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 (5.5)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in labeling:oNephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)].oHypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)].. oNephrogenic Systemic Fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)].. oHypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)].. oMost common adverse reactions (incidence >= 0.5%) are headache, nausea, and dizziness (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch oMost common adverse reactions (incidence >= 0.5%) are headache, nausea, and dizziness (6.1). 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 Gadavist exposure in 7,713 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 55 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 Gadavist administration.Adverse reactions associated with the use of Gadavist were usually mild to moderate in severity and transient in nature. Table lists adverse reactions that occurred in >= 0.1% subjects who received Gadavist. Table 2: Adverse ReactionsReactionRate (%)n=6809Headache1.5Nausea1.1Dizziness0.5Dysgeusia0.4Feeling Hot0.4Injection site reactions0.4Vomiting0.4Rash (includes generalized, macular, papular, pruritic)0.3Erythema0.2Paresthesia0.2Pruritus (includes generalized)0.2Dyspnea0.1Urticaria0.1Adverse reactions that occurred with frequency of 0.1% in subjects who received Gadavist 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 reported during postmarketing use of Gadavist. 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 arrestoNephrogenic Systemic Fibrosis (NSF)oHypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) [see Warnings and Precautions (5.2)] oGeneral Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.oSkin: Gadolinium associated plaques. oCardiac arrest. oNephrogenic Systemic Fibrosis (NSF). oHypersensitivity reactions (anaphylactic shock, circulatory collapse, respiratory arrest, pulmonary edema, bronchospasm, cyanosis, oropharyngeal swelling, laryngeal edema, blood pressure increased, chest pain, angioedema, conjunctivitis, hyperhidrosis, cough, sneezing, burning sensation, and pallor) [see Warnings and Precautions (5.2)] oGeneral Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.. oSkin: Gadolinium associated plaques.

BOXED WARNING SECTION.

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF). Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.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 Gadavist dose and allow sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)].. 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 Gadavist dose and allow sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)].. WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)See full prescribing information for complete boxed warningGadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities.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. (5.1). 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. (5.1).

