ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in clinical setting [see Warnings and Precautions (5.7)].

BOXED WARNING SECTION.

WARNING: RISK ASSOCIATED WITH INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS Risk Associated with Intrathecal UseIntrathecal 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 FibrosisGBCAs 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.oThe risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroAcute kidney injury.oScreen 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.oFor patients at highest risk for NSF, do not exceed the recommended gadobutrol dose and allow sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.2)]. oThe risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroAcute kidney injury.. oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), or. oAcute kidney injury.. oScreen 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.. oFor patients at highest risk for NSF, do not exceed the recommended gadobutrol dose and allow 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 FIBROSISSee full prescribing information for complete boxed warningoIntrathecal 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)oGBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the 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: 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).oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), or oAcute 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). oIntrathecal 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). oGBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the 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: 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).oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), or oAcute kidney injury.. oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), or oAcute kidney injury.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with: oDifferences in proton density oDifferences of the spin-lattice or longitudinal relaxation times (T1) oDifferences in the spin-spin or transverse relaxation time (T2) When placed in magnetic field, gadobutrol shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from gadobutrol, is based upon several factors including the concentration of gadobutrol in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1-weighted magnetic resonance sequences. In T2-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to signal decrease. oDifferences in proton density oDifferences of the spin-lattice or longitudinal relaxation times (T1) oDifferences in the spin-spin or transverse relaxation time (T2) 12.2 Pharmacodynamics Gadobutrol leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37C 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 T1 shortening effect of paramagnetic contrast agents is dependent on concentration and r1 relaxivity (see Table 3). This may improve tissue visualization. Table 3: Relaxivity (r1) of Gadolinium Chelates at 1.5 r1 relaxivity in plasma at 37C Gadolinium-Chelater1 (L.mmol -1 .s -1)Gadobenate 6.3 Gadobutrol 5.2 Gadodiamide 4.3 Gadofosveset 16 Gadopentetate 4.1 Gadoterate 3.6 Gadoteridol 4.1 Gadoversetamide 4.7 Gadoxetate 6.9 Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of gadobutrol results in half the volume of administration and more compact contrast bolus injection. At the site of imaging, the relative height and width of the time intensity curve for gadobutrol varies as function of imaging location and multiple patient, injection, and device-specific factors. Gadobutrol is water-soluble, hydrophilic compound with partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. 12.3 Pharmacokinetics DistributionAfter intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.5)]. MetabolismGadobutrol is not metabolized. EliminationValues 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/(minkg) 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. Specific Populations. GenderGender has no clinically relevant effect on the pharmacokinetics of gadobutrol. GeriatricA single intravenous dose of 0.1 mmol/kg gadobutrol was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects [see Use in Specific Populations (8.5)]. PediatricThe pharmacokinetics of gadobutrol were evaluated in two studies in total of 130 patients age to less than 18 years and in 43 patients less than years of age (including term neonates). Patients received single intravenous dose of 0.1 mmol/kg of gadobutrol. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within hours (this information was derived from the to less than 18 year old age group). Table 4: Pharmacokinetics by Age Group (Median [Range]) to 2 yearsN=432 to yearsN=457 to 11 yearsN=3912 to 18 yearsN=46AdultsN=93AUC (umolxh/L) 781[513, 1891] 846[412, 1331] 1025[623, 2285] 1237[946, 2211] 1072[667, 1992] CL (L/h/kg) 0.128[0.053, 0.195] 0.119[0.08, 0.215] 0.099[0.043, 0.165] 0.081[0.046, 0.103] 0.094[0.051, 0.150] t1/2 (h) 2.91[1.60, 12.4] 1.91[1.04, 2.70] 1.66[0.91, 2.71] 1.68[1.31, 2.48] 1.80[1.20, 6.55] C20 (umol/L) 367[280, 427] 421[369, 673] 462[392, 760] 511[387, 1077] 441[281, 829] Renal ImpairmentIn patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance. After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half-life was 5.8 +- 2.4 hours in mild to moderately impaired patients (80 CLCR 30 mL/min) and 17.6 +- 6.2 hours in severely impaired patients not on dialysis (CLCR< 30 mL/min). The mean AUC of gadobutrol in patients with normal renal function was 1.1 +- 0.1 mmolh/L, compared to 4.0 +- 1.8 mmolh/L in patients with mild to moderate renal impairment and 11.5 +- 4.3 mmolh/L in patients with severe renal impairment. Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within days. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of gadobutrol in order to enhance the contrast agents elimination. Sixty-eight percent (68%) of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6).].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 MRI of the CNS Patients referred for MRI of the central nervous system with contrast were enrolled in two clinical trials that evaluated the visualization characteristics of lesions. In both studies, patients underwent baseline, pre-contrast MRI prior to administration of gadobutrol at dose of 0.1 mmol/kg, followed by post-contrast MRI. In Study A, patients also underwent an MRI before and after the administration of gadoteridol. The studies were designed to demonstrate superiority of gadobutrol MRI to non-contrast MRI for lesion visualization. For both studies, pre-contrast and pre-plus-post contrast images (paired images) were independently evaluated by three readers for contrast enhancement and border delineation using scale of to 4, and for internal morphology using scale of to (Table 5). Lesion counting was also performed to demonstrate non-inferiority of paired gadobutrol image sets to pre-contrast MRI. Readers were blinded to clinical information. Table 5: Primary Endpoint Visualization Scoring System ScoreVisualization CharacteristicsContrast EnhancementBorder DelineationInternal Morphology1 None None Poorly visible Weak Moderate Moderately visible Clear Clear but incomplete Sufficiently visible Clear and bright Clear and complete N/A Efficacy was determined in 657 subjects. The average age was 49 years (range 18 to 85 years) and 42% were male. The ethnic representations were 39% Caucasian, 4% Black, 16% Hispanic, 38% Asian, and 3% of other ethnic groups. Table shows comparison of visualization results between paired images and pre-contrast images. Gadobutrol provided statistically