have been conducted in patients with the following minimum eGFR: 31 mL/min/1.73m² (age 2 to 7 days), 38 mL/min/1.73m² (age 8 to 28 days), 62 mL/min/1.73m² (age 1 to 6 months), and 83 mL/min/1.73m² (age 6 to 12 months).

Juvenile Animal Data

Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants.

Geriatric Use

In clinical studies of Gadavist, 1,377 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.

Renal Impairment

Prior to administration of Gadavist, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. No dosage adjustment is recommended for patients with renal impairment.

Gadavist can be removed from the body by hemodialysis .

SIDE EFFECTS

The following serious adverse reactions are discussed elsewhere in labeling:

• Nephrogenic Systemic Fibrosis (NSF).
• Hypersensitivity reactions.

Clinical Trials 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 adverse reactions described in this section reflect Gadavist exposure in 6,809 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 51% of the subjects were male and the ethnic distribution was 61% Caucasian, 29% Asian, 5% Hispanic, 2% Black, and 3% patients of other ethnic groups. The average age was 55 years (range from 1 week to 93 years).

Overall, approximately 4% 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 were usually mild to moderate in severity and transient in nature.

Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received Gadavist.

Table 2: Adverse Reactions

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.

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 reactions (anaphylactic 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)

DRUG INTERACTIONS

No information provided.

Risk Summary

There are no available data of Gadavist in pregnant women to inform the drug-associated risk. Gadolinium-based contrast agents (GBCAs) are reported to cross the placenta. Limited human data on exposure to GBCAs during pregnancy does not show adverse effects in exposed neonates. Animal reproductive studies were conducted. Although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 8 and 12 times, respectively, the recommended human dose. Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and is 15 to 20%, respectively.

Data

Animal Data

Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 8 times the recommended single human dose (based on body surface area); gadobutrol was not maternally toxic or teratogenic at this dose. Embryolethality and retardation of embryonal development also occurred in pregnant rats receiving maternally toxic doses of gadobutrol ( ≥ 7.5 mmol/kg body weight; equivalent to12 times the human dose based on body surface area) and in pregnant rabbits ( ≥ 2.5 mmol/kg body weight; equivalent to 8 times the recommended human dose based on body surface area). In rabbits, this finding occurred without evidence of pronounced maternal toxicity and with minimal placental transfer (0.01% of the administered dose detected in the fetuses).

Because pregnant animals received repeated daily doses of Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

The following serious adverse reactions are discussed elsewhere in labeling:

• Nephrogenic Systemic Fibrosis (NSF).
• Hypersensitivity reactions.

Clinical Trials 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 adverse reactions described in this section reflect Gadavist exposure in 6,809 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose. Approximately 51% of the subjects were male and the ethnic distribution was 61% Caucasian, 29% Asian, 5% Hispanic, 2% Black, and 3% patients of other ethnic groups. The average age was 55 years (range from 1 week to 93 years).

Overall, approximately 4% 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 were usually mild to moderate in severity and transient in nature.

Table 2 lists adverse reactions that occurred in ≥ 0.1% subjects who received Gadavist.

Table 2: Adverse Reactions

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.

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 reactions (anaphylactic 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)

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.

Gadavist leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37°C and 1.5 T, the relaxivity (r1) - determined from the influence on the relaxation times (T1) of protons in plasma - is 5.2 L/(mmol•sec) and the relaxivity (r2) - determined from the influence on the relaxation times (T2) - is 6.1 L/(mmol•sec). These relaxivities display only slight dependence on the strength of the magnetic field. The T shortening effect of paramagnetic contrast agents is dependent on concentration and r relaxivity (see Table 3). This may improve tissue visualization.

Table 3: Relaxivity (r1) of Gadolinium Chelates at 1.5 T

Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist results in half the volume of administration and a more compact contrast bolus injection. At the site of imaging, the relative height and width of the time intensity curve for Gadavist varies as a function of imaging location and multiple patient, injection, and device-specific factors.

Gadavist is a highly water-soluble, extremely hydrophilic compound with a partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006.

Distribution

After intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After a gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma 2 minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. In rats, gadobutrol does not penetrate the intact blood-brain barrier.

Metabolism

Gadobutrol is not metabolized.

Elimination

Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below.

Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(min•kg) and thus comparable to the renal clearance of inulin, confirming that gadobutrol is eliminated by glomerular filtration.

Within two hours after intravenous administration more than 50% and within 12 hours more than 90% of the given dose is eliminated via the urine. Extra-renal elimination is negligible.