Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE Gadavist is a gadolinium-based contrast agent indicated for use with magnetic resonance imaging (MRI): •To detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system in adult and pediatric patients (including term neonates) (1.1) •To assess the presence and extent of malignant breast disease (1.2) •To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates) (1.3) 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 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.

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Advisory information

contraindications
4 CONTRAINDICATIONS Gadavist is contraindicated in patients with history of severe hypersensitivity reactions to Gadavist. History of severe hypersensitivity reaction to Gadavist (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: •Nephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)]. •Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]. •Most common adverse reactions (incidence ≥ 0.5%) are 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 6.1 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 56 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 Reaction Rate (%) n=6809 Headache 1.5 Nausea 1.1 Dizziness 0.5 Dysgeusia 0.4 Feeling Hot 0.4 Injection site reactions 0.4 Vomiting 0.4 Rash (includes generalized, macular, papular, pruritic) 0.3 Pruritus (includes generalized) 0.2 Erythema 0.2 Hypersensitivity/Anaphylactoid* 0.1 Dyspnea 0.1 Paresthesia 0.1 *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 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) [see Warnings and Precautions (5.2)] •General Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. •Skin: Gadolinium associated plaques

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Recommended dose for adults and pediatric patients (including term neonates) is 0.1 mL/kg body weight (2.1) •Administer as an intravenous bolus injection (2.2) •Follow injection with a normal saline flush (2.2) 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 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. 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. Vials •Draw Gadavist into the syringe immediately before use. •Do not pierce the rubber stopper more than once. Discard any unused vial contents. Pre-filled syringes •Remove the tip cap from the pre-filled syringe immediately before use. Discard any unused syringe contents.
Use in special populations
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data). In animal reproduction studies, 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 [see Data]. Because of the potential risks of gadolinium to the fetus, use Gadavist only if imaging is essential during pregnancy and cannot be delayed. 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 Human Data. Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration. Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported a clear association between GBCAs and adverse effects in the exposed neonates. However, a retrospective cohort study, comparing pregnant women who had a GBCA MRI to pregnant women who did not have an MRI, reported a higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include a lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy. Animal Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least 7 months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age. Reproductive Toxicology 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 to 12 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 8.2 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 to 18 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. 8.4 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 [see Adverse Reactions (6.1)]. No dose adjustment according to age is necessary in pediatric patients [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)]. 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. 8.5 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. 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)].

More information

Category Value
Authorisation number NDA201277
Agency product number 1BJ477IO2L
Orphan designation No
Product NDC 50419-325
Date Last Revised 26-04-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Bayer HealthCare Pharmaceuticals Inc.
Warnings 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)]. WARNING: 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)