significant improvement for each of the three lesion visualization parameters when averaged across three independent readers for each study. Table 6: Visualization Endpoint Results of Central Nervous System Adult MRI Studies with 0.1 mmol/kg Gadobutrol Difference of means (paired mean) (pre-contrast mean) p<0.001 Met noninferiority margin of -0.35 Did not meet noninferiority margin of -0.35 EndpointStudy AN=336Study N=321Pre-contrast Paired Difference1 Pre-contrast Paired Difference Contrast Enhancement 0.97 2.26 1.292 0.93 2.86 1.942 Border Delineation 1.98 2.58 0.602 1.92 2.94 1.022 Internal Morphology 1.32 1.93 0.602 1.57 2.35 0.782 Average Lesions Detected 8.08 8.25 0.174 2.65 2.97 0.323 Performances of gadobutrol and gadoteridol for visualization parameters were similar. Regarding the number of lesions detected, Study met the prespecified noninferiority margin of -0.35 for paired read versus pre-contrast read while in Study A, gadobutrol and gadoteridol did not. For the visualization endpoints contrast enhancement, border delineation, and internal morphology, the percentage of patients scoring higher for paired images compared to pre-contrast images ranged from 93% to 99% for Study A, and 95% to 97% for Study B. For both studies, the mean number of lesions detected on paired images exceeded that of the pre-contrast images; 37% for Study and 24% for Study B. There were 29% and 11% of subjects in which the pre-contrast images detected more lesions for Study and Study B, respectively. The percentage of patients whose average reader mean score changed by <= 0, up to 1, up to 2, and >= scoring categories presented in Table is shown in Table 7. The categorical improvement of (<= 0) represents higher (< 0) or identical (= 0) scores for the pre-contrast read, the categories with scores 0 represent the magnitude of improvement seen for the paired read. Table 7: Primary Endpoint Visualization Categorical Improvement for Average Reader Study N=336Study N=321EndpointCategorical Improvement(Paired Pre-Contrast) %Categorical Improvement (Paired Pre-Contrast) %<= > to 1 to 2 >= <= > to 1 to 2 >= Contrast Enhancement 30 55 13 6 34 57 Border Delineation 73 18 5 38 51 Internal Morphology 79 17 5 61 33 For both studies, the improvement of visualization endpoints in paired gadobutrol images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy. Pediatric PatientsTwo studies in 44 pediatric patients age younger than years and 135 pediatric patients age to less than 18 years with CNS and non-CNS lesions supported extrapolation of adult CNS efficacy findings. For example, comparing pre vs paired pre- and post-contrast images, investigators selected the best of four descriptors under the heading, Visualization of lesion-internal morphology (lesion characterization) or homogeneity of vessel enhancement for 27/44 (62% pre) vs 43/44 (98% paired) MR images from patients age to less than years and 106/135 (78% pre) vs 108/135 (80% paired) MR images from patients age to less than 18 years. 14.2 MRI of the Breast Patients with recently diagnosed breast cancer were enrolled in two identical clinical trials to evaluate the ability of gadobutrol to assess the presence and extent of malignant breast disease prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to gadobutrol (0.1 mmol/kg) breast MRI. BMR images and gadobutrol BMR (combined contrast plus non-contrast) images were independently evaluated in each study by three readers blinded to clinical information. In separate reading sessions the BMR images and gadobutrol BMR images were also interpreted together with X-ray mammography images (XRM). The studies evaluated 787 patients: Study enrolled 390 women with an average age of 56 years, 74% were white, 25% Asian, 0.5% black, and 0.5% other; Study enrolled 396 women and man with an average age of 57 years, 71% were white, 24% Asian, 3% black, and 2% other. The readers assessed regions per breast for the presence of malignancy using each reading modality. The readings were compared to an independent standard of truth (SoT) consisting of histopathology for all regions where excisions were made and tissue evaluated. XRM plus ultrasound was used for all other regions. The assessment of malignant disease was performed using region based within-subject sensitivity. Sensitivity for each reading modality was defined as the mean of the percentage of malignant breast regions correctly interpreted for each subject. The within-subject sensitivity of gadobutrol BMR was superior to that of BMR. The lower bound of the 95% Confidence Interval (CI) for the difference in within-subject sensitivity ranged from 19% to 42% for Study and from 12% to 27% for Study 2. The within-subject sensitivity for gadobutrol BMR and BMR as well as for gadobutrol BMR plus XRM and BMR plus XRM is presented in Table 8. Table 8: Sensitivity of Gadobutrol BMR for Detection of Malignant Breast Disease Study 1Study 2Sensitivity (%)N=388 PatientsSensitivity (%)N=390 PatientsReader BMR BMR Gadobutrol Gadobutrol Reader BMR BMR Gadobutrol Gadobutrol XRM BMR BMR XRM BMR BMR +XRM +XRM 37 71 83 84 73 83 87 90 49 76 80 83 57 81 89 90 63 75 87 87 55 80 86 88 Specificity was defined as the percentage of non-malignant breasts correctly identified as non-malignant. The lower limit of the 95% confidence interval for specificity of gadobutrol BMR was greater than 80% for of readers. (Table 9) Table 9: Specificity of Gadobutrol BMR in Non-Malignant Breasts Study 1Study 2Specificity (%)N=372 Patients Specificity (%)N=367 Patients Reader Gadobutrol BMR Lower Limit95% CI Reader Gadobutrol BMR Lower Limit95% CI 86 82 92 89 95 93 84 80 89 85 83 79 Three additional readers in each study read XRM alone. For these readers over both studies, sensitivity ranged from 68% to 73% and specificity in non-malignant breasts ranged from 86% to 94%. In breasts with malignancy, false positive detection rate was calculated as the percentage of subjects for which the readers assessed region as malignant which could not be verified by SoT. The false positive detection rates for gadobutrol BMR ranged from 39% to 53% (95% CI Upper Bounds ranged from 44% to 58%). 14.3 MRA Patients with known or suspected disease of the supra-aortic arteries (for evaluation up to but excluding the basilar artery) were enrolled in Study C, and patients with known or suspected disease of the renal arteries were enrolled in Study D. In both studies, non-contrast, 2D time-of-flight (ToF) magnetic resonance angiography (MRA) was performed prior to gadobutrol MRA using single intravenous injection of 0.1 mmol/kg. The injection rate of 1.5 mL/second was selected to extend the injection duration to at least half of the imaging duration. Imaging was performed with parallel-channel, 1.5T MRI devices and an automatic bolus tracking technique to trigger the image acquisition following gadobutrol administration using elliptically encoded, T1-weighted, 3D gradient-echo image acquisition and single breath hold. Three central readers blinded to clinical information interpreted the ToF and gadobutrol MRA images. Three additional central readers interpreted separately acquired computed tomographic angiography (CTA) images, which were used as the standard of reference (SoR) in each study. The studies included 749 subjects: 457 were evaluated in Study C, with an average age of 68 (range 25 to 93); 64% were male; 80% white, 28% black, and 16% Asian. An additional 292 subjects were evaluated in Study D, with an average age of 55 (range 18 to 88); 54% were male; 68% white, 7% black, and 22% Asian. Efficacy was evaluated based on anatomical visualization and performance