ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail inother sections of the label:Nephrogenic systemic fibrosis [see Warnings andPrecautions (5.1)] Hypersensitivity reactions [see Warnings and Precautions (5.2)] Nephrogenic systemic fibrosis [see Warnings andPrecautions (5.1)] Hypersensitivity reactions [see Warnings and Precautions (5.2)] The most commonly reported adverse reactionsare nausea (1.3%) and headache (1.2%). (6) To report SUSPECTED ADVERSE REACTIONS,contact Bracco Diagnostics Inc. at 1-800-257-5181 or FDA at 1-800-FDA-1088or www.fda.gov/medwatch 6.1 Clinical TrialsExperience. Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.AdultsIn clinical trials with MultiHance, total of 4967adult subjects (137 healthy volunteers and 4830 patients) receivedMultiHance at doses ranging from 0.005 to 0.4 mmol/kg. There were2838 (57%) men and 2129 (43%) women with mean age of 56.5 years(range 18 to 93 years). total of 4403 (89%) subjects were Caucasian,134 (3%) Black, 275 (6%) Asian, 40 (1%) Hispanic, 70 (1%) in otherracial groups, and for 45 (1%) subjects, race was not reported.The most commonly reported adverse reactionsin adult subjects who received MultiHance were nausea (1.3%) and headache(1.2%). Most adverse reactions were mild to moderate in intensity.One subject experienced serious anaphylactoid reaction with laryngealspasm and dyspnea [see Warnings and Precautions (5.2)]. Serious adverse reactionsconsisting of convulsions, pulmonary edema, acute necrotizing pancreatitis,and anaphylactoid reactions were reported in 0.1% of subjects in clinicaltrials.Adverse reactions thatoccurred in at least 0.5% of 4967 adult subjects who received MultiHanceare listed below (Table 2), in decreasing order of occurrence withineach system.TABLE 2: ADVERSE REACTIONS REPORTED IN >= 0.5% OF ADULT SUBJECTS WHORECEIVED MULTIHANCE IN CLINICAL TRIALSNumber of subjectsdosed4967Number of subjectswith any adverse reaction517 (10.4%)Gastrointestinal Disorders Nausea67 (1.3%)General Disorders andAdministration Site Disorders Injection Site Reaction54 (1.1%)Feeling Hot49 (1.0%)Nervous System Disorders Headache60 (1.2%)Dysgeusia33 (0.7%)Paresthesia24 (0.5%)Dizziness24 (0.5%)The following adverse reactions occurredin less than 0.5% of the 4967 adult subjects who received MultiHance.Serious adverse reactions described above are not repeated below. Blood and Lymphatic System Disorders: Basophilia; Cardiac Disorders: Atrioventricular block first degree; Eye Disorders: Eye pruritus, eye swelling, ocularhyperemia, visual disturbance; GastrointestinalDisorders: Abdominal pain or discomfort, diarrhea,dry mouth, lip swelling, paraesthesia oral, tongue edema, vomiting; General Disorders and Administration Site Conditions: Chest pain or discomfort, chills, malaise; Immune System Disorders: Hypersensitivity; Investigations: Nonspecific changesin laboratory tests (including hematology, blood chemistry, liverenzymes and urinalysis), blood pressure and electrocardiogram parameters(including PR, QRS and QT intervals and ST-T segment changes). Musculoskeletal and Connective Tissue Disorders: Myalgia; Nervous System Disorders: Parosmia, tremor; Respiratory,Thoracic and Mediastinal Disorders: Dyspnea, laryngospasm,nasal congestion, sneezing, wheezing; Skinand Subcutaneous Tissue Disorders: Hyperhidrosis,pruritus, rash, swelling face, urticarial.Pediatric PatientsIn clinical trials of MultiHance in MRI of the CNS, 307 pediatricsubjects received MultiHance at dose of 0.1 mmol/kg. total of160 (52%) subjects were male and the overall mean age was 6.0 years(range, days to 17 years). total of 211 (69%) subjects were Caucasian,24 (8%) Black, 15 (5%) Asian, 39 (13%), Hispanic, (<1%) in otherracial groups, and for 16 (5%), race was not reported.Adverse reactions were reportedfor 14 (4.6%) of the subjects. The frequency and the nature of theadverse reactions were similar to those seen in the adult patients. The most commonly reported adverse reactions were vomiting (1.0%),pyrexia (0.7%), and hyperhidrosis (0.7%). No subject died duringstudy participation.. 6.2 Post-marketing Experience. The following adverse reactions have beenidentified during post approval use of MultiHance. Because thesereactions are reported voluntarily from population of uncertainsize, it is not always possible to reliably estimate their frequencyor establish causal relationship to drug exposure.Immune System Disorders: Anaphylactic,anaphylactoid and hypersensitivity reactions manifested with variousdegrees of severity up to anaphylactic shock, loss of consciousnessand death. The reactions generally involved signs or symptoms ofrespiratory, cardiovascular, and/or mucocutaneous abnormalities.General Disorders andAdministration Site Conditions: Extravasation of MultiHancemay lead to injection site reactions, characterized by local painor burning sensation, swelling, blistering, and necrosis [seeWarnings and Precautions (5.4)].Adverse eventswith variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, andheterogeneous clusters of symptoms in the neurological, cutaneous,and musculoskeletal systems.Skin: Gadolinium associatedplaques.

BOXED WARNING SECTION.

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS. Gadolinium-based contrast agents (GBCAs) increasethe risk for NSF among patients with impaired elimination of the drugs.Avoid use of GBCAs in these patients unless the diagnostic informationis essential and not available with non-contrasted MRI or other modalities.NSF may result in fatal or debilitating systemic fibrosis affectingthe skin, muscle and internal organs.The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR <30 mL/min/1.73m2), oracute kidney injury.Screen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age 60 years, hypertensionor diabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing.For patients at highest risk for NSF, do not exceedthe recommended MultiHance dose and allow sufficient period of timefor elimination of the drug from the body prior to re-administration.[see Warnings and Precautions (5.1) ]. The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR <30 mL/min/1.73m2), oracute kidney injury.. chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or. acute kidney injury.. Screen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age 60 years, hypertensionor diabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing.. For patients at highest risk for NSF, do not exceedthe recommended MultiHance dose and allow sufficient period of timefor elimination of the drug from the body prior to re-administration.[see Warnings and Precautions (5.1) ]. WARNING: NEPHROGENIC SYSTEMIC FIBROSISSee full prescribing informationfor complete boxed warningSee full prescribing information for completeboxed warningGadolinium-based contrast agents (GBCAs)increase the risk for NSF among patients with impaired eliminationof the drugs. Avoid use of GBCAs in these patients unless the diagnosticinformation is essential and not available with non-contrast MRI orother modalities.The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or acute kidney injury.Screen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age >60 years, hypertensionor diabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing. (5.1) .. The risk for NSF appears highest among patients with:chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or acute kidney injury.. chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or acute kidney injury.. Screen patients for acute kidney injury and otherconditions that may reduce renal function. For patients at risk forchronically reduced renal function (e.g. age >60 years, hypertensionor diabetes), estimate the glomerular filtration rate (GFR) throughlaboratory testing. (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been performedto evaluate the carcinogenic potential of MultiHance.The results for MultiHance were negative in the followinggenetic toxicity studies: 1) in vitro bacteria reversemutation assays, 2) an in vitro gene mutation assayin mammalian cells, 3) an in vitro chromosomal aberrationassay, 4) an in vitro unscheduled DNA synthesis assay,and 5) an in vivo micronucleus assay in rats.MultiHance had no effect on fertility andreproductive performance at IV doses of up to mmol/kg/day (3 timesthe human dose on body surface basis) for 13 weeks in male rats andfor 32 days in female rats. However, vacuolation in testes and abnormalspermatogenic cells were observed when MultiHance was intravenouslyadministered to male rats at mmol/kg/day (5 times the human doseon body surface basis) for 28 days. The effects were not reversiblefollowing 28-day recovery period. The effects were not reported indog and monkey studies (at doses up to about 11 and 10 times the humandose on body surface basis for dogs (28 days dosing) and monkeys (14days dosing), respectively).