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 densityoDifferences of the spin-lattice or longitudinal relaxation times (T1)oDifferences in the spin-spin or transverse relaxation time (T2)When placed in magnetic field, Gadavist 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 Gadavist, is based upon several factors including the concentration of Gadavist 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. Gadavist 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 TGadolinium-Chelate r1 (L.mmol -1 .s-1)Gadobenate 6.3Gadobutrol 5.2Gadodiamide 4.3Gadofosveset16Gadopentetate 4.1Gadoterate3.6 Gadoteridol 4.1Gadoversetamide4.7Gadoxetate6.9 r1 relaxivity in plasma at 37C Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist 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 Gadavist varies as function of imaging location and multiple patient, injection, and device-specific factors.Gadavist is water-soluble, hydrophilic compound with partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006. 12.3 Pharmacokinetics. Distribution. After 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 (5.3)]. Metabolism. Gadobutrol is not metabolized. Elimination. Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below.Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(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. Gender. Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol. Geriatric. single IV dose of 0.1 mmol/kg Gadavist 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)]. Pediatric. The 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 Gadavist. 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])0 to 2 years2 to years7 to 11 years12 to 18 yearsAdultsN=43N=45N=39N=46N=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 [0.080, 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 Impairment. In 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 Gadavist 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 (5.1) 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 Gadavist 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 Gadavist 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 Gadavist image sets to pre-contrast MRI. Readers were blinded to clinical information.Table 5: Primary Endpoint Visualization Scoring System Score Visualization CharacteristicsScoreVisualization CharacteristicsContrast EnhancementBorder DelineationInternal Morphology1NoneNonePoorly visible2WeakModerateModerately visible3ClearClear but incompleteSufficiently visible4Clear and brightClear and completeN/AEfficacy 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. Gadavist 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 GadavistEndpointStudy AN=336Study BN=321Pre-contrastPairedDifferenceDifference of means (paired mean) (pre-contrast mean) Pre-contrastPairedDifferenceContrast Enhancement0.972.261.29p<0.001 0.932.861.94 Border Delineation1.982.580.60 1.922.941.02 Internal Morphology1.321.930.60 1.572.350.78 Average Lesions Detected8.088.250.17Did not meet noninferiority margin of -0.35 2.652.970.32Met noninferiority margin of -0.35 Performances of Gadavist 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, Gadavist 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 ReaderStudy AN=336Study BN=321Endpoint Categorical Improvement(Paired Pre-Contrast) %Categorical Improvement(Paired Pre-Contrast) %<= 0> - 11 < 2>= 2<= > - 11 < 2>= Contrast Enhancement1305513363457Border Delineation773181538515Internal Morphology479170561331For both studies, the improvement of visualization endpoints in paired Gadavist images compared to pre-contrast images resulted in improved assessment of normal and abnormal CNS anatomy.. 0 < 1. Pediatric Patients. Two 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 Gadavist to assess the presence and extent of malignant breast disease prior to surgery. Patients underwent non-contrast breast MRI (BMR) prior to Gadavist (0.1 mmol/kg) breast MRI. BMR images and Gadavist 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 Gadavist 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 Gadavist 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 Gadavist BMR and BMR as well as for Gadavist BMR plus XRM and BMR plus XRM is presented in Table 8. Table 8: Sensitivity of Gadavist BMR for Detection of Malignant Breast DiseaseStudy 1Study 2Sensitivity (%)N=388 PatientsSensitivity (%)N=390 PatientsReaderBMRBMR XRM Gadavist BMRGadavist BMR+XRMReaderBMRBMR XRMGadavist BMRGadavist BMR+XRM 137718384 473838790 249768083 557818990363758787 655808688Specificity 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 Gadavist BMR was greater than 80% for of readers. (Table 9)Table 9: Specificity of Gadavist BMR in Non-Malignant BreastsStudy 1Study 2Specificity (%) N=372 PatientsSpecificity (%)N=367 Patients ReaderGadavist BMRLower Limit95% CIReaderGadavist BMRLower Limit95% CI 1868249289 29593584803898568379Three 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 Gadavist 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 