for distinguishing between normal and abnormal anatomy. The visualization metric depended on whether readers selected, Yes, it can be visualized along its entire length... when responding to the question, Is this segment assessable. Twenty-one segments in Study and six segments in Study were presented per subject to each reader. The performance metrics, sensitivity and specificity, depended on digital caliper-based quantitation of arterial narrowing in visualized, non-occluded, abnormal-appearing segments. Significant stenosis was defined as at least 70% in Study and 50% in Study D. Performance of gadobutrol MRA compared to ToF MRA was calculated using an imputation method for non-visualized segments by assigning them as 50% match with SoR and 50% mismatch. Performance of gadobutrol MRA compared to pre-specified threshold of 50% was calculated after excluding non-visualized segments. Measurement variability and visualization of accessory renal arteries was also evaluated. Results were analyzed for each of the three central readers. Table 10: Visualization, Sensitivity, Specificity 1Number of segments varied between readers; number for majority-reader shown. 2Standard of Reference based on aggregate interpretation of three central CTA readers. 395.1/95% (Study C/D) confidence interval for two-sided comparison. 490.1/90% (Study C/D) confidence interval for one-sided comparison against non-inferiority margin of -7.5. GAD MRA Post-contrast Gadobutrol Magnetic Resonance Angiography, ToF Non-contrast 2D-Time of Flight. STUDY C: SUPRA-AORTIC ARTERIES (457 patients)Performance at the segment level95971 segments of which 1581 were positive for stenosis by SoR2 VISUALIZATION (%)SENSITIVITY (%)SPECIFICITY (%)READERGAD MRAToF MRAGAD ToF (CI3)GAD MRAToF MRAGAD ToF (CI4)GAD MRAToF MRAGAD ToF (CI4)1 88 24 64(61, 67) 60 54 6(-4, 14) 92 62 30(29, 32) 95 75 20(18, 21) 60 54 6(-3, 14) 95 85 10(9, 11) 97 82 15(13, 17) 58 55 3(-4, 11) 97 89 8(7, 9) STUDY D: RENAL ARTERIES (292 patients)Performance at the segment level17521 segments of which 1331 were positive for stenosis by SoR2 98 82 16(13, 20) 52 51 1(-9, 11) 94 83 11(9, 14) 96 72 24(21, 28) 54 39 15(6, 24) 95 85 10(8, 12) 96 78 17(14, 21) 53 50 3(-6, 12) 94 81 13(11, 16) For all three supra-aortic artery readers in Study C, the lower bound of confidence for the sensitivity of gadobutrol MRA did not exceed 54%. For all three renal artery readers in Study D, the lower bound of confidence for the sensitivity of gadobutrol MRA did not exceed 46%. Measurement VariabilityFor both MRA and CTA, readers varied in the quantity of narrowing they assigned to the same arterial segments. Table 11 shows the percentage of patients in whom the measurement range was 30% or greater for the left or right internal carotid and proximal renal artery segments. There were approximately four measurements per patient segment, one from the site and three from the central readers. Measurement variability was high for both CTA and MRA, but numerically lower for gadobutrol compared to non-contrast ToF MRA. Table 11: Percent of Patients with Range >= 30%, >= 50%, >= 70% for Measurement of Stenoses and Normal Vessel Diameters Internal CarotidProximal Main RenalN>= 30%>= 50%>= 70%N>= 30%>= 50%>= 70%CTA 456 40 11 292 59 33 ToF MRA 443 55 22 270 44 22 Gadobutrol MRA 454 47 13 286 34 14 . Visualization of Accessory Renal Arteries for Surgical Planning and Renal Donor Evaluation (Study only)Of 1752 main arteries visualized by the central CTA readers, 266 (15%) were also associated with positive visualization of at least one accessory (duplicate) artery. With the central MRA readers, the comparable rates were 232 of 1752 (13%) for gadobutrol MRA compared to 53 of 1752 (3%) for ToF MRA. 14.4 Cardiac MRI Two studies similar in design, Study and Study F, evaluated the sensitivity and specificity of gadobutrol cardiac MRI (CMRI) for detection of coronary artery disease (CAD) in adult patients with known or suspected CAD. Patients were excluded from study if they had history of coronary artery bypass grafting, or if it was known in advance that they were unable to hold their breath, or had atrial fibrillation or other arrhythmia likely to prevent electrocardiogram-gated CMRI. The studies were multi-center, open-label, and evaluated 764 subjects for efficacy: 376 in Study E, with an average age of 59 (range 20 to 84); 69% male; 74% white, 1% black, and 25% Asian; and 388 subjects in Study F, with an average age of 59 (range 23 to 82); 61% male; 67% white, 17% black, and 12% Asian. All subjects underwent dynamic first-pass gadobutrol imaging during vasodilator stress, followed ~10 minutes later by dynamic first-pass gadobutrol imaging at rest, followed ~5 minutes later with imaging during period of gradual gadobutrol washout from the myocardium (late gadolinium enhancement, LGE). Imaging was performed on 1.5 or 3.0 MRI devices equipped with multichannel surface coils to support accelerated acquisitions with parallel imaging, T1-weighted, 2D gradient-echo, dynamic acquisition of perfusion with at least slices per heartbeat. Gadobutrol was administered intravenously at rate of ~4 mL/second as two separate bolus injections (0.05 mmol/kg each), the first at peak pharmacologic stress (~3 minutes after start of ongoing adenosine infusion, or immediately after completion of regadenoson administration, at approved doses). No additional gadobutrol was administered for LGE imaging. Images were read by three independent readers blinded to clinical information. Reader detection of CAD depended on visually detecting defective perfusion or scar on gadobutrol CMRI (stress, rest, LGE) imaging. Quantitative coronary angiography (QCA) was used to measure intraluminal narrowing and served as the standard of reference (SoR). Computed tomographic angiography (CTA) was used as the SoR if disease could be unequivocally excluded, and no coronary angiography (CA) was available. The left ventricular myocardium was divided into six regions. Readers provided per-region (CMRI, CTA) and per-artery (QCA) interpretations for each subject. Subject-level endpoints reflected each subjects most abnormal localized finding. The sensitivity results for gadobutrol CMRI to detect CAD defined as either maximum stenosis >= 50% or >= 70% by QCA are presented in Table 12. For each reader, sensitivity of gadobutrol CMRI larger than 60% can be concluded if the lower 95% confidence limit of the sensitivity estimate exceeds the pre-specified threshold of 60%. Table 12: Sensitivity (%) of Gadobutrol CMRI for Detection of CAD in Patients with Maximum Stenosis of >= 50% and >= 70% Stenosis determined by Quantitative Coronary Angiography (QCA) CMRI images were assessed by six independent blinded readers, three in each study. The bolded value represents the lower limit of the 95% confidence interval, which is compared to pre-specified threshold of 60% for evaluation of sensitivity. Study EStudy F>= 50%N=141 >= 70%N=108 >= 50%N=150 >= 70%N=105 Reader 177 (69, 83) 90 (83, 95) 65 (57, 72) 77 (68, 85) Reader 265 (57, 73) 80 (71, 87) 56 (48, 64) 71 (62, 80) Reader 365 (56, 72) 79 (70, 86) 61 (53, 69) 76 (67, 84) The specificity results for gadobutrol CMRI to detect CAD defined as either maximum stenosis >= 50% or >= 70% by QCA are presented in Table 13. For each reader, specificity of gadobutrol CMRI larger than 55% can be concluded if the lower 95% confidence limit of the specificity estimate exceeds the pre-specified threshold of 55%. Table 13: Specificity (%) of Gadobutrol CMRI for Exclusion of CAD in Patients with Maximum Stenosis of >= 50% and >= 70% Stenosis determined by