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Gadobenate dimeglumine is paramagnetic agent and, as such, developsa magnetic moment when placed in magnetic field. The large magneticmoment produced by the paramagnetic agent results in large localmagnetic field, which can enhance the relaxation rates of water protonsin its vicinity leading to an increase of signal intensity (brightness)of tissue.In magnetic resonanceimaging (MRI), visualization of normal and pathological tissue dependsin part on variations in the radiofrequency signal intensity thatoccur with 1) differences in proton density; 2) differences of thespin-lattice or longitudinal relaxation times (T1); and 3) differencesin the spin-spin or transverse relaxation time (T2). When placed ina magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxationtime in target tissues. At recommended doses, the effect is observedwith greatest sensitivity in the T1-weighted sequences.. 12.2 Pharmacodynamics. Unlike other tested paramagnetic contrast agents (See Table 3), MultiHancedemonstrates weak and transient interactions with serum proteins thatcauses slowing in the molecular tumbling dynamics, resulting in strongincreases in relaxivity in solutions containing serum proteins. Theimproved relaxation effect can contribute to increased contrast-to-noiseratio and lesion-to-brain ratio, which may improve visualization.r1 and r2 relaxivities indicate the efficiencyin shortening T1 and T2 relaxation times, respectively. In heparinized human plasma, at 39C. In citrated human plasma, at 37C.-- Not availableTABLE 3: RELAXIVITY (mM-1s-1) OF GADOLINIUM CHELATES Humanplasma r1 r2 Gadobenate9.71 12.51 Gadopentetate4.91 6.31 Gadodiamide5.42 --Gadoteridol5.42 --Disruption of the blood-brain barrieror abnormal vascularity allows enhancement by MultiHance of lesionssuch as neoplasms, abscesses, and infarcts. Uptake of MultiHance intohepatocytes has been demonstrated.. 12.3 Pharmacokinetics. Three single-dose intravenous studies were conducted in 32 healthymale subjects to assess the pharmacokinetics of gadobenate dimeglumine.The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg.Upon injection, the meglumine salt is completely dissociated fromthe gadobenate dimeglumine complex. Thus, the pharmacokinetics isbased on the assay of gadobenate ion, the MRI contrast effective ionin gadobenate dimeglumine. Data for plasma concentration and areaunder the curve demonstrated linear dependence on the administereddose. The pharmacokinetics of gadobenate ion following intravenousadministration can be best described using two-compartment model.Distribution Gadobenate ion has rapid distribution half-life (reportedas mean +- SD) of 0.084 +- 0.012 to 0.605 +- 0.072 hours. Volume of distributionof the central compartment ranged from 0.074 +- 0.017 to 0.158 +- 0.038L/kg, and estimates of volume of distribution by area ranged from0.170 +- 0.016 to 0.282 +- 0.079 L/kg. These latter estimates are approximatelyequivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenateion to human serum proteins. Following GBCA administration, gadoliniumis present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].Elimination Gadobenate ion is eliminated predominately viathe kidneys, with 78% to 96% of an administered dose recovered inthe urine. Total plasma clearance and renal clearance estimates ofgadobenate ion were similar, ranging from 0.093 +- 0.010 to 0.133 +-0.270 L/hr/kg and 0.082 +- 0.007 to 0.104 +- 0.039 L/hr/kg, respectively.The clearance is similar to that of substances that are subject toglomerular filtration. The mean elimination half-life ranged from1.17 +- 0.26 to 2.02 +- 0.60 hours. small percentage of the administereddose (0.6% to 4%) is eliminated via the biliary route and recoveredin feces.Metabolism There was no detectable biotransformation ofgadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelatingagent being recovered alone in feces.Pharmacokinetics in Special PopulationRenal Impairment: single intravenousdose of 0.2 mmol/kg of MultiHance was administered to 20 subjectswith impaired renal function (6 men and women with moderate renalimpairment [urine creatinine clearance >30 to <60 mL/min] and 5men and women with severe renal impairment [urine creatinine clearance>10 to <30 mL/min]). Mean estimates of the elimination half-lifewere 6.1 +- 3.0 and 9.5 +- 3.1 hours for the moderate and severe renalimpairment groups, respectively as compared with 1.0 to 2.0 hoursin healthy volunteers.Hemodialysis: single intravenousdose of 0.2 mmol/kg of MultiHance was administered to 11 subjects(5 males and females) with end-stage renal disease requiring hemodialysisto determine the pharmacokinetics and dialyzability of gadobenate.Approximately 72% of the dose was recovered by hemodialysis over a4-hour period. The mean elimination half-life on dialysis was 1.21+- 0.29 hours as compared with 42.4 +- 24.4 hours when off dialysis.Hepatic Impairment: single intravenous dose of 0.1 mmol/kg of MultiHancewas administered to 11 subjects (8 males and females) with impairedliver function (Class or modified Child-Pugh Classification).Hepatic impairment had little effect on the pharmacokinetics of MultiHancewith the parameters being similar to those calculated for healthysubjects.Gender, Age, Race: multiple regressionanalysis performed using pooled data from several pharmacokineticstudies found no significant effect of sex upon the pharmacokineticsof gadobenate. Clearance appeared to decrease slightly with increasingage. Since variations due to age appeared marginal, dosage adjustmentfor geriatric population is not recommended. Pharmacokinetic differencesdue to race have not been systematically studied.Pediatric: population pharmacokinetic analysis incorporated data from25 healthy subjects (14 males and 11 females) and 15 subjects undergoingMR imaging of the central nervous system (7 males and females) betweenages of and 16 years. The subjects received single intravenousdose of 0.1 mmol/kg of MultiHance. The geometric mean Cmax was 62.3 ug/mL (n=16) in children to years ofage, and 64.2 ug/mL (n=24) in children older than years. The geometricmean AUC 0- was 77.9 ugh/mL in children 2-5years of age (n=16) and 82.6 ugh/mL in children older than years(n=24). The geometric mean half-life was 1.2 hours in children to5 years of age and 0.93 hours in children older than years. Therewas no significant gender-related difference in the pharmacokineticparameters in the pediatric patients. Over 80% of the dose was recoveredin urine after 24 hours. Pharmacokinetic simulations indicate similarAUC and Cmax values for MultiHance in pediatricsubjects less than years when compared to those reported for adults;no age-based dose adjustment is necessary for this pediatric population.