Gadavist 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 Gadavist 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 Gadavist 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 25-93); 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 18-88); 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 Gadavist 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 Gadavist 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, SpecificitySTUDY C: SUPRA-AORTIC ARTERIES (457 patients)Performance at the segment level9597Number of segments varied between readers; number for majority-reader shown.segments of which 158were positive for stenosis by SoRStandard of Reference based on aggregate interpretation of three central CTA readers.VISUALIZATION (%)SENSITIVITY (%)SPECIFICITY (%)READERGADMRAToF MRAGAD ToF(CI95.1/95% (Study C/D) confidence interval for two-sided comparison.)GAD MRAToF MRAGAD ToF (CI90.1/90% (Study C/D) confidence interval for one-sided comparison against non-inferiority margin of -7.5.)GAD MRAToF MRAGAD ToF (CI)1882464(61, 67)60546(-4, 14)926230(29, 32)2957520(18, 21)60546(-3, 14)958510(9, 11)3978215(13, 17)58553(-4, 11)97898(7, 9)STUDY D: RENAL ARTERIES (292 patients)Performance at the segment level1752 segments of which 133 were positive for stenosis by SoR2 4988216(13, 20)52511(-9, 11)948311(9, 14)5967224(21, 28)543915(6, 24)958510(8, 12)6967817(14, 21)53503(-6, 12)948113(11, 16)GAD MRA Post-contrast Gadavist Magnetic Resonance Angiography, ToF Non-contrast 2D-Time of Flight.For all three supra-aortic artery readers in Study C, the lower bound of confidence for the sensitivity of Gadavist MRA did not exceed 54%. For all three renal artery readers in Study D, the lower bound of confidence for the sensitivity of Gadavist MRA did not exceed 46%.Measurement Variability For 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 central readers. Measurement variability was high for both CTA and MRA, but numerically lower for Gadavist compared to non-contrast ToF MRA. Table 11: Percent of Patients with Range >= 30%, >= 50%, >= 70% for Measurement of Stenoses and Normal Vessel DiametersInternal CarotidProximal Main RenalN>= 30% Carotid >= 50% >= 70% N>= 30%>= 50%>= 70%CTA45640 11429259 339ToF MRA44355 22927044 229Gadavist MRA45447 13428634 144Visualization 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 Gadavist 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 Gadavist 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 20-84); 69% male; 74% white, 1% black, and 25% Asian; and 388 subjects in Study F, with an average age of 59 (range 23-82); 61% male; 67% white, 17% black, and 12% Asian.All subjects underwent dynamic first-pass Gadavist imaging during vasodilator stress, followed ~10 minutes later by dynamic first-pass Gadavist imaging at rest, followed ~5 minutes later with imaging during period of gradual Gadavist 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. Gadavist 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 Gadavist 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 Gadavist 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 Gadavist CMRI to detect CAD defined as either maximum stenosis >= 50% or >= 70% by QCA are presented in Table 12. For each reader, sensitivity of Gadavist 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 Gadavist-CMRI for Detection of CAD in Patients with Maximum Stenosis of >= 50% and >= 70%Study EStudy F>=50% N=141>=70% N=108>=50% N=150>=70% N=105Reader 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) 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. The specificity results for Gadavist CMRI to detect CAD defined as either maximum stenosis >=50% or >=70% by QCA are presented in Table 13. For each reader, specificity of Gadavist 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 Gadavist CMRI for Exclusion of CAD in Patients with Maximum Stenosis of >= 50% and >= 70%.Study EStudy F>=50% N=235>=70% N=268>=50% N=239>=70% N=283Reader 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) 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. In Study E, among the 33 patients with maximum stenosis by QCA between 50% and <70%, the proportion of Gadavist-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 Gadavist-CMRI positive detections of CAD ranged from 20% to 35%. The results of Gadavist CMRI reads to detect CAD in patients with maximum stenosis between 50% and 70% are summarized in Table 14.Table 14: Gadavist-CMRI Detection of CAD in Patients with Maximum Stenosis between 50% and 70%Study (n=33)Study (n=45)Gadavist-CMRIpositiveGadavist-CMRIpositiveReader 111 (33%) 16 (35%) Reader 25 (15%)9 (20%)Reader 36 (18%)12 (26%) Stenosis determined by Quantitative Coronary Angiography (QCA).CMRI images were assessed by six independent blinded readers, three in each study.Left Mainstem Stenosis (LMS)The studies did not include sufficient numbers of subjects to characterize the performance of Gadavist 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).