Quantitative Coronary Angiography (QCA) CMRI images were assessed by six independent blinded readers, three in each study. The bolded value represents the lower limit of the 95% confidence interval, which is compared to pre-specified threshold of 55% for evaluation of specificity. Study EStudy F>= 50%N=235 >= 70%N=268 >= 50%N=239 >= 70%N=283 Reader 185 (80, 89) 83 (78, 87) 85 (80, 90) 82 (77, 86) Reader 292 (88, 95) 91 (87, 94) 89 (84, 92) 87 (83, 91) Reader 392 (88, 95) 91 (87, 94) 90 (85, 93) 87 (82, 91) In Study E, among the 33 patients with maximum stenosis by QCA between 50% and <70%, the proportion of gadobutrol-CMRI positive detections of CAD ranged from 15% to 33%. In Study F, among the 45 patients with maximum stenosis by QCA between 50% and 70%, the proportion of gadobutrol-CMRI positive detections of CAD ranged from 20% to 35%. The results of gadobutrol-CMRI reads to detect CAD in patients with maximum stenosis between 50% and 70% are summarized in Table 14. Table 14: Gadobutrol-CMRI Detection of CAD in Patients with Maximum Stenosis between 50% and 70% Stenosis determined by Quantitative Coronary Angiography (QCA). CMRI images were assessed by six independent blinded readers, three in each study. Study (n=33)Study (n=45)Gadobutrol-CMRI positiveGadobutrol-CMRI positiveReader 111 (33%) 16 (35%) Reader 25(15%) (20%) Reader 36(18%) 12 (26%) Left Mainstem Stenosis (LMS)The studies did not include sufficient numbers of subjects to characterize the performance of gadobutrol CMRI for detection of LMS, subgroup at high risk from false negative reads. In Studies and F, only three subjects had isolated LMS stenosis >50%. In two of the three cases, the CMRI was interpreted as normal by at least two of the three readers (false negative). Sixteen subjects had LMS stenosis >50% (including subjects with isolated LMS stenosis and subjects with LMS stenosis in addition to stenoses elsewhere). In five of these sixteen cases, the CMR was interpreted as normal by at least two of the three readers (false negative).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in labeling: oNephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.2)]. oHypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.3)]. oAcute Respiratory Distress Syndrome [see Warnings and Precautions (5.4)]. oGadolinium Retention [see Warnings and Precautions (5.5)].. oNephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.2)]. oHypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.3)]. oAcute Respiratory Distress Syndrome [see Warnings and Precautions (5.4)]. oGadolinium 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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 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 exposure in 7713 subjects (including 184 pediatric patients, ages 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 week to 93 years). Overall, approximately 4% of subjects reported one or more adverse reactions during follow-up period that ranged from 24 hours to days after gadobutrol administration. Adverse reactions associated with the use of gadobutrol were usually mild to moderate in severity and transient in nature. Table lists adverse reactions that occurred in >= 0.1% subjects who received gadobutrol. Table 2: Adverse Reactions ReactionRate (%)n=7713Headache 1.7 Nausea 1.2 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 Erythema 0.2 Paresthesia 0.2 Pruritus (includes generalized) 0.2 Dyspnea 0.1 Urticaria 0.1 Adverse reactions that occurred with frequency of 0.1% in subjects who received gadobutrol include: hypersensitivity/anaphylactic reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during postmarketing use of gadobutrol or other GBCAs. Because these reactions are reported voluntarily from population of uncertain size, it is not possible to reliably estimate their frequency or establish causal relationship to drug exposure. oCardiac arrest oNephrogenic Systemic Fibrosis (NSF) oHypersensitivity 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). oRespiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edemaoGeneral 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. oSkin: Gadolinium associated plaques oGastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration oCardiac arrest oNephrogenic Systemic Fibrosis (NSF) oHypersensitivity 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). oRespiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema. oGeneral 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. oSkin: Gadolinium associated plaques oGastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 exposure in 7713 subjects (including 184 pediatric patients, ages 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 week to 93 years). Overall, approximately 4% of subjects reported one or more adverse reactions during follow-up period that ranged from 24 hours to days after gadobutrol administration. Adverse reactions associated with the use of gadobutrol were usually mild to moderate in severity and transient in nature. Table lists adverse reactions that occurred in >= 0.1% subjects who received gadobutrol. Table 2: Adverse Reactions ReactionRate (%)n=7713Headache 1.7 Nausea 1.2 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 Erythema 0.2 Paresthesia 0.2 Pruritus (includes generalized) 0.2 Dyspnea 0.1 Urticaria 0.1 Adverse reactions that occurred with frequency of 0.1% in subjects who received gadobutrol include: hypersensitivity/anaphylactic reaction, loss of consciousness, convulsion, parosmia, tachycardia, palpitation, dry mouth, malaise and feeling cold.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION Gadobutrol injection is paramagnetic macrocyclic contrast agent administered intravenously 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 molecular formula of C18H31GdN4O9 and molecular weight of 604.72. Gadobutrol injection is sterile, clear, colorless to pale yellow solution containing 604.72 mg (1.0 mmol) of gadobutrol per mL as the active ingredient with 0.513 mg of calcobutrol sodium, 1.211 mg of trometamol, hydrochloric acid (for pH adjustment) and water for injection. Gadobutrol injection contains no preservatives. The main physicochemical properties of gadobutrol injection (1 mmol/mL solution for injection) are listed below: Density (g/mL at 37C) 1.3 Osmolarity at 37C (mOsm/L solution) 1117 Osmolality at 37C (mOsm/kg H2O) 1603 Viscosity at 37C (mPa.s) 4.96 pH 6.6 to The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively. gadob-struc-01.jpg.