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 MRI of the CNS. Adults:MultiHance was evaluated in 426 adult patientsin controlled clinical trials of the central nervous system (StudyA and Study B), enrolling 217 men and 209 women with mean age of52 years (range 18 to 88 years). The racial and ethnic representationswere 88% Caucasian, 6% Black, 4% Hispanic, 1% Asian, and 1% otherracial or ethnic groups. These trials were designed to compare MultiHancecontrast MRI to non-contrast MRI alone. In Study A, patients highlysuspected of having lesion(s) of the CNS based on nuclear medicineimaging, computed tomography (CT), contrast CT, MRI, contrast- MRI,or angiography were randomized to receive two MRI evaluations with0.05 mmol/kg (n=140) or 0.1 mmol/kg (n=136) of MultiHance. In StudyB, patients with known metastatic disease to the CNS were randomizedto receive two MRI evaluations with 0.05 mmol/kg (n=74) or 0.1 mmol/kg(n=76) of MultiHance. MRI scans were performed pre-contrast and within5 minutes after each injection. The studies were designed to evaluatethe effect of MultiHance MRI compared to the non-contrast MRI on alesion level. Pre-contrast, post-contrast, and pre-plus-post contrastimages (paired images) were independently evaluated by three blindedreaders. The images were evaluated for the following endpoints usinga scale from to 4: the degree of lesion border delineation, thedegree of visualization of lesion internal morphology, and the degreeof lesion contrast enhancement. Lesion counting was also performedfor the pre-contrast and paired image sets.The 0.1 mmol/kg dose of MultiHance demonstrated consistentlybetter visualization for all readers for all visualization endpoints.However, the 0.05 mmol/kg dose of MultiHance provided inconsistentvisualization results between readers.Comparison of pre-contrast versus post-contrast (0.1mmol/kg) images showed that the mean score differences were significantand favored contrast for subjects in Study (all subjects with knownmetastatic lesions) and for subjects with known tumors in Study A.However, the mean score differences between the pre-contrast and post-contrastimages were not significant for non-tumor patients in Study A. Thesenegative results may be attributed to lack of lesion enhancementin non-tumor CNS disease.Table4 shows comparison of paired images (pre-and post-contrast) versuspre-contrast images with respect to the difference in the mean scoreand with respect to the proportion of lesions read as better, worse,or the same as the pre-contrast MRI images. Table shows that basedon lesion-level analysis 0.1 mmol/kg MultiHance provided statisticallysignificant improvement for the three structural parameters evaluated.Also, more lesions were seen in the paired images than in the pre-contrastimages alone.(a)Difference of means (paired mean) (pre mean)(b) Worse= paired score is less than the pre scoreSame pairedscore is the same as the pre scoreBetter paired scoreis greater than the pre score Statistically significant for the mean (paired test)Table 4: LESION LEVEL RESULTS OF MRI CENTRAL NERVOUS SYSTEM ADULTSTUDIES WITH 0.1 mmol/kg MULTIHANCE StudyAStudyB Reader 1Reader 2Reader 3Reader 1Reader 2Reader 3EndpointsN 395N 384N 299N 245N 275N 254Border Delineation: Difference of Means (a)0.80.60.81.81.51.9Worse (b)SameBetter44 (11%)146 (37%)205 (52%)61 (16%)168 (44%)155 (40%)57 (19%)89 (30%)153 (51%)13 (5%)11 (5%)221 (90%)24 (9%)19 (7%)232 (84%)15 (6%)18 (7%)221 (87%)Internal Morphology: Difference of Means0.80.60.71.71.42.1WorseSameBetter37 (10%)147 (37%)211 (53%)63 (17%)151 (39%)170 (44%)62 (21%)84 (28%)153 (51%)13 (5%)16 (7%)216 (88%)26 (10%)22 (8%)227 (82%)14 (5%)22 (9%)218 (86%)Contrast Enhancement: Difference of Means0.70.50.81.91.31.9WorseSameBetter75 (19%)148 (37%)172 (44%)74 (19%)152 (40%)158 (41%)50 (17%)109 (36%)140 (47%)13 (5%)11 (5%)221 (90%)32 (12%)21 (7%)222 (81%)17 (7%)14 (5%)223 (88%)Pediatric to 17 yearsThe efficacy and safety of MultiHance were evaluated in 92 pediatricpatients with known or highly suspected disease of the central nervoussystem. MRI scans were performed pre-contrast and within to 10minutes following the administration of MultiHance 0.1 mmol/kg. Pre-contrast,post-contrast, and pre-plus-post contrast images (paired images) wereindependently evaluated by three blinded readers on lesion level. The images were evaluated for the same endpoints as in the adultcentral nervous system trials using scale from to 4: the degreeof lesion border delineation, the degree of visualization of lesioninternal morphology, and the degree of lesion contrast enhancement. Lesion counting was also performed for the pre-contrast and pairedimage sets. The pre-contrast versus the paired image set was theprimary comparison. Forty-nine percent of study subjects were maleand the overall mean age was 10.6 years (range to 17 years). Theracial and ethnic representations were 77% Caucasian, 13% Asian, 5%Black, and 4% other racial or ethnic groups. MultiHance increasedlesion border delineation, lesion internal morphology, and lesioncontrast enhancement relative to non-contrast and these results werecomparable to those seen in adults.Pediatrics below yearsA studyof 90 pediatric patients younger than years of age was performedwhich supports extrapolation of CNS efficacy findings from adultsand older pediatric patients. Three independent, blinded readersevaluated pre-contrast MRI image sets and paired pre-plus-post-contrastMRI image sets using MultiHance and rated the images according tothree co-primary endpoints at lesion level for the primary analysis.Two of the three readers reported improvement in the paired imagesets in each of the three co-primary endpoints of lesion border delineation,visualization of lesion internal morphology, and lesion contrast enhancement.. 14.2 MRA of Renal and Aorto-ilio-femoral Vessels. Safety and efficacy of MultiHance for usein MRA were evaluated in two prospective, multi-center, open-label,clinical trials (one for each arterial vascular territory: renal andaorto-ilio-femoral). Out of 580 patients who received Multihance inthese two trials, 62.2% were men and 90.9% were Caucasian; the averageage was 63.4 years (range 18 to 93 years). In both trials, patientswith known or suspected arterial disease underwent MRA with and withoutMultiHance as well as catheter-based digital subtraction angiography(DSA). Assessment of diagnostic efficacy for detecting/excluding clinicallysignificant steno-occlusive disease (>= 51% stenosis measured withelectronic calipers) was based on comparisons of sensitivity and specificitybetween MultiHance MRA and non-contrast MRA, with DSA as referencestandard.In each vascular territory,the primary efficacy analyses were designed to demonstrate superiorityin sensitivity and non-inferiority in specificity of MultiHance MRAto non-contrast MRA at the vessel-segment level. The interpretationof MRA images from both trials was conducted by three independentradiologist readers who were blinded to clinical data, including theDSA results. The pre-specified success criteria were to be achievedby at least the same two readers for all primary analyses.Results of both trials showed statisticallysignificant increase in sensitivity and specificity of MultiHanceMRA over non-contrast MRA in detecting clinically significant steno-occlusivedisease.Table 5summarizes the efficacy results by reader.TABLE 5. PERFORMANCE CHARACTERISTICSOF MULTIHANCE-MRA AND NON-CONTRAST MRAREADER SENSITIVITYSPECIFICITYAORTO-ILIO-FEMERALARTERIESMultiHanceMRA [A] Non-contrast MRA[B] [A] [B](95% CI)MultiHanceMRA [A] Non-contrast MRA[B] [A] [B](95% CI)177.8%73.7%4.5(1.5, 7.6)88.1%78.5%10.0 (7.3, 12.6)265.2% 52.5% 12.6 (8.5, 16.6)94.2% 89.4% 4.9(2.7, 7.1)369.0% 59.1% 10.0 (6.1, 14.0)90.0% 75.3% 14.9(12.1, 17.8) RENALARTERIESSENSITIVITYSPECIFICITYMultiHanceMRA [A] Non-contrast MRA[B] [A] [B](95% CI)MultiHanceMRA [A] Non-contrast MRA[B] [A] [B](95% CI)167.8%47.0%20.8(12.8, 28.9)94.0% 86.1%8.3(4.2, 12.4)262.4%46.7%16.2(6.8, 25.6) 94.0%83.5%10.3(5.5, 15.0)365.5%39.6%25.3(15.9, 34.6)94.7%87.3%8.0(3.6, 12.5).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. MultiHance is contraindicated in patients with known allergic orhypersensitivity reactions to gadolinium-based contrast agents [see Warnings and Precautions (5.2)].. MultiHance is contraindicated in patientswith known allergic or hypersensitivity reactions to gadolinium-basedcontrast agents. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. MultiHance injection is supplied as sterile,nonpyrogenic, clear, colorless to slightly yellow aqueous solutionintended for intravenous use only. Each mL of MultiHance contains529 mg gadobenate dimeglumine and water for injection. MultiHancecontains no preservatives.Gadobenatedimeglumine is chemically designated as (4RS)-[4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oato(5-)] gadolinate(2-) dihydrogencompound with 1-deoxy-1-(methylamino)-D-glucitol (1:2) with molecularweight of 1058.2 and an empirical formula of C22H28GdN3O11 2C7H17NO5. The structural formula is as follows:MultiHance has pH of 6.5-7.5. Pertinent physicochemical parametersare provided below:Osmolality1.970 osmol/kg 37CViscosity5.3 mPas 37CDensity1.220 g/mL 20CMultiHance has an osmolality 6.9times that of plasma (285 mOsmol/kg water) and is hypertonic underconditions of use.. MultiHance Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION PHARMACY BULK PACKAGE NOT FOR DIRECTINFUSIONThe recommended dose of MultiHance is 0.2 mL/kg (0.1 mmol/kg)administered as rapid bolus intravenous injection.For MRI of the CNS in pediatric patients below years ofage the recommended dosage range is 0.1 to 0.2 mL/kg.To ensure complete injection of the contrast medium, followthe injection with saline flush of at least mL in MRI of the CNSand at least 20 mL in MRA. (2) The recommended dose of MultiHance is 0.2 mL/kg (0.1 mmol/kg)administered as rapid bolus intravenous injection.. For MRI of the CNS in pediatric patients below years ofage the recommended dosage range is 0.1 to 0.2 mL/kg.. To ensure complete injection of the contrast medium, followthe injection with saline flush of at least mL in MRI of the CNSand at least 20 mL in MRA. (2) 2.1 Dosing and ImagingInstructions. 2.1.1 MRI of theCNS. In adultsand in pediatric patients over years of age, the recommended doseof MultiHance for MRI of the CNS is 0.2 mL/kg (0.1 mmol/kg) administeredas rapid bolus intravenous injection. In pediatric patients below2 years of age, the recommended dosage range is 0.1 to 0.2 mL/kg administeredas rapid bolus intravenous injection. To ensure complete injectionof the contrast medium, follow the injection with saline flush ofat least mL. Imaging of the CNS can be performed starting immediatelyafter the bolus injection of MultiHance.. 2.1.2 MRA of Renaland Aorto-ilio-femoral Vessels. For MRA examination, the recommended dose is 0.2 mL/kg(0.1 mmol/kg) administered as rapid bolus intravenous injectionfollowed by at least 20 mL saline flush either manually or using anautomatic injector system. Start imaging immediately after the administrationof MultiHance, with scan delay calculated by test bolus or automaticbolus detection technique. If an automatic contrast detection pulsesequence is not used for bolus timing, then test bolus injectionof 1-2 mL of MultiHance should be used to calculate the appropriatescan delay.. 2.2 Dosing Table. For pediatric patientsless than years of age, one-half of the per kg dose may be used.TABLE 1: WEIGHT-BASED DOSING VOLUMES FOR:CNS IMAGING(ADULTS AND PEDIATRICS >=2 YEARS OF AGE)ANDMRA IMAGING (ADULTS ONLY) 0.1mM/kg doseKilograms (Kg)Pounds (lb)Volume, Milliliters(mL)2.55.50.55111.010222.015333.020444.025555.030666.035777.040888.045999.05011010.05512111.06013212.06514313.07015414.07516515.08017616.08518717.09019818.09520919.010022020.010523121.011024222.011525323.012026424.012527525.013028626.013529727.014030828.014531929.015033030.0. 2.3 Administration. Inspect the MultiHance vial visually forparticulate matter and discoloration prior to administration. Do notuse the solution if it is discolored or particulate matter is present. Draw MultiHance into syringe and inject using sterile technique.Do not mix intravenous medications orparenteral nutrition solutions with MultiHance. Do not administerother medications in the same intravenous line with MultiHance.. 2.4 Directions for ProperUse of MultiHance Multipack. The pharmacy bulk package is used as multiple dose container withan appropriate transfer device to fill empty syringes.MultiHance Multipack injection should bedrawn into the syringe and administered using sterile technique. Unusedportions of the drug must be discarded.When MultiHance Multipack injection is to be injectedusing plastic disposable syringes, the agent should be drawn intothe syringe and used immediately.The transferring of MultiHance (gadobenate dimeglumine)injection from the Pharmacy Bulk Package should be performed in asuitable work area, such as laminar flow hood, utilizing aseptictechnique.The container closure may be penetrated only one time, utilizinga suitable transfer device. Once the pharmacy bulk package is punctured,it should not be removed from the aseptic work area during the entireperiod of use.The withdrawal of container contents should be accomplishedwithout delay. However, should this not be possible, maximum timeof hours from initial closure entry is permitted to complete fluidtransfer operation. Any unused MultiHance Multipack injection mustbe discarded hours after initial puncture of the bulk package.Temperature of container after the closure has been enteredshould not exceed 25C (77F).. The transferring of MultiHance (gadobenate dimeglumine)injection from the Pharmacy Bulk Package should be performed in asuitable work area, such as laminar flow hood, utilizing aseptictechnique.. The container closure may be penetrated only one time, utilizinga suitable transfer device. Once the pharmacy bulk package is punctured,it should not be removed from the aseptic work area during the entireperiod of use.. The withdrawal of container contents should be accomplishedwithout delay. However, should this not be possible, maximum timeof hours from initial closure entry is permitted to complete fluidtransfer operation. Any unused MultiHance Multipack injection mustbe discarded hours after initial puncture of the bulk package.. Temperature of container after the closure has been enteredshould not exceed 25C (77F).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. MultiHance is sterile, nonpyrogenic, clear,colorless to slightly yellow aqueous solution for intravenous useonly, containing 529 mg gadobenate dimeglumine per mL.. Each mL of MultiHance Injection contains529 mg gadobenate dimeglumine. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1 Transporter-BasedDrug-Drug Interactions. MultiHance and other drugs may compete for the canalicular multispecificorganic anion transporter (MOAT also referred to as MRP2 or ABCC2). Therefore MultiHance may prolong the systemic exposure of drugs suchas cisplatin, anthracyclines (e.g. doxorubicin, daunorubicin), vincaalkaloids (e.g. vincristine), methotrexate, etoposide, tamoxifen,and paclitaxel. In particular, consider the potential for prolongeddrug exposure in patients with decreased MOAT activity (e.g. DubinJohnson syndrome).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Ofthe total number of 4967 adult subjects in clinical studies of MultiHance,33% were 65 or older. No overall differences in safety or effectivenesswere observed between these elderly subjects and the younger subjects.The drug is known to be substantially excretedby the kidney, and the risk of toxic reactions to MultiHance may begreater in patients with impaired renal function. Because elderlypatients are more likely to have decreased renal function it may beuseful to monitor renal function.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGEAND HANDLING. 16.1 HowSuppliedMultiHance Multipack (gadobenate dimeglumine)injection is clear, colorless to slightly yellow solution containing529 mg gadobenate dimeglumine per mL. MultiHance Multipack is suppliedin glass bottles; each multidose bottle is rubber stoppered with analuminum seal and the contents are sterile. MultiHance is suppliedin boxes of:Five 50 mL PharmacyBulk Packages (NDC 0270-5264-16)Five 100 mLPharmacy Bulk Packages (NDC 0270-5264-17)16.2 Storage and HandlingStore at 25C (77F), excursions permitted to 15-30C(59-86F) [see USP Controlled Room Temperature]. Do not freeze.