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

11 DESCRIPTION. Gadavist (gadobutrol) injection is paramagnetic macrocyclic contrast agent administered 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.Gadavist is sterile, clear, colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to mmol/mL) as the active ingredient and the excipients calcobutrol sodium, trometamol, hydrochloric acid (for pH adjustment) and water for injection. Gadavist contains no preservatives. The main physicochemical properties of Gadavist (1 mmol/mL solution for injection) are listed below:Density (g/mL at 37C)1.3Osmolarity at 37C (mOsm/L solution)1117Osmolality at 37C (mOsm/kg H2O)1603Viscosity at 37C (mPa.s)4.96pH6.6-8The thermodynamic stability constants for gadobutrol (log Ktherm and log Kcond at pH 7.4) are 21.8 and 15.3, respectively. Structural Formula.

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 Gadavist 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 Gadavist Injection by Body WeightBody Weight (kg)Volume to be Administered (mL)2.50.25 50.5101151.5202252.5303353.5404454.55056067078089091001011011120121301314014 For Cardiac MRI, the dose is divided into separate, equal injections. 2.2 Administration Guidelines. oGadavist 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.oUse sterile technique when preparing and administering Gadavist.. oGadavist 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.. oUse sterile technique when preparing and administering Gadavist.. MRI of the Central Nervous System oAdminister Gadavist as an intravenous injection, manually or by power injector, at flow rate of approximately mL/second. oFollow Gadavist injection with normal saline flush to ensure complete administration of the contrast. oPost contrast MRI can commence immediately following contrast administration.. oAdminister Gadavist as an intravenous injection, manually or by power injector, at flow rate of approximately mL/second. oFollow Gadavist injection with normal saline flush to ensure complete administration of the contrast. oPost contrast MRI can commence immediately following contrast administration.. MRI of the Breast oAdminister Gadavist as an intravenous bolus by power injector, followed by normal saline flush 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 Gadavist as an intravenous bolus by power injector, followed by normal saline flush 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 Angiography Image acquisition should coincide with peak arterial concentration, which varies among patients.. Adults oAdminister Gadavist by power injector, at flow rate of approximately 1.5 mL/second, followed by 30 mL normal saline flush at the same rate to ensure complete administration of the contrast.. oAdminister Gadavist by power injector, at flow rate of approximately 1.5 mL/second, followed by 30 mL normal saline flush at the same rate to ensure complete administration of the contrast.. Pediatric patients oAdminister Gadavist by power injector or manually, followed by normal saline flush to ensure complete administration of the contrast.. oAdminister Gadavist by power injector or manually, followed by normal saline flush to ensure complete administration of the contrast.. Cardiac MRI. oAdminister Gadavist through separate intravenous line in the contralateral arm if concomitantly providing continuous infusion of pharmacologic stress agent. oAdminister Gadavist 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 Gadavist via power injector at flow rate of approximately mL/second and follow each injection with normal saline flush of 20 mL at the same flow rate.. oAdminister Gadavist through separate intravenous line in the contralateral arm if concomitantly providing continuous infusion of pharmacologic stress agent. oAdminister Gadavist 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 Gadavist via power injector at flow rate of approximately mL/second and follow each injection with normal saline flush of 20 mL at the same flow rate.. 2.3 Drug Handling. oVisually inspect Gadavist for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged. oDo not mix Gadavist with other medications and do not administer Gadavist in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility.oInstructions of the device manufacturer must be followed.. oVisually inspect Gadavist for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged. oDo not mix Gadavist with other medications and do not administer Gadavist in the same intravenous line simultaneously with other medications because of the potential for chemical incompatibility.. oInstructions of the device manufacturer must be followed.. Pharmacy Bulk Package Preparation oPharmacy Bulk Packages are not for use in direct intravenous infusions.oAfter the Pharmacy Bulk Package has been opened, Gadavist remains stable for 24 hours at 20-25C (68-77F). oThe Pharmacy Bulk Package contains many single doses and is used with an appropriate transfer device for filling empty sterile syringes.oThe transfer of Gadavist from the Pharmacy Bulk Package must be performed in an aseptic work area, such as laminar flow hood, using aseptic technique. oOnce the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic work area during the entire 24 hour period of use. oIV tubing and syringes used to administer Gadavist must be discarded at the conclusion of the radiological examination.The contents of the Pharmacy Bulk Package after initial puncture should be used within 24 hours. Discard any unused portion in accordance with regulations dealing with the disposal of such materials.. oPharmacy Bulk Packages are not for use in direct intravenous infusions.. oAfter the Pharmacy Bulk Package has been opened, Gadavist remains stable for 24 hours at 20-25C (68-77F). oThe Pharmacy Bulk Package contains many single doses and is used with an appropriate transfer device for filling empty sterile syringes.. oThe transfer of Gadavist from the Pharmacy Bulk Package must be performed in an aseptic work area, such as laminar flow hood, using aseptic technique. oOnce the Pharmacy Bulk Package is punctured, it should not be removed from the aseptic work area during the entire 24 hour period of use. oIV tubing and syringes used to administer Gadavist must be discarded at the conclusion of the radiological examination.