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oRecommended dose for adults and pediatric patients (including term neonates) is 0.1 mL/kg body weight (2.1) oAdminister as an intravenous bolus injection (2.2) oFollow injection with normal saline flush (2.2) oRecommended dose for adults and pediatric patients (including term neonates) is 0.1 mL/kg body weight (2.1) oAdminister as an intravenous bolus injection (2.2) oFollow injection with normal saline flush (2.2) 2.1 Recommended Dose The recommended dose of gadobutrol injection for adult and pediatric patients (including term neonates) is 0.1 mL/kg body weight (0.1 mmol/kg). Refer to Table to determine the volume to be administered. Table 1: Volume of Gadobutrol Injection by Body Weight For Cardiac MRI, the dose is divided into separate, equal injections Body Weight (kg) Volume to be Administered (mL) 2.5 0.25 0.5 10 15 1.5 20 25 2.5 30 35 3.5 40 45 4.5 50 60 70 80 90 100 10 110 11 120 12 130 13 140 14 2.2 Administration Guidelines Gadobutrol injection is formulated at higher concentration (1 mmol/mL) compared to certain other gadolinium based contrast agents, resulting in lower volume of administration. Use Table to determine the volume to be administered. Use sterile technique when preparing and administering gadobutrol injection. MRI of the Central Nervous SystemoAdminister gadobutrol injection as an intravenous injection, manually or by power injector, at flow rate of approximately mL/second. oFollow gadobutrol injection with flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. oPost contrast MRI can commence immediately following contrast administration. MRI of the BreastoAdminister gadobutrol injection as an intravenous bolus by power injector, followed by flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. oStart image acquisition following contrast administration and then repeat sequentially to determine peak intensity and wash-out. MR AngiographyImage acquisition should coincide with peak arterial concentration, which varies among patients. AdultsoAdminister gadobutrol injection by power injector, at flow rate of approximately 1.5 mL/second, followed by 30 mL flush of 0.9% Sodium Chloride Injection, USP at the same rate to ensure complete administration of the contrast. Pediatric patientsoAdminister gadobutrol injection by power injector or manually, followed by flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. Cardiac MRIoAdminister gadobutrol injection through separate intravenous line in the contralateral arm if concomitantly providing continuous infusion of pharmacologic stress agent. oAdminister gadobutrol injection as two (2) separate bolus injections: 0.05 mL/kg (0.05 mmol/kg) body weight at peak pharmacologic stress followed by 0.05 mL/kg (0.05 mmol/kg) body weight at rest. oAdminister gadobutrol injection via power injector at flow rate of approximately mL/second and follow each injection with flush of 20 mL of 0.9% Sodium Chloride Injection, USP at the same flow rate. oAdminister gadobutrol injection as an intravenous injection, manually or by power injector, at flow rate of approximately mL/second. oFollow gadobutrol injection with flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. oPost contrast MRI can commence immediately following contrast administration. oAdminister gadobutrol injection as an intravenous bolus by power injector, followed by flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. oStart image acquisition following contrast administration and then repeat sequentially to determine peak intensity and wash-out. oAdminister gadobutrol injection by power injector, at flow rate of approximately 1.5 mL/second, followed by 30 mL flush of 0.9% Sodium Chloride Injection, USP at the same rate to ensure complete administration of the contrast. oAdminister gadobutrol injection by power injector or manually, followed by flush of 0.9% Sodium Chloride Injection, USP to ensure complete administration of the contrast. oAdminister gadobutrol injection through separate intravenous line in the contralateral arm if concomitantly providing continuous infusion of pharmacologic stress agent. oAdminister gadobutrol injection as two (2) separate bolus injections: 0.05 mL/kg (0.05 mmol/kg) body weight at peak pharmacologic stress followed by 0.05 mL/kg (0.05 mmol/kg) body weight at rest. oAdminister gadobutrol injection via power injector at flow rate of approximately mL/second and follow each injection with flush of 20 mL of 0.9% Sodium Chloride Injection, USP at the same flow rate. 2.3 Drug Handling oVisually inspect gadobutrol injection 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. oDo not mix gadobutrol injection with other medications and do not administer gadobutrol injection in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility. oInstructions of the device manufacturer must be followed. oVisually inspect gadobutrol injection 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. oDo not mix gadobutrol injection with other medications and do not administer gadobutrol injection in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility. oInstructions of the device manufacturer must be followed. 2.4 Imaging Bulk Package Preparation Instructions Gadobutrol injection Imaging Bulk Package (IBP) is container of sterile preparation for parenteral use that contains many single doses of gadobutrol for use with medical imaging device. Gadobutrol injection Imaging Bulk Package is for intravenous use and not for direct infusion. Gadobutrol injection Imaging Bulk Package is for use only with an automated contrast injection system, contrast management system, or contrast media transfer set approved or cleared for use with this contrast agent in this Imaging Bulk Package. Please see drug and device labeling for information on devices indicated for use with this Imaging Bulk Package and techniques to help assure safe use. 1.The Gadobutrol injection Imaging Bulk Package is to be used only in room designated for radiological procedures that involve intravascular administration of contrast agent. 2.Utilize aseptic technique for penetrating the container closure of the Gadobutrol injection Imaging Bulk Package and transferring Gadobutrol injection. 3.The container closure must be penetrated only one time with suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) approved or cleared for use with this contrast agent in this Imaging Bulk Package. 4.Once the Gadobutrol injection Imaging Bulk Package is punctured, do not remove it from the work area during the entire period of use. Storage temperature of Gadobutrol injection Imaging Bulk Package after the closure has been entered is 20C to 25C (68F to 77F). 5.A maximum use time of 24 hours from initial puncture is permitted to complete fluid transfer. Discard any unused Gadobutrol injection 24 hours after initial puncture of the Imaging Bulk Package. 6.After the container closure is punctured, if the integrity of the Imaging Bulk Package and the delivery system cannot be assured through direct continuous supervision, the Imaging Bulk Package and all associated disposables for the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) should be discarded. 1.The Gadobutrol injection Imaging Bulk Package is to be used only in room designated for radiological procedures that involve intravascular administration of contrast agent. 2.Utilize aseptic technique for penetrating the container closure of the Gadobutrol injection Imaging Bulk Package and transferring Gadobutrol injection. 3.The container closure must be penetrated only one time with suitable sterile component of the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) approved or cleared for use with this contrast agent in this Imaging Bulk Package. 4.Once the Gadobutrol injection Imaging Bulk Package is punctured, do not remove it from the work area during the entire period of use. Storage temperature of Gadobutrol injection Imaging Bulk Package after the closure has been entered is 20C to 25C (68F to 77F). 5.A maximum use time of 24 hours from initial puncture is permitted to complete fluid transfer. Discard any unused Gadobutrol injection 24 hours after initial puncture of the Imaging Bulk Package. 6.After the container closure is punctured, if the integrity of the Imaging Bulk Package and the delivery system cannot be assured through direct continuous supervision, the Imaging Bulk Package and all associated disposables for the automated contrast injection system, contrast management system, or contrast media transfer set (e.g., transfer spike) should be discarded.