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. magnetic resonance imaging (MRI) of the central nervoussystem (CNS) in adults and pediatric patients (including term neonates),to visualize lesions with abnormal blood-brain barrier or abnormalvascularity of the brain, spine, and associated tissues (1.1) magnetic resonance angiography (MRA) to evaluate adultswith known or suspected renal or aorto-ilio-femoral occlusive vasculardisease. (1.2) magnetic resonance imaging (MRI) of the central nervoussystem (CNS) in adults and pediatric patients (including term neonates),to visualize lesions with abnormal blood-brain barrier or abnormalvascularity of the brain, spine, and associated tissues (1.1) magnetic resonance angiography (MRA) to evaluate adultswith known or suspected renal or aorto-ilio-femoral occlusive vasculardisease. (1.2) 1.1 Magnetic ResonanceImaging (MRI) of the Central Nervous System (CNS). MultiHance is indicatedfor intravenous use in magnetic resonance imaging (MRI) of the centralnervous system (CNS) in adults and pediatric patients (including termneonates), to visualize lesions with abnormal blood-brain barrieror abnormal vascularity of the brain, spine, and associated tissues.. 1.2 Magnetic ResonanceAngiography (MRA) of Renal and Aorto-ilio-femoral Vessels. MultiHance is indicated for use in magneticresonance angiography (MRA) to evaluate adults with known or suspectedrenal or aorto-ilio-femoral occlusive vascular disease.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling(Medication Guide).Nephrogenic SystemicFibrosisInstruct patientsto inform their physician if they:have history of kidney and/or liver disease, orhave recently received GBCA.GBCAs increase the risk for NSF amongpatients with impaired elimination of the drugs. To counsel patientsat risk for NSF:Describe the clinical manifestations of NSFDescribe procedures to screen for the detection of renalimpairment.Instruct the patients to contacttheir physician if they develop signs or symptoms of NSF followingMultiHance 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 straighteningthe arms, hands, legs or feet; pain in the hip bones or ribs; or muscleweakness.Common Adverse ReactionsInform patients that they may experience:reactions along the venous injection site, such as mildand transient burning or pain or feeling of warmth or coldness atthe injection site side effects of feeling hot, nausea, and headache.Gadolinium RetentionAdvise patients that gadolinium is retained for monthsor years in brain, bone, skin, and other organs in patients with normalrenal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administrationof linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].Rx only US Patent No. 4,916,246Manufactured for Bracco DiagnosticsInc.Monroe Twp, NJ 08831By BIPSO GmbH78224 Singen (Germany)Revised April 2018. Advise the patient to read the FDA-approved patient labeling(Medication Guide).. have history of kidney and/or liver disease, or. have recently received GBCA.. Describe the clinical manifestations of NSF. Describe procedures to screen for the detection of renalimpairment.. reactions along the venous injection site, such as mildand transient burning or pain or feeling of warmth or coldness atthe injection site side effects of feeling hot, nausea, and headache.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Gadobenate dimeglumine is paramagnetic agent and, as such, developsa magnetic moment when placed in magnetic field. The large magneticmoment produced by the paramagnetic agent results in large localmagnetic field, which can enhance the relaxation rates of water protonsin its vicinity leading to an increase of signal intensity (brightness)of tissue.In magnetic resonanceimaging (MRI), visualization of normal and pathological tissue dependsin part on variations in the radiofrequency signal intensity thatoccur with 1) differences in proton density; 2) differences of thespin-lattice or longitudinal relaxation times (T1); and 3) differencesin the spin-spin or transverse relaxation time (T2). When placed ina magnetic field, gadobenate dimeglumine decreases the T1 and T2 relaxationtime in target tissues. At recommended doses, the effect is observedwith greatest sensitivity in the T1-weighted sequences.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been performedto evaluate the carcinogenic potential of MultiHance.The results for MultiHance were negative in the followinggenetic toxicity studies: 1) in vitro bacteria reversemutation assays, 2) an in vitro gene mutation assayin mammalian cells, 3) an in vitro chromosomal aberrationassay, 4) an in vitro unscheduled DNA synthesis assay,and 5) an in vivo micronucleus assay in rats.MultiHance had no effect on fertility andreproductive performance at IV doses of up to mmol/kg/day (3 timesthe human dose on body surface basis) for 13 weeks in male rats andfor 32 days in female rats. However, vacuolation in testes and abnormalspermatogenic cells were observed when MultiHance was intravenouslyadministered to male rats at mmol/kg/day (5 times the human doseon body surface basis) for 28 days. The effects were not reversiblefollowing 28-day recovery period. The effects were not reported indog and monkey studies (at doses up to about 11 and 10 times the humandose on body surface basis for dogs (28 days dosing) and monkeys (14days dosing), respectively).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Clinicalconsequences of overdosage with MultiHance have not been reported. Treatment of an overdosage should be directed toward support of vitalfunctions and prompt institution of symptomatic therapy. In Phase1 clinical study, doses up to 0.4 mmol/kg were administered to patients. MultiHance has been shown to be dialyzable [seeClinical Pharmacology (12.3)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Multihance Multipack 50 mLNDC 0270-5264-16. MultiHance MPK5x50mLBOX 3000238. MultiHance MPK50mLlab 3000240.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. MultiHanceis approved for intravenous use for MRI of the CNS to visualize lesionswith abnormal blood brain barrier or abnormal vascularity of the brain,spine, and associated tissues in pediatric patients from birth, includingterm neonates, to less than 17 years of age. Pediatric use is basedon evidence of effectiveness in adults and in 202 pediatric patients2 years of age and older, in addition to experience in 105 pediatricpatients birth to less than years of age that supported extrapolationfrom adult data [see Clinical Studies (14)]. Adverse reactions in pediatric patients weresimilar to those reported in adults [see Adverse Reactions(6.1)]. No dose adjustmentaccording to age is necessary in pediatric patients two years of ageand older. For pediatric patients, less than years of age, the recommendeddosage range is 0.1 to 0.2 mL/kg [see Dosage and Administration(2.1), Pharmacokinetics (12.3)]. The safety of MultiHancehas not been established in preterm neonates.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Unlike other tested paramagnetic contrast agents (See Table 3), MultiHancedemonstrates weak and transient interactions with serum proteins thatcauses slowing in the molecular tumbling dynamics, resulting in strongincreases in relaxivity in solutions containing serum proteins. Theimproved relaxation effect can contribute to increased contrast-to-noiseratio and lesion-to-brain ratio, which may improve visualization.r1 and r2 relaxivities indicate the efficiencyin shortening T1 and T2 relaxation times, respectively. In heparinized human plasma, at 39C. In citrated human plasma, at 37C.-- Not availableTABLE 3: RELAXIVITY (mM-1s-1) OF GADOLINIUM CHELATES Humanplasma r1 r2 Gadobenate9.71 12.51 Gadopentetate4.91 6.31 Gadodiamide5.42 --Gadoteridol5.42 --Disruption of the blood-brain barrieror abnormal vascularity allows enhancement by MultiHance of lesionssuch as neoplasms, abscesses, and infarcts. Uptake of MultiHance intohepatocytes has been demonstrated.