DOSAGE FORMS & STRENGTHS SECTION.

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

GERIATRIC USE SECTION.

8.5 Geriatric Use In clinical studies of Gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of Gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No dose adjustment according to age is necessary in this population.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Gadavist is sterile, clear and colorless to pale yellow solution containing 604.72 mg gadobutrol per mL (equivalent to mmol gadobutrol) per mL. Gadavist is supplied in the following sizes:30 mL Pharmacy Bulk Package, rubber stoppered in cartons of 5, Boxes of 10 (NDC 50419-325-14)65 mL Pharmacy Bulk Package, rubber stoppered, Boxes of 10 (NDC 50419-325-15). 16.2 Storage and Handling. Store at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature].Should freezing occur, Gadavist should be brought to room temperature before use. If allowed to stand at room temperature, Gadavist should return to clear and colorless to pale yellow solution. Visually inspect Gadavist for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored, if particulate matter is present or if the container appears damaged.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Gadavist is gadolinium-based contrast agent indicated for use with magnetic resonance imaging (MRI):oTo detect and visualize areas with disrupted blood brain barrier (BBB) 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 (BBB) 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). Gadavist is indicated for use with magnetic resonance imaging (MRI) in adult and pediatric patients, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system.. 1.2 MRI of the Breast. Gadavist is indicated for use with MRI in adult patients to assess the presence and extent of malignant breast disease.. 1.3 Magnetic Resonance Angiography (MRA) Gadavist is indicated for use in magnetic resonance angiography (MRA) in adult and pediatric patients (including term neonates) to evaluate known or suspected supra-aortic or renal artery disease. 1.4 Cardiac MRI Gadavist 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).

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, oroHave recently received GBCAGBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel patients at risk of NSF:oDescribe the clinical manifestation of NSFoDescribe procedures to screen for the detection of renal impairmentInstruct the patients to contact their physician if they develop signs or symptoms of NSF following Gadavist 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 Reactions Inform 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 hotGeneral Precautions Gadolinium RetentionoAdvise 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 (5.3)].Instruct patients receiving Gadavist to inform their physician if they:oAre pregnant or breastfeedingoHave history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder. (C) 2011, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.Manufactured for:Bayer HealthCare Pharmaceuticals Inc.Whippany, NJ 07981Manufactured in Germany. 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 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 (5.3)].. oAre pregnant or breastfeeding. oHave history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder.

LACTATION SECTION.

8.2 Lactation Risk Summary There are no data on the presence of gadobutrol in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breast-fed infant. Gadobutrol is present in rat milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for Gadavist and any potential adverse effects on the breastfed infant from Gadavist 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 densityoDifferences of the spin-lattice or longitudinal relaxation times (T1)oDifferences in the spin-spin or transverse relaxation time (T2)When placed in magnetic field, Gadavist 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 Gadavist, is based upon several factors including the concentration of Gadavist 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 (5.5)].