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Gadobutrol injection is sterile, clear, and colorless to pale yellow solution for injection containing 604.72 mg gadobutrol per mL (equivalent to mmol gadobutrol/mL). Gadobutrol injection contains 604.72 mg gadobutrol/mL (equivalent to mmol gadobutrol/mL) (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use In clinical studies of gadobutrol, 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 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Gadobutrol injection is sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to mmol gadobutrol per mL). Gadobutrol injection is supplied in the following Multiple-Dose container sizes: Product CodeUnit of SaleEach287230 NDC 65219-287-30Packaged in cartons of 10. NDC 65219-287-1030 mL Imaging Bulk Package with rubber stopper. 287265 NDC 65219-289-65Packaged in cartons of 10. NDC 65219-289-1065 mL Imaging Bulk Package with rubber stopper. 16.2 Storage and Handling Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Should freezing occur, gadobutrol injection should be brought to room temperature before use. If allowed to stand at room temperature, gadobutrol injection should return to clear and colorless to pale yellow solution. Visually inspect gadobutrol injection 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.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Gadobutrol injection is gadolinium-based contrast agent indicated for use with magnetic resonance imaging (MRI): oTo 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) oTo assess the presence and extent of malignant breast disease in adult patients (1.2) oTo evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates) (1.3) oTo assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD). (1.4). oTo 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) oTo assess the presence and extent of malignant breast disease in adult patients (1.2) oTo evaluate known or suspected supra-aortic or renal artery disease in adult and pediatric patients (including term neonates) (1.3) oTo assess myocardial perfusion (stress, rest) and late gadolinium enhancement in adult patients with known or suspected coronary artery disease (CAD). (1.4). 1.1 Magnetic 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. 1.2 MRI of the Breast Gadobutrol injection is indicated for use with MRI in adult patients to assess the presence and extent of malignant breast disease. 1.3 Magnetic 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. 1.4 Cardiac 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).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Gadobutrol leads to distinct shortening of the relaxation times even in low concentrations. At pH 7, 37C 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 T1 shortening effect of paramagnetic contrast agents is dependent on concentration and r1 relaxivity (see Table 3). This may improve tissue visualization. Table 3: Relaxivity (r1) of Gadolinium Chelates at 1.5 r1 relaxivity in plasma at 37C Gadolinium-Chelater1 (L.mmol -1 .s -1)Gadobenate 6.3 Gadobutrol 5.2 Gadodiamide 4.3 Gadofosveset 16 Gadopentetate 4.1 Gadoterate 3.6 Gadoteridol 4.1 Gadoversetamide 4.7 Gadoxetate 6.9 Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of gadobutrol results in half the volume of administration and more compact contrast bolus injection. At the site of imaging, the relative height and width of the time intensity curve for gadobutrol varies as function of imaging location and multiple patient, injection, and device-specific factors. Gadobutrol is water-soluble, hydrophilic compound with partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION oAdvise the patient to read the FDA-approved patient labeling (Medication Guide). Nephrogenic Systemic Fibrosis Instruct patients to inform their physician if they: oHave history of kidney disease and/or liver disease, or oHave recently received GBCA GBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel patients at risk of NSF: oDescribe the clinical manifestation of NSF oDescribe procedures to screen for the detection of renal impairment Instruct the patients to contact their physician if they develop signs or symptoms of NSF following gadobutrol injection administration, such as burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain in the hip bones or ribs; or muscle weakness. Common Adverse ReactionsInform patients that they may experience: oReactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site oSide effects of headache, nausea, abnormal taste and feeling hot Acute Respiratory Distress SyndromeoAdvise patients that acute respiratory distress syndrome (ARDS) has occurred with gadobutrol injection. Inform patients on the symptoms of the observed ARDS cases, and instruct patients to inform their healthcare provider if they experience these symptoms [see Warnings and Precautions (5.4)].General PrecautionsGadolinium Retention oAdvise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.5)]. Instruct patients receiving gadobutrol injection to inform their physician if they: oAre pregnant or breastfeeding oHave history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder Manufactured for: Lake Zurich, IL 60047 www.fresenius-kabi.com/us Product of ChinaRevised: May 2025 451796C26EUF04 oAdvise the patient to read the FDA-approved patient labeling (Medication Guide). oHave history of kidney disease and/or liver disease, or oHave recently received GBCA oDescribe the clinical manifestation of NSF oDescribe procedures to screen for the detection of renal impairment oReactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site oSide effects of headache, nausea, abnormal taste and feeling hot oAdvise patients that acute respiratory distress syndrome (ARDS) has occurred with gadobutrol injection. Inform patients on the symptoms of the observed ARDS cases, and instruct patients to inform their healthcare provider if they experience these symptoms [see Warnings and Precautions (5.4)].. oAdvise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.5)]. oAre pregnant or breastfeeding oHave history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder gadob-img-01.jpg.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere 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 mothers clinical need for gadobutrol and any potential adverse effects on the breastfed infant from gadobutrol or from the underlying maternal condition. 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 hours after administration, and the gastrointestinal absorption is poor (approximately 5% of the dose orally administered was excreted in the urine).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occurs with: oDifferences in proton density oDifferences of the spin-lattice or longitudinal relaxation times (T1) oDifferences in the spin-spin or transverse relaxation time (T2) When placed in magnetic field, gadobutrol shortens the T1 and T2 relaxation times. The extent of decrease of T1 and T2 relaxation times, and therefore the amount of signal enhancement obtained from gadobutrol, is based upon several factors including the concentration of gadobutrol in the tissue, the field strength of the MRI system, and the relative ratio of the longitudinal and transverse relaxation times. At the recommended dose, the T1 shortening effect is observed with greatest sensitivity in T1-weighted magnetic resonance sequences. In T2-weighted sequences the induction of local magnetic field inhomogeneities by the large magnetic moment of gadolinium and at high concentrations (during bolus injection) leads to signal decrease. oDifferences in proton density oDifferences of the spin-lattice or longitudinal relaxation times (T1) oDifferences in the spin-spin or transverse relaxation time (T2).