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Three single-dose intravenous studies were conducted in 32 healthymale subjects to assess the pharmacokinetics of gadobenate dimeglumine.The doses administered in these studies ranged from 0.005 to 0.4 mmol/kg.Upon injection, the meglumine salt is completely dissociated fromthe gadobenate dimeglumine complex. Thus, the pharmacokinetics isbased on the assay of gadobenate ion, the MRI contrast effective ionin gadobenate dimeglumine. Data for plasma concentration and areaunder the curve demonstrated linear dependence on the administereddose. The pharmacokinetics of gadobenate ion following intravenousadministration can be best described using two-compartment model.Distribution Gadobenate ion has rapid distribution half-life (reportedas mean +- SD) of 0.084 +- 0.012 to 0.605 +- 0.072 hours. Volume of distributionof the central compartment ranged from 0.074 +- 0.017 to 0.158 +- 0.038L/kg, and estimates of volume of distribution by area ranged from0.170 +- 0.016 to 0.282 +- 0.079 L/kg. These latter estimates are approximatelyequivalent to the average volume of extracellular body water in man. In vitro studies showed no appreciable binding of gadobenateion to human serum proteins. Following GBCA administration, gadoliniumis present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)].Elimination Gadobenate ion is eliminated predominately viathe kidneys, with 78% to 96% of an administered dose recovered inthe urine. Total plasma clearance and renal clearance estimates ofgadobenate ion were similar, ranging from 0.093 +- 0.010 to 0.133 +-0.270 L/hr/kg and 0.082 +- 0.007 to 0.104 +- 0.039 L/hr/kg, respectively.The clearance is similar to that of substances that are subject toglomerular filtration. The mean elimination half-life ranged from1.17 +- 0.26 to 2.02 +- 0.60 hours. small percentage of the administereddose (0.6% to 4%) is eliminated via the biliary route and recoveredin feces.Metabolism There was no detectable biotransformation ofgadobenate ion. Dissociation of gadobenate ion in vivo has been shown to be minimal, with less than 1% of the free chelatingagent being recovered alone in feces.Pharmacokinetics in Special PopulationRenal Impairment: single intravenousdose of 0.2 mmol/kg of MultiHance was administered to 20 subjectswith impaired renal function (6 men and women with moderate renalimpairment [urine creatinine clearance >30 to <60 mL/min] and 5men and women with severe renal impairment [urine creatinine clearance>10 to <30 mL/min]). Mean estimates of the elimination half-lifewere 6.1 +- 3.0 and 9.5 +- 3.1 hours for the moderate and severe renalimpairment groups, respectively as compared with 1.0 to 2.0 hoursin healthy volunteers.Hemodialysis: single intravenousdose of 0.2 mmol/kg of MultiHance was administered to 11 subjects(5 males and females) with end-stage renal disease requiring hemodialysisto determine the pharmacokinetics and dialyzability of gadobenate.Approximately 72% of the dose was recovered by hemodialysis over a4-hour period. The mean elimination half-life on dialysis was 1.21+- 0.29 hours as compared with 42.4 +- 24.4 hours when off dialysis.Hepatic Impairment: single intravenous dose of 0.1 mmol/kg of MultiHancewas administered to 11 subjects (8 males and females) with impairedliver function (Class or modified Child-Pugh Classification).Hepatic impairment had little effect on the pharmacokinetics of MultiHancewith the parameters being similar to those calculated for healthysubjects.Gender, Age, Race: multiple regressionanalysis performed using pooled data from several pharmacokineticstudies found no significant effect of sex upon the pharmacokineticsof gadobenate. Clearance appeared to decrease slightly with increasingage. Since variations due to age appeared marginal, dosage adjustmentfor geriatric population is not recommended. Pharmacokinetic differencesdue to race have not been systematically studied.Pediatric: population pharmacokinetic analysis incorporated data from25 healthy subjects (14 males and 11 females) and 15 subjects undergoingMR imaging of the central nervous system (7 males and females) betweenages of and 16 years. The subjects received single intravenousdose of 0.1 mmol/kg of MultiHance. The geometric mean Cmax was 62.3 ug/mL (n=16) in children to years ofage, and 64.2 ug/mL (n=24) in children older than years. The geometricmean AUC 0- was 77.9 ugh/mL in children 2-5years of age (n=16) and 82.6 ugh/mL in children older than years(n=24). The geometric mean half-life was 1.2 hours in children to5 years of age and 0.93 hours in children older than years. Therewas no significant gender-related difference in the pharmacokineticparameters in the pediatric patients. Over 80% of the dose was recoveredin urine after 24 hours. Pharmacokinetic simulations indicate similarAUC and Cmax values for MultiHance in pediatricsubjects less than years when compared to those reported for adults;no age-based dose adjustment is necessary for this pediatric population.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryGBCAs cross the placentaand result in fetal exposure and gadolinium retention. The human dataon the association between GBCAs and adverse fetal outcomes are limitedand inconclusive (see Data). In animal reproduction studies, gadobenate dimegluminehas been shown to be teratogenic in rabbits following repeated intravenousadministration during organogenesis at doses up to times the recommendedhuman dose. There were no adverse developmental effects observed inrats with intravenous administration of gadobenate dimeglumine duringorganogenesis at doses up to three times the recommended human dose (see Data). Becauseof the potential risks of gadolinium to the fetus, use MultiHanceonly if imaging is essential and cannot be delayed.The estimated background risk of majorbirth defects and miscarriage for the indicated population is unknown.All pregnancies have background risk of birth defect, loss, or otheradverse outcomes. In the U.S. general population, the estimated backgroundrisk of major birth defects and miscarriage in clinically recognizedpregnancies is to 4% and is 15 to 20%, respectively.DataHuman DataContrast enhancementis visualized in the placenta and fetal tissues after maternal GBCAadministration.Cohortstudies and case reports on exposure to GBCAs during pregnancy havenot reported clear association between GBCAs and adverse effectsin the exposed neonates. However, retrospective cohort study, comparingpregnant women who had GBCA MRI to pregnant women who did not havean MRI, reported higher occurrence of stillbirths and neonatal deathsin the group receiving GBCA MRI. Limitations of this study includea lack of comparison with non-contrast MRI and lack of informationabout the maternal indication for MRI. Overall, these data precludea reliable evaluation of the potential risk of adverse fetal outcomeswith the use of GBCAs in pregnancy.Animal DataGadoliniumRetentionGBCAs administered to pregnant non-human primates(0.1 mmol/kg on gestational days 85 and 135) result in measurablegadolinium concentration in the offspring in bone, brain, skin, liver,kidney, and spleen for at least months. GBCAs administered to pregnantmice (2 mmol/kg daily on gestational days 16 through 19) result inmeasurable gadolinium concentrations in the pups in bone, brain, kidney,liver, blood, muscle, and spleen at one month postnatal age.Reproductive ToxicologyGadobenate dimeglumine has been shown to be teratogenic in rabbitswhen administered intravenously at mmol/kg/day (6 times the recommendedhuman dose based on body surface area) during organogenesis (day 6to 18) inducing microphthalmia/small eye and/or focal retinal foldin fetuses from separate litters. In addition, MultiHance administeredintravenously at mmol/kg/day (10 times the recommended human dosebased on body surface area) has been shown to increase intrauterinedeaths in rabbits. There was no evidence that MultiHance induced teratogeniceffects in rats at doses up to mmol/kg/day (3 times the recommendedhuman dose based on body surface area), however, rat dams exhibitedno systemic toxicity at this dose. There were no adverse effects onthe birth, survival, growth, development and fertility of the F1 generationat doses up to mmol/kg in rat peri- and post-natal (Segment III)study.

RECENT MAJOR CHANGES SECTION.

