Gadobutrol

• RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS Risk Associated with Intrathecal Use Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Gadobutrol injection is not approved for intrathecal use [see Warnings and Precautions ( 5.1 )] . Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of drugs.
• Avoid use of gadobutrol injection 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:
• o Chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ), or o 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 gadobutrol injection 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 ( 5.2 )] . WARNING:
• RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS See full prescribing information for complete boxed warning
• Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Gadobutrol injection is not approved for intrathecal use ( 5.1 )
• GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of drugs.
• Avoid use of gadobutrol injection 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:
• o Chronic, severe kidney disease (GFR < 30 mL/min/1.73m 2 ), or o 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. ( 5.2 ).

Gadobutrol injection is contraindicated in patients with history of severe hypersensitivity reactions to gadobutrol injection. History of severe hypersensitivity reaction to gadobutrol injection ( 4 )

• 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 )
• 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 ) 5.1 Risk 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 )] . 5.2 Nephrogenic 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 )]. 5.3 Hypersensitivity 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. 5.4 Acute 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. 5.5 Gadolinium 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 (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 ( 5.2 )] . 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. 5.6 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. 5.7 Extravasation 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 )] . 5.8 Overestimation 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 )]. 5.9 Low 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 )].

• 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.
• IN SPECIFIC POPULATIONS Pregnancy:
• Use only if imaging is essential during pregnancy and cannot be delayed.
• ( 8.1 )
• 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 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.
• 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.
• Gadobutrol is present in rat milk (see Data ).
• The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for gadobutrol injection and any potential adverse effects on the breastfed infant from gadobutrol injection or from the underlying maternal condition.
• Data In lactating rats receiving 0.5 mmol/kg of intravenous [ 153 Gd]-gadobutrol, 0.01% of the total administered radioactivity was transferred to the pup via maternal milk within 3 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine).
• 8.4 Pediatric Use The safety and effectiveness of gadobutrol injection have been established in pediatric patients, including term neonates, for use with MRI to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system and for use in MRA to evaluate known or suspected supra-aortic or renal artery disease.
• Use of gadobutrol injection in these indications is supported by adequate and well-controlled studies in
• adults and supportive imaging data in two studies in 135 patients 2 to less than 18 years of age and 44 patients less than 2 years of age with CNS and non-CNS lesions, and pharmacokinetic data in 130 patients 2 to less than 18 years of age and 43 patients less than 2 years of age, including term neonates [ see Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.1 ) ].
• 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 gadobutrol injection have not been established in preterm neonates for any indication or in pediatric patients of any age for use with MRI to assess the presence and extent of malignant breast disease, or for use in CMRI to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (CAD).
• NSF Risk No case of NSF associated with gadobutrol injection or any other GBCA has been identified in pediatric patients ages 6 years and younger.
• Pharmacokinetic studies suggest that clearance of gadobutrol injection 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/1.73m 2 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/1.73m 2 (age 2 to 7 days), 38 mL/min/1.73m 2 (age 8 to 28 days), 62 mL/min/1.73m 2 (age 1 to 6 months), and 83 mL/min/1.73m 2 (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 gadobutrol injection, 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 gadobutrol injection 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 gadobutrol injection, screen all patients for renal dysfunction by obtaining a history and/or laboratory tests [see Warnings and Precautions ( 5.2 )] .
• No dosage adjustment is recommended for patients with renal impairment.
• Gadobutrol can be removed from the body by hemodialysis [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] .

• The maximum dose of gadobutrol injection 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.
• Gadobutrol can be removed by hemodialysis [see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )] .