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 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). 13.2 Animal Toxicology and/or Pharmacology Local intolerance reactions, including moderate irritation associated with infiltration of inflammatory cells was observed after paravenous administration to rabbits, suggesting the possibility of occurrence of local irritation if the contrast medium leaks around veins in clinical setting [see Warnings and Precautions (5.7)].

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 mmol/30 mL (1 mmol/mL) Shelf Carton Dose: 0.1 mL/kgNDC 65219-287-30 Gadobutrol Injection 30 mmol/30 mL (1 mmol/mL) Imaging Bulk Package Not for Direct InfusionFor Intravenous Use OnlyDiscard 24 hours after initial punctureDispense the enclosed Medication Guide to each patient.. gadob-label-01.jpg.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of gadobutrol 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 in these indications is supported by adequate and well-controlled studies in adults and supportive imaging data in two studies in 135 patients to less than 18 years of age and 44 patients less than years of age with CNS and non-CNS lesions, and pharmacokinetic data in 130 patients to less than 18 years of age and 43 patients less than 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 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 RiskNo case of NSF associated with gadobutrol or any other GBCA has been identified in pediatric patients ages years and younger. Pharmacokinetic studies suggest that clearance of gadobutrol is similar in pediatric patients and adults, including pediatric patients age younger than 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 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than year of age have been conducted in patients with the following minimum eGFR: 31 mL/min/1.73m2 (age to days), 38 mL/min/1.73m2 (age to 28 days), 62 mL/min/1.73m2 (age to months), and 83 mL/min/1.73m2 (age to 12 months). Juvenile Animal DataSingle and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of specific risk for use in pediatric patients including term neonates and infants.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics DistributionAfter intravenous administration, gadobutrol is rapidly distributed in the extracellular space. After gadobutrol dose of 0.1 mmol/kg body weight, an average level of 0.59 mmol gadobutrol/L was measured in plasma minutes after the injection and 0.3 mmol gadobutrol/L 60 minutes after the injection. Gadobutrol does not display any particular protein binding. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.5)]. MetabolismGadobutrol is not metabolized. EliminationValues 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/(minkg) 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. Specific Populations. GenderGender has no clinically relevant effect on the pharmacokinetics of gadobutrol. GeriatricA single intravenous dose of 0.1 mmol/kg gadobutrol was administered to 15 elderly and 16 non-elderly subjects. AUC was slightly higher and clearance slightly lower in elderly subjects as compared to non-elderly subjects [see Use in Specific Populations (8.5)]. PediatricThe pharmacokinetics of gadobutrol were evaluated in two studies in total of 130 patients age to less than 18 years and in 43 patients less than years of age (including term neonates). Patients received single intravenous dose of 0.1 mmol/kg of gadobutrol. The pharmacokinetic profile of gadobutrol in pediatric patients is similar to that in adults, resulting in similar values for AUC, body weight normalized plasma clearance, as well as elimination half-life. Approximately 99% (median value) of the dose was recovered in urine within hours (this information was derived from the to less than 18 year old age group). Table 4: Pharmacokinetics by Age Group (Median [Range]) to 2 yearsN=432 to yearsN=457 to 11 yearsN=3912 to 18 yearsN=46AdultsN=93AUC (umolxh/L) 781[513, 1891] 846[412, 1331] 1025[623, 2285] 1237[946, 2211] 1072[667, 1992] CL (L/h/kg) 0.128[0.053, 0.195] 0.119[0.08, 0.215] 0.099[0.043, 0.165] 0.081[0.046, 0.103] 0.094[0.051, 0.150] t1/2 (h) 2.91[1.60, 12.4] 1.91[1.04, 2.70] 1.66[0.91, 2.71] 1.68[1.31, 2.48] 1.80[1.20, 6.55] C20 (umol/L) 367[280, 427] 421[369, 673] 462[392, 760] 511[387, 1077] 441[281, 829] Renal ImpairmentIn patients with impaired renal function, the serum half-life of gadobutrol is prolonged and correlated with the reduction in creatinine clearance. After intravenous injection of 0.1 mmol gadobutrol/kg body weight, the elimination half-life was 5.8 +- 2.4 hours in mild to moderately impaired patients (80 CLCR 30 mL/min) and 17.6 +- 6.2 hours in severely impaired patients not on dialysis (CLCR< 30 mL/min). The mean AUC of gadobutrol in patients with normal renal function was 1.1 +- 0.1 mmolh/L, compared to 4.0 +- 1.8 mmolh/L in patients with mild to moderate renal impairment and 11.5 +- 4.3 mmolh/L in patients with severe renal impairment. Complete recovery in the urine was seen in patients with mild or moderate renal impairment within 72 hours. In patients with severely impaired renal function about 80% of the administered dose was recovered in the urine within days. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of gadobutrol in order to enhance the contrast agents elimination. Sixty-eight percent (68%) of gadobutrol is removed from the body after the first dialysis, 94% after the second dialysis, and 98% after the third dialysis session. [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6).].

PREGNANCY SECTION.

8.1 Pregnancy Risk SummaryGBCAs 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 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses and 12 times, respectively, the recommended human dose (see Data). Because of the potential risks of gadolinium to the fetus, use gadobutrol 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 DataContrast 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 clear association between GBCAs and adverse effects in the exposed neonates. However, retrospective cohort study, comparing pregnant women who had GBCA MRI to pregnant women who did not have an MRI, reported higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.Animal DataGadolinium RetentionGBCAs 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 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 ToxicologyEmbryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 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 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, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions,Acute Respiratory Distress Syndrome (5.4) 3/2025.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment Prior to administration of gadobutrol, screen all patients for renal dysfunction by obtaining 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)].

SPL MEDGUIDE SECTION.