Indications and Usage, MRI of the Central Nervous System (1.1)01/2018Warnings and Precautions, Gadolinium Retention (5.3)04/2018.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S.Food and Drug AdministrationIssued 04/2018COEB403MEDICATION GUIDEMULTIHANCE(R) (ml-te-han(t)s) (gadobenatedimeglumine)Injection for intravenous useWhat is MULTIHANCEMULTIHANCE is prescription medicine called gadolinium-basedcontrast agent (GBCA). MULTIHANCE, like other GBCAs, is injected intoyour vein and used with magnetic resonance imaging (MRI) scanner. An MRI exam with GBCA, including MULTIHANCE, helps yourdoctor to see problems better than an MRI exam without GBCA.Your doctor has reviewed your medical records and has determinedthat you would benefit from using GBCA with your MRI exam.What is themost important information should know about MULTIHANCEMULTIHANCE contains metal called gadolinium. Small amountsof gadolinium can stay in your body including the brain, bones, skinand other parts of your body for long time (several months to years).It is not known how gadolinium may affect you, but so far,studies have not found harmful effects in patients with normal kidneys.Rarely, patients have reported pains, tiredness, and skin,muscle or bone ailments for long time, but these symptoms have notbeen directly linked to gadolinium.There are different GBCAs that can be used for your MRIexam. The amount of gadolinium that stays in the body is differentfor different gadolinium medicines. Gadolinium stays in the body moreafter Omniscan or Optimark than after Eovist, Magnevist, or MultiHance.Gadolinium stays in the body the least after Dotarem, Gadavist, orProHance.People who get many doses of gadolinium medicines, womenwho are pregnant and young children may be at increased risk fromgadolinium staying in the body.Some people with kidney problems who get gadolinium medicinescan develop condition with severe thickening of the skin, musclesand other organs in the body (nephrogenic systemic fibrosis). Yourhealthcare provider should screen you to see how well your kidneysare working before you receive MULTIHANCE.Do not receiveMULTIHANCE if you have had severe allergic reaction to GBCAsincluding gadobenate dimeglumine, or any of the ingredients in MULTIHANCE.Before receivingMULTIHANCE, tell your healthcare provider about all your medical conditions,including if you:have had any MRI procedures in the past where you receiveda GBCA. Your healthcare provider may ask you for more informationincluding the dates of these MRI procedures.are pregnant or plan to become pregnant. It is not knownif MULTIHANCE can harm your unborn baby. Talk to your healthcare providerabout the possible risks to an unborn baby if GBCA such as MULTIHANCEis received during pregnancyhave kidney problems, diabetes, or high blood pressure.have had an allergic reaction to dyes (contrast agents)including GBCAsWhat are thepossible side effects of MULTIHANCESee What is the most important information shouldknow about MULTIHANCEAllergic reactions. MULTIHANCE can cause allergicreactions that can sometimes be serious. Your healthcare providerwill monitor you closely for symptoms of an allergic reaction.The most common side effects of MULTIHANCE include: nausea,headache, feeling hot, or burning at the injection site.These are not all the possible side effects of MULTIHANCE.Call your doctor for medical advice about side effects. You mayreport side effects to FDA at 1-800-FDA-1088.General informationabout the safe and effective use of MULTIHANCE.Medicinesare sometimes prescribed for purposes other than those listed in aMedication Guide. You can ask your healthcare provider for informationabout MULTIHANCE that is written for health professionals.What are theingredients in MULTIHANCEActive ingredient:gadobenate dimeglumineInactive ingredients: waterManufactured by: BIPSO GmbH-78224 Singen (Germany)Manufactured for: Bracco Diagnostics Inc., Monroe Township, NJ 08831US Patent No. 4,916,246For more information, go to www.imaging.bracco.comor call 1-800-257-5181.. MULTIHANCE is prescription medicine called gadolinium-basedcontrast agent (GBCA). MULTIHANCE, like other GBCAs, is injected intoyour vein and used with magnetic resonance imaging (MRI) scanner. An MRI exam with GBCA, including MULTIHANCE, helps yourdoctor to see problems better than an MRI exam without GBCA.. Your doctor has reviewed your medical records and has determinedthat you would benefit from using GBCA with your MRI exam.. MULTIHANCE contains metal called gadolinium. Small amountsof gadolinium can stay in your body including the brain, bones, skinand other parts of your body for long time (several months to years).. It is not known how gadolinium may affect you, but so far,studies have not found harmful effects in patients with normal kidneys.. Rarely, patients have reported pains, tiredness, and skin,muscle or bone ailments for long time, but these symptoms have notbeen directly linked to gadolinium.. There are different GBCAs that can be used for your MRIexam. The amount of gadolinium that stays in the body is differentfor different gadolinium medicines. Gadolinium stays in the body moreafter Omniscan or Optimark than after Eovist, Magnevist, or MultiHance.Gadolinium stays in the body the least after Dotarem, Gadavist, orProHance.. People who get many doses of gadolinium medicines, womenwho are pregnant and young children may be at increased risk fromgadolinium staying in the body.. Some people with kidney problems who get gadolinium medicinescan develop condition with severe thickening of the skin, musclesand other organs in the body (nephrogenic systemic fibrosis). Yourhealthcare provider should screen you to see how well your kidneysare working before you receive MULTIHANCE.. have had any MRI procedures in the past where you receiveda GBCA. Your healthcare provider may ask you for more informationincluding the dates of these MRI procedures.. are pregnant or plan to become pregnant. It is not knownif MULTIHANCE can harm your unborn baby. Talk to your healthcare providerabout the possible risks to an unborn baby if GBCA such as MULTIHANCEis received during pregnancy. have kidney problems, diabetes, or high blood pressure.. have had an allergic reaction to dyes (contrast agents)including GBCAs. See What is the most important information shouldknow about MULTIHANCE. Allergic reactions. MULTIHANCE can cause allergicreactions that can sometimes be serious. Your healthcare providerwill monitor you closely for symptoms of an allergic reaction.

SPL UNCLASSIFIED SECTION.

1.1 Magnetic ResonanceImaging (MRI) of the Central Nervous System (CNS). MultiHance is indicatedfor intravenous use in magnetic resonance imaging (MRI) of the centralnervous system (CNS) in adults and pediatric patients (including termneonates), to visualize lesions with abnormal blood-brain barrieror abnormal vascularity of the brain, spine, and associated tissues.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Use only if imagingis essential during pregnancy and cannot be delayed. (8.1). 8.1 Pregnancy. Risk SummaryGBCAs cross the placentaand result in fetal exposure and gadolinium retention. The human dataon the association between GBCAs and adverse fetal outcomes are limitedand inconclusive (see Data). In animal reproduction studies, gadobenate dimegluminehas been shown to be teratogenic in rabbits following repeated intravenousadministration during organogenesis at doses up to times the recommendedhuman dose. There were no adverse developmental effects observed inrats with intravenous administration of gadobenate dimeglumine duringorganogenesis at doses up to three times the recommended human dose (see Data). Becauseof the potential risks of gadolinium to the fetus, use MultiHanceonly if imaging is essential and cannot be delayed.The estimated background risk of majorbirth defects and miscarriage for the indicated population is unknown.All pregnancies have background risk of birth defect, loss, or otheradverse outcomes. In the U.S. general population, the estimated backgroundrisk of major birth defects and miscarriage in clinically recognizedpregnancies is to 4% and is 15 to 20%, respectively.DataHuman DataContrast enhancementis visualized in the placenta and fetal tissues after maternal GBCAadministration.Cohortstudies and case reports on exposure to GBCAs during pregnancy havenot reported clear association between GBCAs and adverse effectsin the exposed neonates. However, retrospective cohort study, comparingpregnant women who had GBCA MRI to pregnant women who did not havean MRI, reported higher occurrence of stillbirths and neonatal deathsin the group receiving GBCA MRI. Limitations of this study includea lack of comparison with non-contrast MRI and lack of informationabout the maternal indication for MRI. Overall, these data precludea reliable evaluation of the potential risk of adverse fetal outcomeswith the use of GBCAs in pregnancy.Animal DataGadoliniumRetentionGBCAs administered to pregnant non-human primates(0.1 mmol/kg on gestational days 85 and 135) result in measurablegadolinium concentration in the offspring in bone, brain, skin, liver,kidney, and spleen for at least months. GBCAs administered to pregnantmice (2 mmol/kg daily on gestational days 16 through 19) result inmeasurable gadolinium concentrations in the pups in bone, brain, kidney,liver, blood, muscle, and spleen at one month postnatal age.Reproductive ToxicologyGadobenate dimeglumine has been shown to be teratogenic in rabbitswhen administered intravenously at mmol/kg/day (6 times the recommendedhuman dose based on body surface area) during organogenesis (day 6to 18) inducing microphthalmia/small eye and/or focal retinal foldin fetuses from separate litters. In addition, MultiHance administeredintravenously at mmol/kg/day (10 times the recommended human dosebased on body surface area) has been shown to increase intrauterinedeaths in rabbits. There was no evidence that MultiHance induced teratogeniceffects in rats at doses up to mmol/kg/day (3 times the recommendedhuman dose based on body surface area), however, rat dams exhibitedno systemic toxicity at this dose. There were no adverse effects onthe birth, survival, growth, development and fertility of the F1 generationat doses up to mmol/kg in rat peri- and post-natal (Segment III)study.. 