Gadobutrol injection 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 in adult patients ( 1.2 ) To evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates) ( 1.3 ) To assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD) ( 1.4 )
1.1Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS)
Gadobutrol injection 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.
1.2MRI of the Breast
Gadobutrol injection is indicated for use with MRI in adult patients to assess the presence and extent of malignant breast disease.
1.3Magnetic Resonance Angiography (MRA)
Gadobutrol injection 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.
1.4Cardiac MRI
Gadobutrol injection 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).
Contraindications
Gadobutrol injection is contraindicated in patients with history of severe hypersensitivity reactions to gadobutrol injection. History of severe hypersensitivity reaction to gadobutrol injection ( 4 )
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Hypersensitivity Reactions: Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have occurred. Monitor patients closely during and after administration of gadobutrol injection. ( 5.3 ) Acute Respiratory Distress Syndrome: For patients demonstrating respiratory distress after administration, assess oxygen requirement and monitor for worsening respiratory function.
( 5.4 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.5 )
5.1Risk Associated with Intrathecal Use
Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of gadobutrol injection have not been established with intrathecal use. Gadobutrol injection is not approved for intrathecal use [see Dosage and Administration ( 2.2 )] .
5.2Nephrogenic Systemic Fibrosis
GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of gadobutrol injection 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/1.73m 2 ) 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/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m 2 ). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following gadobutrol injection administration to Slate Run Pharmaceuticals, LLC at 1-888-341-9214 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 gadobutrol injection 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 )] .
5.3Hypersensitivity Reactions Anaphylactic
and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following gadobutrol injection administration [see Adverse Reactions ( 6 )] . Before gadobutrol injection 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 gadobutrol injection.
Administer gadobutrol injection 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 gadobutrol injection 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 gadobutrol injection administration.
5.4Acute Respiratory Distress Syndrome
Acute respiratory distress syndrome (ARDS) has been reported in patients administered gadobutrol injection and may be characterized by severe hypoxemia requiring oxygen support and mechanical ventilation. These manifestations may resemble an immediate hypersensitivity reaction with onset of respiratory distress within <30 minutes to 24 hours after gadobutrol injection administration. For patients demonstrating respiratory distress after gadobutrol injection administration, assess oxygen requirement and monitor for worsening respiratory function.
5.5Gadolinium 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), gadobutrol injection, 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 ( 5.2 )] . 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.
5.6Acute 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.
5.7Extravasation and Injection Site Reactions
Ensure catheter and venous patency before the injection of gadobutrol injection. Extravasation into tissues during gadobutrol injection administration may result in moderate irritation [see Nonclinical Toxicology ( 13.2 )] .
5.8Overestimation of Extent of Malignant Disease in MRI of the Breast
Gadobutrol injection 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 )] .
5.9Low Sensitivity for Significant Arterial Stenosis
The performance of gadobutrol injection 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 [see Clinical Studies ( 14.3
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Pregnancy and breastfeeding
8.1Pregnancy 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 gadobutrol injection 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 gadobutrol injection, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.
Adverse reactions
The following serious adverse reactions are discussed elsewhere in labeling: Nephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.2 )] . Hypersensitivity reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )] . Acute Respiratory Distress Syndrome [see Warnings and Precautions ( 5.4 )] Gadolinium Retention [see Warnings and Precautions ( 5.5 )] Most common adverse reactions (incidence ≥0.5%) are headache, nausea, and dizziness ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 gadobutrol injection exposure in 7,713 subjects (including 184 pediatric patients, ages 0 to 17 years) with the majority receiving the recommended dose.
Approximately 52% of the subjects were male and the ethnic distribution was 62% Caucasian, 28% Asian, 5% Hispanic, 2.5% Black, and 2.5% 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 gadobutrol injection administration. Adverse reactions associated with the use of gadobutrol injection were usually mild to moderate in severity and transient in nature.
Table 2 lists adverse reactions that occurred in ≥0.1% subjects who received gadobutrol injection. Table 2: Adverse Reactions Reaction Rate (%) n=7713 Headache
0.1 Adverse reactions that occurred with a frequency of <0.1% in subjects who received gadobutrol injection include: hypersensitivity/anaphylactic reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold.
6.2Postmarketing Experience
The following additional adverse reactions have been reported during postmarketing use of gadobutrol injection or other GBCAs. 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, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) Respiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema General Disorders and Administration Site Conditions: Adverse reactions with variable onset and duration have been reported after GBCA administration.
These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems. Skin: Gadolinium associated plaques Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration
Composition
Active ingredients
GADOBUTROL 9.0708GM/15ML (604.72MG/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