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL Gadavist Pharmacy Bulk Pack 65 mL LabelDose: 0.1 mL/kgNDC 50419-325-0565 mLRx onlysterile solutionGadaviststerile solutionGadavist(gadobutrol) injection mmol/mLFor Intravenous Administration.Multi-dose container.Discard unused portion 24 hours after initial puncture.. 65 Ml LABEL.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of Gadavist 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 Gadavist 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 Gadavist have not been established in preterm neonates for any indication or in pediatric patients of any age for use with MRI to assess the presence and extent of malignant breast disease, or for use in CMRI to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (CAD).. NSF Risk No case of NSF associated with Gadavist or any other GBCA has been identified in pediatric patients ages years and younger. Pharmacokinetic studies suggest that clearance of Gadavist 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 Data Single 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.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Gadavist 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 TGadolinium-Chelate r1 (L.mmol -1 .s-1)Gadobenate 6.3Gadobutrol 5.2Gadodiamide 4.3Gadofosveset16Gadopentetate 4.1Gadoterate3.6 Gadoteridol 4.1Gadoversetamide4.7Gadoxetate6.9 r1 relaxivity in plasma at 37C Compared to 0.5 molar gadolinium-based contrast agents, the higher concentration of Gadavist 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 Gadavist varies as function of imaging location and multiple patient, injection, and device-specific factors.Gadavist is water-soluble, hydrophilic compound with partition coefficient between n-butanol and buffer at pH 7.6 of about 0.006.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Distribution. After 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 (5.3)]. Metabolism. Gadobutrol is not metabolized. Elimination. Values for AUC, body weight normalized plasma clearance and half-life are given in Table 4, below.Gadobutrol is excreted in an unchanged form via the kidneys. In healthy subjects, renal clearance of gadobutrol is 1.1 to 1.7 mL/(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. Gender. Gender has no clinically relevant effect on the pharmacokinetics of gadobutrol. Geriatric. single IV dose of 0.1 mmol/kg Gadavist 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)]. Pediatric. The 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 Gadavist. 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])0 to 2 years2 to years7 to 11 years12 to 18 yearsAdultsN=43N=45N=39N=46N=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 [0.080, 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 Impairment. In 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 Gadavist 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 (5.1) and Use in Specific Populations (8.6).].

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data). In animal reproduction studies, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 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 Gadavist only if imaging is essential during pregnancy and cannot be delayed.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and is 15 to 20%, respectively. Data Human Data. Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration.Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported 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 Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.. Reproductive Toxicology Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 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 Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.

RISKS.

Risk Summary GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data). In animal reproduction studies, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 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 Gadavist only if imaging is essential during pregnancy and cannot be delayed.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and is 15 to 20%, respectively.

SPL MEDGUIDE SECTION.

Medication Guide GADAVIST(gad-a-vist)(gadobutrol) Injection for intravenous useWhat is GadavistoGadavist is prescription medicine called gadolinium-based contrast agent (GBCA). Gadavist, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner. oAn MRI exam with GBCA, including Gadavist, 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. What is the most important information should know about GadavistoGadavist 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, Gadavist, 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 Gadavist.Do not receive Gadavist if you have had severe allergic reaction to Gadavist.Before receiving Gadavist, 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 Gadavist can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as Gadavist is received during pregnancy.ohave kidney problems, diabetes, or high blood pressure. ohave had an allergic reaction to dyes (contrast agents) including GBCAsWhat are the possible side effects of GadavistoSee What is the most important information should know about GadavistoAllergic reactions. Gadavist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.The most common side effects of Gadavist include: headache, nausea, and dizziness.These are not all the possible side effects of Gadavist.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 Gadavist.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your healthcare provider for information about Gadavist that is written for health professionals.What are the ingredients in GadavistActive ingredient: gadobutrolInactive ingredients: calcobutrol sodium, trometamol, hydrochloric acid (for pH adjustment) and water for injectionManufactured for Bayer HealthCare Pharmaceuticals Inc.Manufactured in Germany(C) 2011, Bayer HealthCare Pharmaceuticals Inc. All rights reserved.For more information, go to www.gadavist.com or call 1-888-842-2937.This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev. 4/2018The following is representative example of Gadavist labeling. See the How Supplied section for complete listing of all components.. oGadavist is prescription medicine called gadolinium-based contrast agent (GBCA). Gadavist, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner. oAn MRI exam with GBCA, including Gadavist, 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. oGadavist 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, Gadavist, 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 Gadavist.. 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 Gadavist can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as Gadavist 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 Gadavist. oAllergic reactions. Gadavist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.

SPL UNCLASSIFIED SECTION.