8.2 Lactation. Risk SummaryLimited literature reports that breastfeeding after gadobenate dimeglumineadministration to the mother would result in the infant receivingan oral dose of 0.001%-0.04% of the maternal dose. There is no informationon the effects of the drug on the breastfed infant or the effectsof the drug on milk production. Additionally, there is limited GBCAgastrointestinal absorption. The developmental and health benefitsof breastfeeding should be considered together with the mothers clinicalneed for MultiHance and any potential adverse effects on the breastfedinfant from MultiHance or from the underlying maternal condition.. 8.4 Pediatric Use. MultiHanceis approved for intravenous use for MRI of the CNS to visualize lesionswith abnormal blood brain barrier or abnormal vascularity of the brain,spine, and associated tissues in pediatric patients from birth, includingterm neonates, to less than 17 years of age. Pediatric use is basedon evidence of effectiveness in adults and in 202 pediatric patients2 years of age and older, in addition to experience in 105 pediatricpatients birth to less than years of age that supported extrapolationfrom adult data [see Clinical Studies (14)]. Adverse reactions in pediatric patients weresimilar to those reported in adults [see Adverse Reactions(6.1)]. No dose adjustmentaccording to age is necessary in pediatric patients two years of ageand older. For pediatric patients, less than years of age, the recommendeddosage range is 0.1 to 0.2 mL/kg [see Dosage and Administration(2.1), Pharmacokinetics (12.3)]. The safety of MultiHancehas not been established in preterm neonates.. 8.5 Geriatric Use. Ofthe total number of 4967 adult subjects in clinical studies of MultiHance,33% were 65 or older. No overall differences in safety or effectivenesswere observed between these elderly subjects and the younger subjects.The drug is known to be substantially excretedby the kidney, and the risk of toxic reactions to MultiHance may begreater in patients with impaired renal function. Because elderlypatients are more likely to have decreased renal function it may beuseful to monitor renal function.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Nephrogenic Systemic Fibrosis has occurred in patients withimpaired elimination of GBCAs. Higher than recommended dosing or repeateddosing appears to increase the risk (5.1) Hypersensitivity: anaphylactic/anaphylactoid reactions withcardiovascular, respiratory and cutaneous manifestations, rangingfrom mild to severe reactions including shock can occur. Monitor patientsclosely for need of emergency cardiorespiratory support. (5.2) Gadolinium is retained for months or years in brain, bone,and other organs. (5.3) Nephrogenic Systemic Fibrosis has occurred in patients withimpaired elimination of GBCAs. Higher than recommended dosing or repeateddosing appears to increase the risk (5.1) Hypersensitivity: anaphylactic/anaphylactoid reactions withcardiovascular, respiratory and cutaneous manifestations, rangingfrom mild to severe reactions including shock can occur. Monitor patientsclosely for need of emergency cardiorespiratory support. (5.2) Gadolinium is retained for months or years in brain, bone,and other organs. (5.3) 5.1 Nephrogenic SystemicFibrosis (NSF). Gadolinium-basedcontrast agents (GBCAs) increase the risk for nephrogenic systemicfibrosis (NSF) among patients with impaired elimination of the drugs.Avoid use of GBCAs among these patients unless the diagnostic informationis essential and not available with non-contrast enhanced MRI or othermodalities. The GBCA-associated NSF risk appears highest for patientswith chronic, severe kidney disease (GFR <30 mL/min/1.73m2) as well as patients with acute kidney injury. Therisk appears lower for patients with chronic, moderate kidney disease(GFR 30-59 mL/min/1.73m2) and little, ifany, for patients with chronic, mild kidney disease (GFR 60-89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosisaffecting the skin, muscle and internal organs. Report any diagnosisof NSF following MultiHance administration to Bracco Diagnostics (1-800-257-5181)or FDA (1-800-FDA-1088 or www.fda.gov/medwatch).Screen patients for acute kidney injury and other conditions thatmay reduce renal function. Features of acute kidney injury consistof rapid (over hours to days) and usually reversible decrease in kidneyfunction, commonly in the setting of surgery, severe infection, injuryor drug-induced kidney toxicity. Serum creatinine levels and estimatedGFR may not reliably assess renal function in the setting of acutekidney injury. For patients at risk for chronically reduced renalfunction (e.g., age >60 years, diabetes mellitus or chronic hypertension),estimate the GFR through laboratory testing.Among the factors that may increase the risk for NSFare repeated or higher than recommended doses of GBCA and the degreeof renal impairment at the time of exposure. Record the specific GBCAand the dose administered to patient. For patients at highest riskfor NSF, do not exceed the recommended MultiHance dose and allow asufficient period of time for elimination of the drug prior to re-administration.For patients receiving hemodialysis, physicians may consider the promptinitiation of hemodialysis following the administration of GBCAin order to enhance the contrast agents elimination. The usefulnessof hemodialysis in the prevention of NSF is unknown [see Dosage and Administration (2) andClinical Pharmacology (12)].. 5.2 HypersensitivityReactions. Anaphylacticand anaphylactoid reactions have been reported, involving cardiovascular,respiratory, and/or cutaneous manifestations. Some patients experiencedcirculatory collapse and died. In most cases, initial symptoms occurredwithin minutes of MultiHance administration and resolved with promptemergency treatment.Prior toMultiHance administration, ensure the availability of personnel trainedand medications to treat hypersensitivity reactions. If such reactionoccurs stop MultiHance and immediately begin appropriate therapy.Additionally, consider the risk for hypersensitivity reactions, especiallyin patients with history of hypersensitivity reactions or historyof asthma or other allergic disorders. Observe patients for signsand symptoms of hypersensitivity reaction during and for up to 2hours after MultiHance administration.. 5.3 Gadolinium Retention. Gadoliniumis retained for months or years in several organs. The highest concentrations(nanomoles per gram of tissue) have been identified in the bone, followedby other organs (e.g. brain, skin, kidney, liver, and spleen). Theduration of retention also varies by tissue and is longest in bone.Linear GBCAs cause more retention than macrocyclic GBCAs. At equivalentdoses, gadolinium retention varies among the linear agents with Omniscan(gadodiamide) and Optimark (gadoversetamide) causing greater retentionthan 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 retentionin skin and other organs have been established in patients with impairedrenal function [see Warnings and Precautions (5.1)]. There are rare reportsof pathologic skin changes in patients with normal renal function.Adverse events involving multiple organ systems have been reportedin patients with normal renal function without an established causallink to gadolinium retention [see Adverse Reactions (6.2)].While clinicalconsequences of gadolinium retention have not been established inpatients with normal renal function, certain patients might be athigher 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 choosinga GBCA for these patients. Minimize repetitive GBCA imaging studies,particularly closely spaced studies when possible.. 5.4 Acute Renal Failure. In patients with renal insufficiency, acuterenal failure requiring dialysis or worsening renal function haveoccurred with the use of gadolinium-based contrast agents. The riskof renal failure may increase with increasing dose of the contrastagent. Screen all patients for renal dysfunction by obtaining historyand/or laboratory tests. Consider follow-up renal function assessmentsfor patients with history of renal dysfunction.. 5.5 Extravasation andInjection Site Reactions. Extravasation of MultiHance may lead to injection site reactions,characterized by local pain or burning sensation, swelling, blistering,and necrosis. In animal experiments, local reactions including escharand necrosis were noted even on Day post perivenous injection ofMultiHance. Exercise caution to avoid local extravasation duringintravenous administration of MultiHance. If extravasation occurs,evaluate and treat as necessary if local reactions develop.. 5.6 Cardiac Arrhythmias. Cardiac arrhythmias have been observed inpatients receiving MultiHance in clinical trials [see Adverse Reactions (6.1) ]. Assess patients for underlying conditions or medicationsthat predispose to arrhythmias.A double-blind, placebo-controlled, 24-hour post dose continuousmonitoring, crossover study in 47 subjects evaluated the effect of0.2 mmol/kg MultiHance on ECG intervals, including QTc. The averagechanges in QTc values compared with placebo were minimal (<5 msec). QTc prolongation between 30 and 60 msec were noted in 20 subjectswho received MultiHance vs. 11 subjects who received placebo. Prolongations>=61 msec were noted in subjects who received MultiHance and in 3subjects who received placebo. None of these subjects had associatedmalignant arrhythmias. The effects on QTc by MultiHance dose, otherdrugs, and medical conditions were not systematically studied.. 5.7 Interference withVisualization of Certain Lesions. Certain lesions seen on non-contrast images may notbe seen on contrast- images. Exercise caution when interpreting contrastMR images in the absence of companion non-contrast MR images.