MEDICATION GUIDE Gadobutrol InjectionGadobutrol (gad oh bue trol)Injection for intravenous useWhat is the most important information should know about gadobutrol injectionoGBCAs like Gadobutrol injection may cause serious side effects including death, coma, encephalopathy, and seizures when it is given intrathecally (injection given into the spinal canal). It is not known if Gadobutrol injection is safe and effective with intrathecal use. Gadobutrol injection is not approved for this use.oGadobutrol injection contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for long time (several months to years).oIt is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.oRarely, patients have reported pains, tiredness, and skin, muscle or bone ailments for long time, but these symptoms have not been directly linked to gadolinium.oThere are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadobutrol injection, or ProHance.oPeople who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.oSome people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive gadobutrol injection.What is gadobutrol injectionoGadobutrol injection is prescription medicine called gadolinium-based contrast agent (GBCA). Gadobutrol injection, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner.oAn MRI exam with GBCA, including gadobutrol injection, helps your doctor to see problems better than an MRI exam without GBCA.oYour doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.Do not receive gadobutrol injection if you have had severe allergic reaction to gadobutrol injection. Before receiving gadobutrol injection, tell your healthcare provider about all your medical conditions, including if you:ohave had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures. oare pregnant or plan to become pregnant. It is not known if gadobutrol injection can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as gadobutrol injection is received during pregnancy. ohave kidney problems, diabetes, or high blood pressure ohave had an allergic reaction to dyes (contrast agents) including GBCAs What are the possible side effects of gadobutrol injectionoSee What is the most important information should know about gadobutrol injectionoAllergic reactions. Gadobutrol injection can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.oA serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing after receiving gadobutrol injection.The most common side effects of gadobutrol injection include: headache, nausea, and dizziness.These are not all the possible side effects of gadobutrol injection.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of gadobutrol injection.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your healthcare provider for information about gadobutrol injection that is written for health professionals. What are the ingredients in gadobutrol injectionActive ingredient: gadobutrolInactive ingredients: calcobutrol sodium, trometamol, hydrochloric acid (for pH adjustment) and water for injectionManufactured for:Lake Zurich, IL 60047www.fresenius-kabi.com/usFor more information, call Fresenius Kabi USA, LLC at 1-800-551-7176. This Medication Guide has been approved by the U.S. Food and Drug Administration. 5/2025 26EUF04 451796C oGBCAs like Gadobutrol injection may cause serious side effects including death, coma, encephalopathy, and seizures when it is given intrathecally (injection given into the spinal canal). It is not known if Gadobutrol injection is safe and effective with intrathecal use. Gadobutrol injection is not approved for this use.. oGadobutrol injection contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for long time (several months to years).. oIt is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.. oRarely, patients have reported pains, tiredness, and skin, muscle or bone ailments for long time, but these symptoms have not been directly linked to gadolinium.. oThere are different GBCAs that can be used for your MRI exam. The amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadobutrol injection, or ProHance.. oPeople who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.. oSome people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive gadobutrol injection.. oGadobutrol injection is prescription medicine called gadolinium-based contrast agent (GBCA). Gadobutrol injection, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner.. oAn MRI exam with GBCA, including gadobutrol injection, helps your doctor to see problems better than an MRI exam without GBCA.. oYour doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.. ohave had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures. oare pregnant or plan to become pregnant. It is not known if gadobutrol injection can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as gadobutrol injection is received during pregnancy. ohave kidney problems, diabetes, or high blood pressure ohave had an allergic reaction to dyes (contrast agents) including GBCAs oSee What is the most important information should know about gadobutrol injection. oAllergic reactions. Gadobutrol injection can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.. oA serious lung problem called acute respiratory distress syndrome (ARDS). Call your healthcare provider right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing after receiving gadobutrol injection.. gadob-img-02.jpg.

SPL UNCLASSIFIED SECTION.

1.1 Magnetic 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.

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling Store at 25C (77F); excursions permitted to 15 to 30C (59 to 86F) [see USP Controlled Room Temperature]. Should freezing occur, gadobutrol injection should be brought to room temperature before use. If allowed to stand at room temperature, gadobutrol injection should return to clear and colorless to pale yellow solution. Visually inspect gadobutrol injection 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. (8.1) 8.1 Pregnancy Risk SummaryGBCAs 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 times and above the recommended human dose. Retardation of embryonal development was observed in rabbits and rats receiving intravenous gadobutrol during organogenesis at doses and 12 times, respectively, the recommended human dose (see Data). Because of the potential risks of gadolinium to the fetus, use gadobutrol 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 DataContrast 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 clear association between GBCAs and adverse effects in the exposed neonates. However, retrospective cohort study, comparing pregnant women who had GBCA MRI to pregnant women who did not have an MRI, reported higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.Animal DataGadolinium RetentionGBCAs 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 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 ToxicologyEmbryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 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 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, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.. 8.2 Lactation Risk SummaryThere 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 mothers clinical need for gadobutrol and any potential adverse effects on the breastfed infant from gadobutrol or from the underlying maternal condition. 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 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 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 in these indications is supported by adequate and well-controlled studies in adults and supportive imaging data in two studies in 135 patients to less than 18 years of age and 44 patients less than years of age with CNS and non-CNS lesions, and pharmacokinetic data in 130 patients to less than 18 years of age and 43 patients less than 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 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 RiskNo case of NSF associated with gadobutrol or any other GBCA has been identified in pediatric patients ages years and younger. Pharmacokinetic studies suggest that clearance of gadobutrol is similar in pediatric patients and adults, including pediatric patients age younger than 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 year of age, reflecting growth in both glomerular function and relative body surface area. Clinical studies in pediatric patients younger than year of age have been conducted in patients with the following minimum eGFR: 31 mL/min/1.73m2 (age to days), 38 mL/min/1.73m2 (age to 28 days), 62 mL/min/1.73m2 (age to months), and 83 mL/min/1.73m2 (age to 12 months). Juvenile Animal DataSingle and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of specific risk for use in pediatric patients including term neonates and infants. 8.5 Geriatric Use In clinical studies of gadobutrol, 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 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, screen all patients for renal dysfunction by obtaining 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHypersensitivity 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. (5.3) oAcute Respiratory Distress Syndrome: For patients demonstrating respiratory distress after administration, assess oxygen requirement and monitor for worsening respiratory function. (5.4)oGadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. (5.5) oHypersensitivity 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. (5.3) oAcute Respiratory Distress Syndrome: For patients demonstrating respiratory distress after administration, assess oxygen requirement and monitor for worsening respiratory function. (5.4). oGadolinium 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/1.73m2) 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 gadobutrol 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 GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to patient. For patients at highest risk for NSF, do not exceed the recommended gadobutrol dose and allow 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 GBCA in order to enhance the contrast agents 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 administration [see Adverse Reactions (6)]. oBefore gadobutrol administration, assess all patients for any history of reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for hypersensitivity reaction to gadobutrol. oAdminister gadobutrol 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 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 administration. oBefore gadobutrol administration, assess all patients for any history of reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for hypersensitivity reaction to gadobutrol. oAdminister gadobutrol only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. 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 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. Extravasation into tissues during gadobutrol 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 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 MRA for detecting arterial segments with significant stenosis (>50% renal, >70% supra-aortic) has not been shown to exceed 55%. Therefore, negative MRA study alone should not be used to rule out significant stenosis [see Clinical Studies (14.3)].