1.1 Magnetic Resonance Imaging (MRI) of the Central Nervous System (CNS). Gadavist is indicated for use with magnetic resonance imaging (MRI) in adult and pediatric patients, including term neonates, to detect and visualize areas with disrupted blood brain barrier and/or abnormal vascularity of the central nervous system.

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 Summary GBCAs cross the placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive (see Data). In animal reproduction studies, although teratogenicity was not observed, embryolethality was observed in monkeys, rabbits and rats receiving intravenous gadobutrol during organogenesis at doses 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 Gadavist only if imaging is essential during pregnancy and cannot be delayed.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and is 15 to 20%, respectively. Data Human Data. Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration.Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported 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 Data Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, liver, kidney, and spleen for at least months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.. Reproductive Toxicology Embryolethality was observed when gadobutrol was administered intravenously to monkeys during organogenesis at doses 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 Gadavist, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans. 8.2 Lactation Risk Summary There are no data on the presence of gadobutrol in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breast-fed infant. 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 Gadavist and any potential adverse effects on the breastfed infant from Gadavist 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 Gadavist 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 Gadavist 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 Gadavist have not been established in preterm neonates for any indication or in pediatric patients of any age for use with MRI to assess the presence and extent of malignant breast disease, or for use in CMRI to assess myocardial perfusion (stress, rest) and late gadolinium enhancement in patients with known or suspected coronary artery disease (CAD).. NSF Risk No case of NSF associated with Gadavist or any other GBCA has been identified in pediatric patients ages years and younger. Pharmacokinetic studies suggest that clearance of Gadavist 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 Data Single 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 Gadavist, 1,377 patients were 65 years of age and over, while 104 patients were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of Gadavist in elderly patients should be cautious, reflecting the greater frequency of impaired renal function and concomitant disease or other drug therapy. No dose adjustment according to age is necessary in this population.. 8.6 Renal Impairment Prior to administration of Gadavist, screen all patients for renal dysfunction by obtaining history and/or laboratory tests [see Warnings and Precautions (5.1)]. No dosage adjustment is recommended for patients with renal impairment. Gadavist can be removed from the body by hemodialysis [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oNephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk (5.1)oAnaphylactic 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 Gadavist (5.2)oGadolinium is retained for months or years in brain, bone, and other organs. (5.3). oNephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk (5.1). oAnaphylactic 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 Gadavist (5.2). oGadolinium is retained for months or years in brain, bone, and other organs. (5.3). 5.1 Nephrogenic Systemic Fibrosis. Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following Gadavist administration to Bayer Healthcare (1-888-842-2937) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of 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 Gadavist 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)]. 5.2 Hypersensitivity Reactions Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory or cutaneous manifestations, ranging from mild to severe, including death, have uncommonly occurred following Gadavist administration [see Adverse Reactions (6)]. oBefore Gadavist 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 Gadavist. oAdminister Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. Most hypersensitivity reactions to Gadavist have occurred within half an hour after administration. Delayed reactions can occur up to several days after administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following Gadavist administration.. oBefore Gadavist 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 Gadavist. oAdminister Gadavist only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. 5.3 Gadlinium 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), Gadavist (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 (5.1)]. 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.. 5.4 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.. 5.5 Extravasation and Injection Site Reactions. Ensure catheter and venous patency before the injection of Gadavist. Extravasation into tissues during Gadavist administration may result in moderate irritation [see Nonclinical Toxicology (13.2)]. 5.6 Overestimation of Extent of Malignant Disease in MRI of the Breast. Gadavist MRI of the breast overestimated the histologically confirmed extent of malignancy in the diseased breast in up to 50% of the patients [see Clinical Studies (14.2)]. 5.7 Low Sensitivity for Significant Arterial Stenosis The performance of Gadavist MRA for detecting arterial segments with significant stenosis (>50% renal, >70% supra-aortic) has not been shown to exceed 55%. Therefore, negative MRA study alone should not be used to rule out significant stenosis [see Clinical Studies (14.3)].